research articles in vitro fertilization

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• Published: 05 September 2024

Effect of single blastocyst-stage versus single cleavage-stage embryo transfer on cumulative live births in women with good prognosis undergoing in vitro fertilization: Multicenter Randomized Controlled Trial

• Xiang Ma 1   na1 ,
• Jing Wang   ORCID: orcid.org/0000-0002-0546-6614 1   na1 ,
• Yuhua Shi 2   na1 ,
• Jichun Tan 3 , 4   na1 ,
• Yichun Guan   ORCID: orcid.org/0000-0002-6255-2551 5   na1 ,
• Yun Sun 6 , 7   na1 ,
• Bo Zhang 8   na1 ,
• Junli Zhao 9   na1 ,
• Jianqiao Liu 10 , 11 ,
• Yunxia Cao 12 , 13 ,
• Hong Li 14 ,
• Cuilian Zhang   ORCID: orcid.org/0000-0002-5210-5272 15 ,
• Feng Chen 16 ,
• Honggang Yi 16 ,
• Ze Wang 2 ,
• Xing Xin 3 , 4 ,
• Pingping Kong 5 ,
• Yao Lu 6 , 7 ,
• Ling Huang 8 ,
• Yingying Yuan 9 ,
• Haiying Liu 10 , 11 ,
• Caihua Li 12 , 13 ,
• Ben Willem J. Mol   ORCID: orcid.org/0000-0001-8337-550X 17 , 18 , 19 ,
• Zhibin Hu   ORCID: orcid.org/0000-0002-8277-5234 1 , 20 , 21 ,
• Heping Zhang   ORCID: orcid.org/0000-0002-0688-4076 22 ,
• Zi-Jiang Chen   ORCID: orcid.org/0000-0001-6637-6631 2 , 7 &
• Jiayin Liu   ORCID: orcid.org/0000-0002-1472-4013 1  

Nature Communications volume  15 , Article number:  7747 ( 2024 ) Cite this article

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• Outcomes research
• Randomized controlled trials

In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage ( n  = 497) or cleavage-stage ( n  = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; P non-inferiority  < 0.001, P superiority  = 0.003) (1-year cumulative live birth rates of 75.7% versus 68.9%). Blastocyst transfer increased the risk of spontaneous preterm birth (4.6% vs 2.0%; P  = 0.02) and neonatal hospitalization >3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).

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Introduction.

In vitro fertilization (IVF) is the cornerstone of modern infertility treatment. More than 2 million treatment cycles are performed worldwide each year 1 , 2 , 3 . However, in the last decade, the live birth rate of IVF has been stable at 30% per transfer, resulting in cumulative live birth rates over 50% 4 . In an attempt to increase the success rates, extended culture of embryos from cleavage stage to blastocyst stage has been introduced 5 , 6 . It has been hypothesized that extended culture to blastocyst stage allows selection of embryos with higher implantation potential, which also facilitates elective single embryo transfer (SET) to reduce multiple gestations and associated pregnancy complications 7 , 8 .

In recent years, blastocyst transfers have become increasingly popular worldwide, whereas most countries still widely use cleavage-stage transfers, driven by the risk of no or fewer embryos available for transfer after blastocyst culture 3 , 9 , 10 . The evidence regarding the effectiveness and safety of the blastocyst-stage versus cleavage-stage embryo transfers is however limited 11 , 12 .

Initial studies showing that single blastocyst transfers generated higher live birth rates were halted early 13 . Systematic reviews show substantial study heterogeneity with conflicting results 11 . Some studies reported benefits of cleavage-stage transfer 14 , some found similar results 15 , 16 and others gave preference to blastocyst transfer 17 , 18 . Many trials were single-center and had a small sample size, with unclear randomization and concealment methods. Only one small trial reported on cumulative live birth rates, the most important outcome from a patient perspective 19 . No trials reported obstetric and perinatal outcomes. Furthermore, most trials conducted a decade ago do not reflect modern IVF practice, including SET and vitrification freezing. As a consequence, the most recent Cochrane review only provides low-quality evidence and does not report on cumulative live birth outcomes, and recommends large-scale trials on the subject 11 .

In this work, we assessed the effectiveness and safety of single blastocyst transfer vs single cleavage-stage embryo transfer, and show improved cumulative live birth rates and relatively unfavorable perinatal outcomes after blastocyst transfer among women with good prognosis (three or more transferrable cleavage-stage embryos).

Between 8 October 2018 and 22 August 2019, we screened 1439 women, of whom 1105 were eligible, of which 113 declined to participate. Therefore, 992 women were randomized to transfer at the blastocyst stage ( n  = 497) or cleavage stage ( n  = 495) (Fig.  1 ). Follow-up of all live births was completed on 6 September 2021 (trial status: completed). Baseline characteristics, including details of ovarian stimulation, were comparable between the two groups (Table  1 and Table  2 ).

IVF, in-vitro fertilization; ICSI, intracytoplasmic sperm injection; IVM, in-vitro maturation. a Woman had protocol deviation in at least one transfer. b Two women in the blastocyst group never had embryo transfer but had frozen blastocysts for the reasons of endometrial factor and personal issues, respectively; 1 woman in the cleavage group never had embryo transfer but had frozen cleavage-stage embryos for the reason of personal issues. c Among the 2 women with double cleavage-stage transfer, 1 woman had double cleavage-stage transfer in the fresh embryo transfer cycle and double blastocyst transfer in the second frozen embryo transfer cycle. d Among the 6 women with double blastocyst transfer, 1 woman had double cleavage-stage transfer in the fresh embryo transfer cycle, and double blastocyst transfer in the subsequent frozen embryo transfer cycle; 1 woman had one blastocyst transfer in the first frozen transfer cycle, and double blastocysts transfer in the second frozen transfer cycle.

Among 497 women assigned to the blastocyst group, four women (0.8%) had frozen cleavage-stage embryos, and two of them also had frozen blastocysts. Five women (1.0%) did not have blastocyst-stage embryos after extended culture. Of 727 embryo transfer cycles in the blastocyst group, 8 (1.1%) were transferred at the cleavage stage. There were 18 double embryo transfers (2.5%) in the blastocyst group (Table  2 ).

Among 495 women assigned to the cleavage-stage group, nine women (1.8%) frozen blastocysts only; 130 women (26.3%) frozen both cleavage-stage and blastocyst-stage embryos, with 114 women (87.7%) freezing ≥3 cleavage-stage embryos. Of 875 embryo transfer cycles in the cleavage-stage group, 42 (4.8%) were transferred at the blastocyst stage. There were 33 double embryo transfers (3.8%) in the cleavage-stage group (Table  2 ).

Fewer women in the blastocyst group underwent a second or third transfer than in the cleavage-stage group (189 vs 261 for second transfer; 52 vs 123 for third transfer) (Table  2 ). Protocol deviations of crossover occurred in 8 of 497 women (1.6%) in the blastocyst-stage group versus 33 of 495 women (6.7%) in the cleavage-stage group (Fig.  1 ). Only 7 women (1.4%) in the cleavage-stage group received day 2 embryo transfer, all occurring in fresh transfer cycle at one study site due to their work schedule.

Primary outcome

The primary outcome live birth occurred in 372 of 497 women (74.8%) in the blastocyst group versus 328 of 495 (66.3%) in the cleavage-stage group (AD 8.6% [95% CI 2.9% to 14.2%]; RR 1.13 [95% CI 1.04 to 1.22]; P -value non-inferiority <0.001; P -value superiority=0.003) (Table  3 ). Both non-inferiority and superiority were confirmed in the intention-to-treat population as well as in the per-protocol population (Supplementary Fig.  1 and Supplementary Table  5 ). The Kaplan-Meier curves for the primary outcome are shown in Fig.  2 .

HR, hazard ratio. Shaded areas indicate 95% confidence intervals (CI). Median time to live birth in the blastocyst group was 344 days (95% CI, 334–353 days); median time to live birth in the cleavage-stage group was 373 days (95% CI, 353–416 days). Hazard ratio and the associated 95% CIs were estimated by using a Cox proportional hazards model. Source data are provided as a Source Data file.

Secondary outcomes

Blastocyst transfer was associated with higher cumulative rates of biochemical, clinical, and ongoing pregnancy than was cleavage-stage transfer (Table  3 ). The cumulative incidence of twins and pregnancy loss did not differ significantly between the two groups (Table  3 ). Median time to live birth was significantly shorter in the blastocyst group versus the cleavage-stage group (344 days vs 373 days; HR 1.26[95% CI 1.09 to 1.47]; P  = 0.002) (Table  3 ). Between-group comparisons for pregnancy outcomes of each transfer showed higher frequencies of live birth, implantation, biochemical, clinical, and ongoing pregnancy after blastocyst transfer (Supplementary Table  2 – 4 ). Post hoc analysis showed a significantly fewer number of unused frozen embryos (4.1 [SD3.3] vs 5.9 [SD4.0]; P  < 0.001), while a higher number of women without a frozen embryo (14.3% vs 4.6%; P  < 0.001) in blastocyst group versus cleavage-stage group (Table  3 ).

Safety outcomes

Blastocyst transfer was associated with a higher cumulative rate of preterm premature rupture of membrane (PPROM) (5.0% vs 1.6%; AD 3.4%[95%CI 1.2% to 5.6%]; RR 3.11 [95%CI 1.42 to 6.83]; P  = 0.003), preterm birth (6.0% vs 3.6%; AD 2.4%[95%CI −0.3% to 5.1%]; RR 1.66 [95%CI 0.94 to 2.94]; P  = 0.08), neonatal hospitalization >3 days (11.5% vs 6.3%; AD 5.2%[95%CI 1.7% to 8.7%]; RR 1.83 [95%CI 1.20 to 2.79]; P  = 0.004), and neonatal infection (4.8% vs 2.2%; AD 2.6%[95%CI 0.3% to 4.9%]; RR 2.17 [95%CI 1.08 to 4.39]; P  = 0.03); but a lower cumulative rate of preeclampsia (1.0% vs 2.8%; AD −1.8%[95%CI −3.5% to −0.1%]; RR 0.36 [95%CI 0.13 to 0.98]; P  = 0.04) (Table  4 ). Of preterm birth, spontaneous preterm birth occurred more frequently in the blastocyst group versus the cleavage-stage group (4.6% vs 2.0%; AD 2.6% [95%CI 0.4% to 4.8%]; RR 2.29 [95%CI 1.10 to 4.76]; P  = 0.02), whereas the frequency of iatrogenic preterm birth was similar. Women after blastocyst transfer had an increased risk of developing at least one of the maternal or neonatal complications compared with those after cleavage-stage transfer (50.9% vs 43.8%; AD 7.1%[95%CI 0.9% to 13.3%]; RR 1.16 [95%CI 1.02 to 1.32]; P  = 0.03). In addition, more preeclampsia occurred after fresh cleavage-stage transfer (6/14 [42.9%] vs 0/5 [0.0%] for fresh cycles (Supplementary Table  11 ), and logistic regression analyzes showed that the risk of preeclampsia remained higher in the cleavage-stage group than in the blastocyst group after adjustment for frozen or fresh embryo transfer (Supplementary Table  12 ). The number of uncomplicated live birth and incidences of other obstetrical and neonatal complications including congenital anomalies were comparable (Table  4 ; Supplementary Table  7 , 8 ).

Sensitivity Analyzes

The results of the per-protocol analyzes (Supplementary Table  5 – 6 ) and full analysis set as well as embryo transfers within 1 year of randomization and all embryo transfers within the study period (Supplementary Table  9 – 10 ) were consistent with those of the intention-to-treat analysis for the rates of live birth, pregnancy, and perinatal outcomes. The results for the primary outcomes remained robust after controlling for centers.

Post Hoc Subgroup Analyzes

Hyper-responders ( > 15 oocytes retrieved) benefitted more from blastocyst transfer with regard to the primary outcome than poor or normal responders ( P -value for interaction = 0.03). For women with estradiol on hCG day at the highest and medium tertiles, there seemed to be a benefit of blastocyst transfer ( P -value for interaction = 0.01). There were no differential effects of treatment on other subgroups (Supplementary Fig.  2 ).

Post Hoc Analyzes of long-term follow-up outcomes

When analyzing follow-ups of embryo transfers from day of randomization to July 28th, 2023, cumulative live birth rate was not significantly higher in the blastocyst group than in the cleavage-stage group (80.9% [402/497] vs 77.6% [384/495]; AD, 3.3% [95%CI −1.7 to 8.4]; RR 1.04 [95%CI 0.98 to 1.11]; P  = 0.199) (Table  5 ). Among the deviations that occurred after the study period (1 year after randomization), 41.3% of transfers in the cleavage-stage group were blastocyst transfers, whereas all transfers in the blastocyst group were blastocyst transfers (Supplementary Table  13 ). Furthermore, 48.8% of women in cleavage-stage group obtained an extra live birth through blastocyst transfers (Supplementary Table  14 ).

In this multicenter randomized clinical trial, we found that among infertile women with good prognosis ( ≥ 3 transferrable cleavage-stage embryos), single blastocyst-stage transfer was non-inferior and even superior to single cleavage-stage transfer for improving cumulative live birth rates, with a shorter time to live birth. From a perinatal perspective, blastocyst transfer was associated with a higher cumulative rate of PPROM, spontaneous preterm birth and neonatal hospitalization >3 days, and a lower rate of preeclampsia than the cleavage-stage transfer.

Blastocyst or cleavage-stage embryo transfers are both widely used in current IVF practices. Although blastocyst transfer has become popular in some regions, the limited quality of the available evidence has prevented a shift in practice in other areas 11 . This resulted in a call for better quality data by the most recent Cochrane review and European IVF Monitoring Consortium for European Society of Human Reproduction and Embryology 3 , 11 . As our large trial provides reports of clearly higher cumulative live birth rates after single blastocyst transfer in women with good prognosis, this could support a shift to single blastocyst transfer in this population.

A recent Cochrane systematic review comparing blastocyst and cleavage-stage transfers concluded that live birth rate after fresh blastocyst transfer was higher than fresh cleavage-stage transfer, but the evidence was graded as low quality 11 . This review included five relatively small, single-center trials conducted at the early years (632 women in total, mainly with a good prognosis) reporting cumulative pregnancy rates with considerable heterogeneity 11 . Moreover, none of the previous trials reported on the cumulative live birth rate 20 . One additional pilot trial that reported higher cumulative live birth rate after blastocyst transfer in oocyte recipients did not apply SET and was terminated after reaching half of the planned sample size 18 . Our trial shows that the cumulative live birth rate after three single blastocyst transfers is higher than that after three cleavage-stage transfers, which might be hypothesized based on previous reports of higher live birth rates after one fresh blastocyst transfer 11 . Since the depletion of embryos by blastocyst culture leads to a reduction in the number of embryos, data are needed to confirm whether blastocyst transfer really improves the cumulative outcomes in couples undergoing IVF.

Our large trial, which directly compared cumulative live birth rate after SET and vitrification cryopreservation in women with good prognosis, showed that single blastocyst transfer resulted in an 8.6% absolute increase in cumulative live birth rates from conceptions with 12 months after randomization. As the number of women in the blastocyst group without live birth and with no frozen embryos left was 4.8% higher than in the cleavage-stage group, it is unlikely for cleavage-stage transfer to catch up with blastocyst transfer in cumulative live birth rate, due to long timeframe of transfers required to make up 8.6% lower cumulative live birth rate. Furthermore, our data show that blastocyst transfer results in a shorter time to live birth despite similar number of freeze-all cycles in both groups.

Extended embryo culture to blastocyst stage is likely to self-select the most viable embryos in vitro 13 , yield a lower risk of aneuploidy embryos 21 , have better embryo-endometrial synchronization by mimicking the natural in vivo embryo implantation process 7 ; and therefore, increase the chances of having a baby. In view of 8.6% higher cumulative live birth rate with only 4.8% more couples without extra embryos in blastocyst group, we speculate that apart from better selection the day 5 culture itself results in higher live birth rates. In our trial, the higher implantation rates after each single blastocyst transfer translated into higher live birth rates in women with good prognosis. The cumulative live birth rates of blastocyst culture were not compromised by reduced number of embryos in our study population. Since more frozen cleavage-stage embryos were left than frozen blastocysts in women who did not achieve a live birth (4.9 vs 2.2), we continued the follow-ups and will conduct a life-course analysis to reveal the results in real-world practice.

We conducted a secondary, post-hoc analysis of the long-term follow-ups from randomization day to July 28th, 2023, and found similar cumulative live birth rate between the two group. However, treatment after the study period (1 year of randomization) did not follow our prespecified protocol, as 41.3% of transfers in the cleavage-stage group were blastocyst transfers. Therefore, it is difficult to determine whether the catch-up in live birth rates among women in the cleavage-stage group is due to crossover to blastocyst transfer, more embryo transfer cycles, or both. Therefore, this analysis cannot be used as a basis for conclusions. In addition, the number of frozen embryos remaining in the cleavage-stage group, among women who have not achieved a live birth, was higher than in the blastocyst group (2.8 vs 1.2). The number and quality of embryos derived from an oocyte-retrieval cycle are key determinants of cumulative pregnancy and live birth rates. Thus, mathematically, the cumulative live birth rate might in the end be the same in both treatment groups, assuming that women in the cleavage-stage group would continue to return for embryo transfers. Of note, our results of increased cumulative live birth rate and reduced time to live birth after blastocyst transfer should be applied in the context of a maximum of the first three SETs and embryo transfers within 1 year of randomization in good-prognosis patients. From the perspective of cumulative transfers, extended embryo culture to blastocyst may negatively affect the pregnancy outcomes due to poor laboratory performance or the fact that most embryos are arrested between cleavage and blastocyst stages in certain subgroups of women (e.g., women with low prognosis), which would produce a pregnancy if transferred at cleavage stage. Therefore, we should not perform routine blastocyst transfer on everybody, similar to the recommendations for the utilization of PGT-A.

Our results showed that blastocyst transfer was associated with a higher rate of spontaneous preterm birth, consistent with previous observational reports 22 , 23 , and a higher risk of PPROM might be the main cause for preterm birth. The underlying mechanism linking blastocyst culture to preterm birth and PPROM remains unknown but may involve altered placentation and trophoblast function through epigenetic changes 24 . Of note, rate of preterm birth after single blastocyst transfer was much lower than the transfer of two cleavage-stage embryos (15.5%) 25 , which emphasizes the importance of SET in compliance with European and American guidelines 8 , 26 , 27 . Additionally, the higher rates of prolonged neonatal hospitalization and neonatal infection warrant attention. Our results showed that women after blastocyst transfer had a 7.1% higher absolute risk and 16% higher relative risk of developing at least one obstetrical-perinatal complication, in contrast to an 8.6% absolute and 13% relatively higher cumulative live birth rates. We evaluate the cumulative obstetrical-perinatal complications because each complication has a low frequency. Patients should be well informed of the information before deciding on an embryo transfer strategy. We will conduct a cost-effectiveness analysis after this original publication to further explore the benefit-risk ratio of blastocyst transfer in our study population.

Our study found more preeclampsia after fresh cleavage-stage transfer, however the mechanism is unclear. Although frozen embryo transfer may be a confounder for the increased incidence of pre-eclampsia, the risk of pre-eclampsia remained higher in the cleavage-stage group after adjustment for frozen embryo transfer. The higher rate of monozygotic twins in blastocyst group is consistent with previous findings 7 , although not statistically significant in our study. Furthermore, in contrast to previous studies 22 , the incidence of large for gestational age infants did not differ between the two groups (RR1.16 [95%CI 0.83 to 1.63]), which was defined based on a Chinese reference population consisting of natural conceptions 28 . The discrepant results may be attributed to different study populations. In addition, the long-term impact on the infants born from blastocyst transfers warrants further study with large maternal and neonatal cohorts, as a recent study reported the possible implications of blastocyst transfer on shortened leukocyte telomeres which predicts a reduction in lifespan 29 .

Our post-hoc subgroup analysis suggested the benefit of blastocyst transfer appeared to decrease with increasing age. Patients with younger age ( ≤ 30 years), representing subgroups of women with very good prognosis, benefitted from single blastocyst transfer. Conversely, women with older age, diminished ovarian reserve and fewer oocyte retrieved did not appear to have between-group differences in cumulative livebirth rates 10 , 12 . Given our study was not powered for post-hoc subgroup analysis and the majority of participants were ≤35 years, we cannot draw definitive conclusions on treatment effects in other subgroups. Further studies of specific subgroups with sufficient power are needed to support our exploratory findings in the use of blastocyst transfer in different populations, especially in women with older age or poor prognosis.

To our knowledge, this is the largest randomized controlled trial to date and the first to provide robust data on cumulative live birth and obstetrical-perinatal outcomes of the two embryo transfer strategies. The strengths of this study include its large sample size, the low loss-to-follow-up rate, randomized allocation in multiple cycles over the course of a year, the multicenter and pragmatic design that improves the generalizability of our results, and strict adherence to SETs in both groups, that ensures the comparable number of embryos between groups. In addition, our study informs the discussion on blastocyst versus cleavage-stage transfer and the design of such studies. We use both absolute and relative terms in expressing success rates and risks, which strongly contributes to the clinical message conveyed to clinicians and patients. Furthermore, our study had for pragmatic reasons a follow-up period of 1 year after randomization. While this might favor blastocyst transfer, as the cleavage stage group has more unused embryos left, we also think that a 1-year follow-up reflects the reality of clinical practice.

Our study has several limitations. First, we include women with a good prognosis of no less than three cleavage-stage embryos and a mean age of 29.8 years, with the age distribution ≤35 years accounting for 93% (924) of the women. As shown in Supplementary fig.  2 , the benefits of blastocyst transfer appear to diminish with advancing age. Therefore, our results may not be generalizable to other populations including women with older age, fewer oocytes retrieved and less than three cleavage-stage embryos available. However, our trial fills the research gap concerning cumulative live birth outcomes after blastocyst versus cleavage-stage transfer, which has been an important questionable debate for decades and has significant practice value on shift to blastocyst transfer in our study population 3 , 11 . Our study provides exploratory results for future studies evaluating whether other populations would benefit from blastocyst transfer. Second, there were protocol deviations, mainly in the cleavage-stage group, where 6.7% of participants received at least one blastocyst transfer. However, the results did not change in the per-protocol analysis. Third, our study was not adequately powered to detect the differences in pregnancy and perinatal complications. A future meta-analysis pooling all the evidence might answer these questions. Fourth, open-label design has the potential to introduce treatment bias, including crossovers and double embryo transfer, thereby underestimating the effects. However, except for stages of embryo transferred, all interventions were strictly adhered to the same standard protocol and patient management in both groups. Moreover, regular investigator meetings and monitoring were conducted to ensure compliance with the study protocol.

Finally, we calculated a maximum of the first three SETs as the primary outcome and all embryo transfers within the study period as the secondary outcome. Ideally, the “true” cumulative live birth rate would be obtained after all embryos have been transferred. However, considering that the first three SETs may achieve the most pregnancies, as well as the feasibility and applicability of the trial to real-world clinical practice, we studied the live births from a maximum of the first three SETs as the primary outcome, which happened in the first year after randomization, ensuring equal number of embryos transferred in both groups, to reveal the efficacy and safety of the two strategies.

In conclusion, among infertile women undergoing IVF with good prognosis ( ≤ 40 years with at least three cleavage-stage embryos), single blastocyst transfer was non-inferior and even superior to single cleavage-stage transfer in improving cumulative live birth rates and reducing time to live birth. However, the increased risk of preterm premature rupture of membranes, preterm birth and neonatal hospitalization after blastocyst transfer need to be fully informed of patients before deciding on an embryo transfer strategy. The cost-effectiveness of blastocyst transfer in this population and the long-term impact on the infants warrants further studies.

Trial design, Oversight and Governance

This is a multicenter, open-label, non-inferiority, randomized clinical trial conducted at 11 academic clinical centers throughout China. The aim of the trial was to assess the effectiveness and safety of blastocyst-stage vs cleavage-stage embryo transfer in IVF/ICSI treatment cycle, taking into account subsequent vitrified embryo transfers. This trial was approved by the ethics committee at each study site (including Ethics Committee at First Affiliated Hospital of Nanjing Medical University, Ethics Committee of Hospital for Reproductive Medicine Affiliated to Shandong University, Ethics Committee for Reproductive Medicine of Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Ethics Committee for Reproductive Medicine of First Affiliated Hospital of Anhui Medical University, Medical Ethics Committee of Maternal and Child Health Hospital/Obstetrics and Gynecology hospital of Guangxi Zhuang Autonomous Region, Ethics Committee of Shengjing Hospital of China Medical University, Ethics Committee of the Third Affiliated Hospital of Guangzhou Medical University, Ningxia Medical University General Hospital Scientific Research Ethics Committee, Ethics Committee for Reproductive Medicine of Suzhou Municipal Hospital, Ethics Committee for Reproductive Medicine of Henan Provincial People’s Hospital, Ethics Committee of The Third Affiliated Hospital of Zhengzhou University), and performed in accordance with principles of Good Clinical Practice and Declaration of Helsinki. All participants provided written informed consent. The study protocol including statistical analysis plan are available in Supplementary note. The trial was registered at ClinicalTrial.gov, NCT03152643 ( https://clinicaltrials.gov/study/NCT03152643 ). A data and safety monitoring board oversaw the study. The data in this trial was collected using a Web-based data management system at https://www.medresman.org.cn/login.aspx .

Participants

We enrolled infertile women who met the following inclusion criteria: aged 20 to 40 years, undergoing their first or second IVF or intracytoplasmic sperm injection (ICSI) cycle, and with the number of transferrable cleavage embryos ≥3. The exclusion criteria for this study are as follows: women diagnosed with uterine abnormalities (confirmed by three-dimensional ultrasonography or hysteroscopy, including uterus unicornis, septate or duplex uterus, submucous myoma, or intrauterine adhesions); women planned for in vitro maturation, or preimplantation genetic testing (PGT); women with hydrosalpinx visible on ultrasound; women who had experienced recurrent pregnancy loss, defined as 2 or more previous pregnancy losses; women who planned “freeze-all” treatment for purpose of subsequent surgery, such as salpingectomy due to hydrosalpinx after oocytes retrieval. We also excluded women with contraindications to assisted reproductive technology and/or pregnancy, such as uncontrolled hypertension, symptomatic heart disease, uncontrolled diabetes, undiagnosed liver disease or dysfunction (based on serum liver enzyme test results), undiagnosed renal disease or abnormal renal function, severe anemia, history of deep venous thrombosis, pulmonary embolus or cerebrovascular accident, history of or suspicious for cancer, undiagnosed vaginal bleeding. Sex was self-reported and confirmed by transvaginal ultrasound with female reproductive organs, and mostly karyotype result of 46, XX.

Couples were counseled by local investigators at the office visit at the time of their decision to undergo IVF or ICSI treatment; both female and male partners of the infertile couple provided written informed consent prior to participation after completing all tests in preparation for IVF or ICSI. Actual randomization was performed on day 2 or 3 after oocyte retrieval when the presence of ≥3 transferrable embryos was confirmed. Enrollment began on 8 October 2018 and ended on 22 August 2019. Follow-up of all live births was completed on 6 September 2021.

Interventions, randomization, and follow-up

Controlled ovarian stimulation was performed with Gonadotropin-releasing hormone (GnRH) agonist protocols or GnRH antagonist protocol according to local investigator’s preference. The long GnRH agonist protocol included the use of a short-acting GnRH agonist starting at the luteal phase or a long-acting GnRH agonist on days 1–2 of the menstrual cycle or during the luteal phase. When pituitary down-regulation was achieved, recombinant follicular stimulating hormone was initiated with a dose of 75 to 225 IU per day. Short GnRH agonist regimen and antagonist regimen were as reported previously 30 , 31 . When at least two follicles reached 18 mm or three follicles reached 17 mm in mean diameter, oocyte maturation was achieved by administration of human chorionic gonadotropin (hCG) or GnRH agonist or both. Oocyte retrieval was performed 36 to 37 hours later.

After oocyte retrieval, the quality of embryos was assessed by morphological criteria based mainly on the number and regularity of blastomeres as well as percentage fragmentation 32 . On day 2 or 3, women with ≥3 transferrable cleavage-stage embryos were randomly assigned to undergo blastocyst-stage or cleavage-stage embryo transfer in a 1:1 ratio with block randomization (variable block size of four, six or eight), and stratified by study sites. Allocation concealment was ensured through use of an online central randomization system with a randomization sequence generated by an independent statistician in the data coordinating center. Allocation was done by trained coordinators using password-protected accounts. Since it was impractical to conduct masking and since all outcomes were objective indicators, the trial was not blinded after randomization. Investigators, participants and trial coordinators were aware of the allocation after randomization.

For women assigned to blastocyst-stage group, embryos were cultured to day 5 or 6. A single fresh blastocyst of best quality was transferred after oocyte retrieval, using sequential media for blastocyst culture and with a preference for day 5 over day 6 transfer. Blastocyst quality was evaluated with the Gardner morphological criteria, according to blastocyst expansion, inner cell mass, and trophectoderm development 33 , 34 . For women assigned to the cleavage-stage group, a single fresh cleavage-stage embryo of best quality was transferred after oocyte retrieval.

For both groups, surplus embryos (to be transferred within the study period) were vitrified for future frozen embryo transfer as per the allocation group. When a patient was unable to undergo fresh transfer for risk of ovarian hyperstimulation syndrome (OHSS) or other reasons, all embryos were cryopreserved by vitrification. Frozen embryo transfer was initiated on the second menstrual cycle after oocyte retrieval, and a single frozen embryo with best morphology score was transferred first. Day 6 frozen transfers were performed on the same day as the day 5 transfer.

For the first three embryo transfers within 1 year after randomization (with a 3-month extension for those unable to undergo transfers due to COVID-19), SET was required. For transfers beyond the third attempt within the intervention period, SET was no longer mandatory 26 , 27 . If the initial embryo transfer did not result in a live birth, patients went through cryopreserved cycles within the study period and pregnancy was followed up.

Luteal phase support for fresh embryo transfer was vaginal progesterone gel 90 mg per day plus oral dydrogesterone 10 mg twice daily, starting on the day of oocyte retrieval and continuing until 10 weeks’ gestation if the pregnancy was achieved. For frozen transfers, endometrial preparation including natural cycle, minimal stimulation cycle or hormone replacement cycle was performed based on local routine as previously reported 25 , 35 .

The primary outcome was the cumulative live birth rate for a maximum of the first three embryo transfers resulting from one oocyte retrieval cycle, as long as these transfers happened in the first year after randomization (or 1 year and 3 months in case of delays due to COVID-19). Live birth was defined as the delivery of any neonate ≥24 weeks gestation that had a heartbeat and was breathing. The cumulative live birth rate was calculated by dividing the number of participants obtaining their first live birth by a number of randomized participants.

Secondary outcomes included biochemical pregnancy, clinical pregnancy, implantation, ongoing pregnancy, live birth, pregnancy loss, birth weight and sex ratio. The safety outcomes included moderate or severe OHSS, ectopic pregnancy, multiple pregnancies, obstetric and perinatal complications, and congenital anomalies. The definitions of secondary outcomes are listed in Supplementary Table  1 . Outcomes from all embryo transfers within 1 year of randomization were followed up for the occurrence of live birth until two years after randomization as the secondary outcome.

Post hoc secondary outcomes included the number of embryo transfers, the number of unused frozen embryos, women without a frozen embryo and live birth without a complication. The non-prespecified outcome of cumulative live birth rate was also calculated, including follow-up of embryo transfers from day of randomization to July 28th, 2023. The treatments after the study period (1 year of randomization) did not follow our prespecified protocol.

Sample size calculations

We hypothesized that the cumulative live birth rate of blastocyst-stage transfers is non-inferior to that of cleavage-stage transfers. Assuming that a cumulative live birth rate of 52% 36 , a minimum sample size of 392 subjects per treatment arm would provide 80% power to show the non-inferiority of blastocyst transfer to cleavage-stage transfer at one-sided significance level of 0.025, with a non-inferiority margin of 10% for the lower 95% confidence interval (CI) for the difference in cumulative live birth rates between the two groups. Considering a withdrawal, cross-over and lost-to-follow-up rate of 20%, we planned to enroll 980 participants. The non-inferiority margin of 10% was agreed to be clinically meaningful by the study leadership of reproductive endocrinologists.

Statistical Analysis

The primary and secondary analysis were performed according to the intent-to-treat principle (ITT) including all subjects who were randomly allocated into the treatment groups. Cumulative outcomes after up to the first three SETs within the study period were analyzed. Between-group difference in cumulative live births and its 95% CI were estimated using the Newcombe-Wilson method. If the lower limit of one-sided 95% CI for absolute difference (AD) in the cumulative live birth rates was larger than the prespecified non-inferiority margin (−10%), the blastocyst group was considered non-inferior to the cleavage-stage group. If non-inferiority would be demonstrated, a superiority test would be performed.

Time to cumulative live birth rates were estimated using Kaplan-Meier methods and analyzed with log-rank tests. Hazard ratio (HR) with 95% CIs were estimated by using a Cox proportional hazards model. Categorical data were represented as a frequency and percentage, and assessed by the Chi-square analysis or Fisher’s Exact Test. Continuous data were expressed as mean and standard deviation, with Student’s t -test for testing between-group differences.

The AD and relative risks, as well as their 95% CI, are presented. To ensure robustness of the results, analyses for per-protocol population and full analysis set were conducted in participants who fully complied with the protocol and those who did not meet major entry criteria and lacked any post-randomization data, respectively. The sensitivity analyzes of cumulative live birth rate for a maximum of the first three transfers without 3-month extension were also performed, as well as secondary analyzes of cumulative outcomes from all transfers within the study period.

We did post-hoc subgroup analyses to test the treatment effect at different maternal ages, previous conception, previous IVF, ovarian reserve, ovarian response based on number of oocytes retrieved, estradiol and progesterone on hCG day.

For the non-inferiority test of the primary outcome, a one-sided p -value of less than 0.025 was considered statistically significant, whereas for all other analyzes, a two-sided p -value of less than 0.05 was statistically significant. All analyzes were performed using SAS software (version 9.4; SAS institute, Cary, NC).

Reporting summary

Further information on research design is available in the  Nature Portfolio Reporting Summary linked to this article.

Data availability

The study protocol is available as Supplementary Note in the Supplementary Information. Clinical data are not publicly available due to the privacy of patients. Deidentified participant data, including specified dataset and a data dictionary that defines each field in the set, will be provided one year after publication of the primary manuscript for research purposes to the corresponding author([email protected]). Analyzes with a written protocol including analysis plan and signed data sharing/access agreement are required. Request for data sharing will be handled in line with the regulations for data access and sharing of Human Genetic Resource Administration of China, and approved by publication committee of the trial. The remaining data are available within the Article, Supplementary Information or Source Data file.  Source data are provided with this paper.

Code availability

No custom code was used for statistical analysis in this study.

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Acknowledgements

We thank all couples who consented to participate in this study, all research staff in study sites, and staff of Resman central randomization platform. We are thankful to Daimin Wei and Tianxiang Ni at the Center for Reproductive Medicine, Shandong University for their technical support; Lijuan Lin, Xuan Wang and Qian Ye at the Department of Biostatistics, School of Public Health, Nanjing Medical University for statistical support; Richard S. Legro at Penn State College of Medicine, Hershey, PA for guiding the design, conduct and data interpretation of the trial as the steering committee member; and the members of the data and safety monitoring committee: Robert Rebar (chair), Tin Chiu Li, Jun Zhang, Xiuqing Wang, and Yan Liu. They received no compensation for their contributions. This work was supported by the Key Program of National Natural Science Foundation of China (81730041(J.L.)), Shandong Provincial Key Research and Development Program (2020ZLYS02(Z-J.C.)), the National Key Research and Development Program of China (2021YFC2700404(J.L.)), Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210200(Z-J.C.)), and Jiangsu Provincial Science and Technology Department Social Development Project (BE2021743(X.M.)). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

These authors contributed equally: Xiang Ma, Jing Wang, Yuhua Shi, Jichun Tan, Yichun Guan, Yun Sun, Bo Zhang, Junli Zhao.

Authors and Affiliations

State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Clinical Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China

Xiang Ma, Jing Wang, Zhibin Hu & Jiayin Liu

State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, China

Yuhua Shi, Ze Wang & Zi-Jiang Chen

Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China

Jichun Tan & Xing Xin

Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China

Reproductive Medicine Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Yichun Guan & Pingping Kong

Department of Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

Yun Sun & Yao Lu

Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

Yun Sun, Yao Lu & Zi-Jiang Chen

Department of Reproductive Medicine Center, Maternal and Child Health Hospital in Guang Xi, Guangxi, China

Bo Zhang & Ling Huang

Reproductive Medicine Center, General Hospital of Ningxia Medical University, Ningxia, China

Junli Zhao & Yingying Yuan

Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Jianqiao Liu & Haiying Liu

Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, the Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China

Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

Yunxia Cao & Caihua Li

NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, China

Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China

Reproductive Medical Center, Henan Provincial People’s Hospital, Zhengzhou, China

Cuilian Zhang

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China

Feng Chen & Honggang Yi

Department of Obstetrics and Gynaecology, The Ritchie Center, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia

Ben Willem J. Mol

Department of Obstetrics and Gynaecology, Amsterdam University Medical Center, Amsterdam, The Netherlands

Department of Obstetrics and Gynaecology, Monash Health, Melbourne, VIC, Australia

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China

State Key Laboratory of Reproductive Medicine (Suzhou Center), the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China

Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA

Heping Zhang

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Contributions

X.M., J.W., Y.S., J.T., Y.G., Y.S., B.Z. and J.Z. contributed equally as first authors to this work. J.L. and Z-J.C. contributed equally as corresponding authors. Senior author (J.L., Z-J.C., H.Z., Z.H., B.M.) jointly directed this work. X.M., J.W., Y.S., H.Z., Z-J.C. and J.L. were responsible for the study conception and design, and wrote the study protocol. X.M., J.W., Y.S., J.T., Y.G., Y.S., B.Z., J.Z., JQ.L., Y.C., H.L., C.Z., Z.W., X.X., P.K., Y.L., L.H., Y.Y., HY.L., C.L., Z-J.C. and J.L. were involved in recruitment of patients and acquisition of the data. F.C., Z.H., H.Z., Z-J.C. and J.L. supervised the study. J.W., B.M., H.Z., F.C., X.M., Z-J.C. and J.L. drafted the manuscript. X.M., J.W., F.C., B.M., Z.H., H.Z., Z-J.C. and J.L. contributed analysis, interpretation of data, and critical revision of the manuscript for important intellectual content. J.W., F.C., H.Y. and H.Z. did the statistical analysis. All authors read and approved the final draft of the report.

Corresponding authors

Correspondence to Zi-Jiang Chen or Jiayin Liu .

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B.M. reported that he received Investigator grant support from the National Health and Medical Research Council (NHMRC) (GNT1176437) and consultancy, travel support and research funding from Merck. The remaining authors report no competing interests.

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Ma, X., Wang, J., Shi, Y. et al. Effect of single blastocyst-stage versus single cleavage-stage embryo transfer on cumulative live births in women with good prognosis undergoing in vitro fertilization: Multicenter Randomized Controlled Trial. Nat Commun 15 , 7747 (2024). https://doi.org/10.1038/s41467-024-52008-y

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The Future of IVF: The New Normal in Human Reproduction

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Increased demand for in vitro fertilization (IVF) due to socio-demographic trends, and supply facilitated by new technologies, converged to transform the way a substantial proportion of humans reproduce. The purpose of this article is to describe the societal and demographic trends driving increased worldwide demand for IVF, as well as to provide an overview of emerging technologies that promise to greatly expand IVF utilization and lower its cost.

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Introduction

Since its clinical introduction in 1978, in vitro fertilization (IVF) has redefined the ability of the human species to procreate. Initially developed to aid the infertile couple, clinical indications for IVF have since rapidly expanded to include medical and genetic conditions, as well as fertility preservation. While IVF access and utilization vary widely globally, the practice now accounts for the conception of over 5% of all newborns in some European countries where IVF is more affordable and/or is covered by insurance [ 1 ]. The corresponding figure presently stands at 4.1% in Australia and New Zealand, 1.9% in the USA, and 1.7% in China and is rapidly rising in all regions of the world [ 2 , 3 ]. Infertility, which affects approximately 10% of couples, remains the main driver of IVF utilization. These simple statistics suggest that IVF utilization may significantly grow in the coming decades if barriers to its utilization are lowered; this is without even considering an increasing number of indications for IVF beyond infertility.

Changing demographics and societal norms are driving increased IVF utilization. Improved access of women to educational and career opportunities, as well as effective contraception has contributed to progressively delayed childbearing and overall lower fertility rates worldwide. In many countries and in virtually all US states, fertility rates are now substantially below population replacement levels of 2100 births per 1000 women. In a growing number of metropolitan areas as well as in entire highly developed countries, the average age at first birth now exceeds 30 years, that is, well beyond peak fertility which occurs in the mid 20s. Inadvertently, a growing proportion of women is delaying childbearing to a point where age-related fertility decline contributes to the prevalence of infertility and to increased demand for fertility treatments including IVF and oocyte cryopreservation. These trends will likely accelerate due to the socio-economic impact of the COVID-19 pandemic, which has forestalled new family formation. Indeed, preliminary data from Chinese cities indicate that birth rates declined between 9 and 32.6% in the second half of 2020 compared with 2019, reflecting effects of the COVID-19 lockdowns [ 4 ]. Declining fertility rates in China have prompted its government to reverse a decades old one-child policy in favor of a two-child policy in 2016, and to a three-child policy in 2021.

The utilization of IVF is closely linked to its affordability and accessibility [ 5 ]. Indeed, a growing number of countries and US states are adopting various policies intended to reverse declining fertility rates. These policies range from legally mandated insurance coverage for fertility treatments to subsidies intended to ease the burdens of child-rearing. The concept that fertility is a basic human right is just starting to gain traction and is sure to accelerate wider adoption of such policies [ 6 ]. Another recent development is the growing number of prominent corporations opting to fund fertility benefits as a part of their social mission and as a means of attracting and retaining employees. Combined, the various policies that promote improved insurance coverage are bound to lower the cost of IVF to patients and increase its utilization.

The distribution of established fertility clinics thus closely corresponds to affluent metropolitan areas with the lowest fertility rates and the most advanced maternal ages at birth. Conversely, less densely populated and less affluent areas are characterized by relatively poor IVF access. Moreover, racial and ethnic disparities in the utilization of IVF, largely due to socio-economic factors, are inversely correlated with fertility rates [ 7 ]. An additional driver of IVF utilization is the growing societal acceptance of non-traditional families including single and same-sex parents. Finally, third-party IVF that includes the use of donor oocytes, sperm, or embryo and gestational carrier is rapidly growing, now accounting for over 20% of all birth conceived through IVF in the USA [ 8 ].

The IVF process is complex and stressful, it consists of multiple steps which can take up to several months to complete. The main reasons patient prematurely drop-out of IVF prior to achieving a pregnancy are the financial, physical, and psychological burdens of the treatment regimen [ 9 ]. Here, we describe promising future approaches and technological innovations which might improve IVF accessibility while reducing its costs and burden of care.

Medical Advancements

Controlled ovarian hyperstimulation (COH) is performed to increase the number of oocytes available for IVF. COH involves multiple injections of gonadotropins and serial visits to the fertility clinic for the conduct of transvaginal ultrasound evaluations and the measurement of circulating hormone levels. It follows that COH is complex, time sensitive, and intensive. Various strategies intent on reducing the number of injections by utilizing long-acting gonadotropins or oral medications are already available and are gaining increased acceptance in the field for the treatment of select patient populations [ 10 , 11 ]. Similarly, an emerging strategy to measure salivary estradiol levels may help decrease the need for blood draws during COH [ 12 ]. Recent advancements in portable lower cost ultrasound devices may further simplify follicular and endometrial monitoring by way of convenient mobile facilities and potentially even self-operated endovaginal telemonitoring [ 13 ]. Combined, these approaches may greatly simplify COH by rendering it less invasive and by decreasing the time commitment required. Finally, interventions which may further decrease the treatment burden may include screening of patients for psychological issues as well as offering counseling and coping interventions such as e-therapy as an integral part of IVF [ 14 , 15 ].

Technological Advancements

Perhaps the most promising technological development that might democratize IVF access in the near-term is the automation and miniaturization of the IVF laboratory. Building, staffing, and manually operating an IVF laboratory account for much of the high cost, maldistribution in access, and variability of outcomes. The basic steps in the IVF laboratory include:

identification and separation of sperm and oocytes

fertilization

embryo culture

embryo selection for transfer

cryopreservation of surplus embryos and gametes

Great progress has already been made towards the automation of these individual steps by way of new technologies. Still, the IVF process in its entirety remains highly manual. The altogether novel IVF lab-on-a-chip concept has the potential to revolutionize IVF by enabling the automation of virtually all of the steps involved in a single system [ 16 , 17 , 18 ].

Microfluidics is defined as a multidisciplinary field of study and design whereby fluid behaviors are accurately controlled and manipulated with small scale geometric constraints that yields dominance of surface forces over volumetric counterparts. Past procedures in the IVF laboratory, though successful, apply a macroscale approaches to microscale cellular biological events [ 18 ]. Integration of microfluidics into the IVF laboratory may give rise to at least four foreseeable advantages: (1) precisely controlled fluidic gamete/embryo manipulations; (2) providing biomimetic environments for culture; (3) facilitating microscale genetic and molecular bioassays; and (4) enabling miniaturization and automation. The basic utility and advantages of individual microfluidic devices for gamete and preimplantation embryo isolation, manipulation, and assessment have been demonstrated [ 18 ]. Current efforts are focused on integrating extant individualized microfluidic procedural components into a future IVF lab-on-a-chip.

Microfluidic sperm-sorting devices [ 19 , 20 , 21 ] and automated sperm analyzers [ 22 ] are already being introduced into routine IVF practice. Indeed, microfluidics has been used for the isolation of sperm from semen and testicular biopsies [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. These novel sperm-isolating microfluidics devices provide for the collection of highly motile sperm populations replete with enriched normal morphology, and most importantly, reduced DNA fragmentation relative to conventional methods of sperm isolation [ 19 , 27 , 30 , 31 ].

Microfluidic in vitro insemination has been demonstrated [ 32 ], whereas conventional fertilization is suitable for the vast majority of IVF patients, microfluidic systems may further decrease the need for Intracytoplasmic Sperm Injection (ICSI). Such outcomes may even be possible in the setting of oligospermia, because even a low concentration of sperm may still be sufficient to achieve fertilization [ 32 ]. As ICSI has become a dominant method of insemination in human clinical IVF, the importance of precise microfluidic push/pull cumulus-oocyte-complex cumulus cell removal has been shown to yield good visualization of the oocyte cytoplasm/orientation [ 33 ]. The fertilization step by ICSI is perhaps the most technically difficult step to achieve on a commercial scale, but feasibility of one such system has been demonstrated [ 34 ]. Future automated ICSI will likely involve a combination of microfluidics, robotics, and refined optics [ 34 , 35 ].

Embryo culture has already been fully automated with use of time-lapse incubators which allow continuous monitoring of embryo development. Data generated from time-lapse incubators can be analyzed with machine learning to aid in the selection of embryos with the highest pregnancy potential [ 36 , 37 , 38 ]. Additional information about embryo viability may be gleaned from other omics technologies which can either sample the embryo directly or indirectly via its culture media. The technologies in question include genomic, transcriptomic, proteomic, and metabolomic analyses [ 39 ]. Although the use of preimplantation genetic testing (PGT) of trophectoderm cells of blastocyst stage embryos is quite common in clinical practice, the utility of such testing for the ascertainment of aneuploidy remains controversial on both biological and technical grounds [ 40 ]. Microfluidics technology has been successfully used to culture mammalian preimplantation embryos from the zygote to the blastocyst stage both individually and in groups [ 41 , 42 , 43 , 44 , 45 , 46 ]. These experiments have proven informative to overcoming the hurdles of microenvironment manipulations in microfluidic devices involving microchannels [ 42 ], microfunnels [ 45 ], microwells [ 44 ], and microdroplets [ 46 ] that can induce shear stresses and osmotic shifts that can be detrimental to embryo development [ 45 , 47 ]. The importance of individual embryo culture in microfluidic devices can be appreciated when one considers the desire to integrate real-time imaging and morphometrics [ 48 ], molecular [ 49 ], and/or metabolomic [ 50 , 51 ] bioassays, biomechanics [ 52 ], and non-invasive PGT of cell-free DNA in spent media [ 53 ]. Noninvasive PGT, which utilizes cell-free DNA released into the spent embryo culture media, is likely to become the first omics technology used clinically in conjunction with a microfluidic system [ 53 ].

Finally, cryopreservation of sperm, oocytes, and embryos has become the standard of care. Vitrification has become the dominant method for oocyte and embryo cryopreservation. While semi-automated/automated systems for oocyte/embryo vitrification have been reported and are now in early stages of clinical adoption [ 54 , 55 , 56 ], these devices do not necessarily use or require microfluidics. If one looks to the future of a microfluidic automated lab-on-a-chip, the question arises of whether or not microfluidics is useful and/or beneficial in the vitrification process? Microfluidics can be used to precisely control cryoprotectant exposures (gradual versus step-wise exposure) to oocytes/zygotes/embryos and thus reduce osmotic strain, reduce sub-lethal membrane damage, and improve subsequent development [ 57 , 58 , 59 , 60 ]. Future potential benefits of integrating microfluidics with vitrification and automation have been carefully enumerated in recent reviews [ 59 , 61 , 62 ]. Integrated microfluidics for vitrification with automation is promising. Such a system/device will reduce reagent consumption, decrease labor intensity, facilitate ease of use, offer medium to high throughput, and may foster point-of-care cryopreservation and/or promote in-office cryopreservation procedures that require less in the way of technical/personnel expertise and sophisticated laboratory/equipment needs.

Figure  1 illustrates the future IVF lab-on-a-chip concept, including all of the laboratory steps performed during IVF while integrating emerging non-invasive techniques of embryo assessment. Adoption of automated IVF systems offers multiple potential advantages: standardization of workflows, reduction in errors, reduction in cost, reduction in contamination, and the potential for incremental system improvement via machine learning. Additionally, miniaturization and automation of the IVF laboratory can greatly improve accessibility to IVF treatment for underserved communities, especially those who are economically disadvantaged and who reside in rural areas. Regulatory approval will doubtlessly be required if automated systems are to be adequately validated to produce clinical outcomes superior to those attained with the current manual process in the IVF laboratory. Furthermore, automation will likely significantly decrease the staffing requirements and alter the type of skills required to operate fertility centers. It is likely that the technical aspects of IVF will be gradually assumed by machines. This may well increase the emphasis placed on human interactions which supports the medical and psychological needs of patients during their fertility journey.

Future IVF lab-on-a-chip concept displaying the integration of all the steps performed during the IVF process and of emerging non-invasive techniques of embryo assessment

Scientific Advancements

Fertility preservation research has steadily increased our understanding of the mechanisms that govern folliculogenesis [ 63 ]. The development of in vitro culture systems for follicles provided insights into the relationship between oocytes and their surrounding somatic cells, as well as the requisite hormones and growth factors. Multi-step culture systems have advanced to a point where primordial follicles residing in ovarian cortical tissue can undergo activation, growth, and in vitro maturation (IVM) to yield metaphase II (MII) oocytes [ 64 ]. These advancements are expanding fertility preservation via ovarian tissue cryopreservation and subsequent chance at parenthood via IVF to pre-pubertal girls and young women at-risk to develop primary ovarian insufficiency (POI) due to gonadotoxic chemotherapy for cancer or due to other serious diseases. Intriguing extensions of this technology may enable the isolation of oocytes from patients who have already developed POI or have entered natural menopause so long as some dormant follicles remain within their ovarian cortex. Another avenue of research is to develop an artificial ovary as has been achieved in a murine model using 3D printed scaffolds for tissue engineering [ 65 , 66 ]. Microfluidic culture systems may also be utilized to support follicle development while mimicking the natural menstrual cycle [ 67 ].

In Vitro Gametogenesis (IVG)

Perhaps the most revolutionary concept in modern reproductive science is that of in vitro gametogenesis (IVG). IVG comprises various approaches, including organ culture systems, embryonic stem cells (ESC), induced pluripotent stem cells (iPSC), and spermatogonial stem cells (SSCs). Several of these approaches led to the creation of functional gametes in rodent models [ 68 ]. Japanese scientists, who have been at the forefront of IVG research, have recently succeeded in extending these techniques to the generation of human oogonia from iPSCs [ 69 ]. Yet, another approach to IVG involves reconstruction of functional oocytes by nuclear transfer of the first polar body genome from an MII oocyte into an enucleated donor MII cytoplasm [ 70 ]. This latter technique may well increase the number of oocytes available for the treatment of infertility of women with few or poor-quality autologous oocytes.

The existence of human oogonial stem cells (OSCs) capable of giving rise to new oocytes has been an area of some controversy for nearly a decade. Reports to the effect that cells isolated from human ovarian tissue using fluorescence-activated cell sorting and an antibody against the DDX4 protein constituted OSCs challenged the long-standing dogma that the ovarian reserve is finite [ 71 , 72 ]. Multiple follow up studies by several groups were unable to confirm the presence of OSCs in the human ovary. Recently, single-cell analysis of the human ovarian cortex failed to identify OSCs [ 73 ]. Instead, cells captured by the DDX4-directed antibody proved to be perivascular cellular elements [ 73 ].

SSCs constitute the progenitor cells in the process of spermatogenesis. As such, these cells are the focus of in vitro spermatogenesis (IVS) and in vivo restoration of male fertility. While IVS has been achieved in rodent models, it has proven far more difficult to realize in primate counterparts [ 74 ]. One recent approach to IVS involved the culture of SSCs with immortalized Sertoli cells. Meiosis and the production of spermatid-like cells followed, albeit in the face of improper activation of cognate meiotic checkpoints [ 75 ]. In yet another approach, sperm nuclear transfer allowed production of androgenetic haploid embryonic stem cells which were able to “fertilize” oocytes and support early embryonic development, diploid blastocysts, and ESC generation [ 76 ]. Once fully realized, IVS is destined to offer genetic parenthood via IVF to infertile men diagnosed with azoospermia and pre-pubertal boys undergoing gonadotoxic treatments.

Reproductive Genetics

The convergence of IVF with reproductive genetics has been at the forefront of the field for the past few decades. The development of next generation sequencing has expedited the adoption of PGT of embryos with an eye toward detecting the presence of chromosomal abnormalities. Moreover, increased use of carrier screening of infertile couples has increased the use of PGT for monogenic diseases. As cost of carrier screening decreases and the number of detected mutations expands, a substantial new population of patients identified as carriers may pursue IVF with PGT to build their families. Indeed, population genomic screening of young adults may offer significant healthcare savings through the prevention of rare disorders and cancers [ 77 ]. Future applications of PGT may expand to multifactorial diseases and whole-exome screening, though current attempts at introduction of embryo selection based on polygenic scores into clinical practice seem premature and fraught with ethical challenges [ 78 ]. Recent improvements in micromanipulation techniques and the development of CRISPR-Cas9 gene editing tools [ 79 ] raise the prospect of germline genome modification (GGM) for severe monogenic disorders. Indeed, GGM has already been achieved in human embryos [ 80 ]. Mitochondrial replacement therapy (MRT) for the prevention of heritable mitochondrial DNA diseases is even further developed than GGM, with clinical trials already underway in the UK [ 81 ].

The growing utilization of IVF will transform the way a substantial proportion of the human species procreates. It is likely that in the near future, as many as 10% of all children will be conceived through IVF in many parts of the world. Given the rapid scientific and technological evolution of IVG and of reproductive genetics, it is imperative that both the public and regulatory bodies be engaged in establishing a framework for the ethical evaluation of emerging technologies [ 82 , 83 , 84 ]. Such public engagement is critical. The absence of such may well result in reactionary bans against clinical research as has been the case for GGM and MRT in the USA [ 85 ]. Moreover, the introduction of innovative technologies into clinical practice must be rooted in science and supported by well-designed clinical trials [ 86 ]. Premature commercialization of costly and unproven “add-ons” to IVF has been an ongoing issue in the field, ranging from procedures to medicines to laboratory techniques [ 87 , 88 ]. Collectively, routine application and marketing of unproven IVF add-ons may erode the public trust in the reproductive medicine field. Thus, it is imperative for the field to prioritize requiring confirmation of safety and efficacy of technologies before allowing them to be offered routinely to IVF patients. Reproductive medicine, and especially IVF, is rapidly transforming human reproduction and is thus bound to remain of fundamental importance to both science and society.

Data availability

Not applicable.

Code Availability

Abbreviations.

Controlled ovarian hyperstimulation

Embryonic stem cells

Germline stem cells

Germline genome modification

Induced pluripotent stem cells

Intracytoplasmic sperm injection

• In vitro fertilization
• In vitro gametogenesis

In vitro maturation

In vitro spermatogenesis

Metaphase II

Mitochondrial replacement therapy

Oogonial stem cells

Preimplantation genetic testing

Primary ovarian insufficiency

Spermatogonial stem cells

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Kushnir, V.A., Smith, G.D. & Adashi, E.Y. The Future of IVF: The New Normal in Human Reproduction. Reprod. Sci. 29 , 849–856 (2022). https://doi.org/10.1007/s43032-021-00829-3

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Effect of paternal age on clinical outcomes of in vitro fertilization-embryo transfer cycles

Affiliations.

• 1 School of Clinical Medicine, Qingdao University, Qingdao, China.
• 2 Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
• 3 Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
• 4 National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China.
• 5 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China.
• 6 Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Shandong University, Jinan, Shandong, China.
• 7 Tengzhou Maternal and Child Health Hospital, Zaozhuang, Shandong, China.
• 8 Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
• PMID: 39268240
• PMCID: PMC11390372
• DOI: 10.3389/fendo.2024.1325523

Purpose: This study aimed to investigate the impact of paternal age > 40 years on clinical pregnancy and perinatal outcomes among patients undergoing in vitro fertilization treatment.

Methods: We selected 75 male patients (aged > 40 years) based on predefined inclusion and exclusion criteria. Propensity score matching was performed in a 1:3 ratio, resulting in a control group (aged ≤ 40 years) of 225 individuals. Various statistical tests, including the Mann-Whitney U test, Chi-square test, Fisher's exact test, and binary logistic regression, were used to analyze the association between paternal age and clinical outcomes.

Results: We found no statistically significant differences in semen routine parameters, clinical pregnancy outcomes, and perinatal outcomes between paternal aged > 40 and ≤ 40 years. However, in the subgroup analysis, the live birth rate significantly decreased in those aged ≥ 45 compared to those aged 41-42 and 43-44 years (31.25% vs. 69.23% and 65%, respectively; all p < 0.05). Additionally, the clinical pregnancy rate was significantly lower among those aged ≥ 45 than among those aged 41-42 (43.75% vs. 74.36%; p=0.035).

Conclusion: Paternal age ≥ 45 years was associated with lower live birth and clinical pregnancy rates.

Keywords: clinical pregnancy rate; in vitro fertilization; live birth rate; paternal age; perinatal outcomes.

Copyright © 2024 Gao, Li, Wang, Cai, Sun and Lu.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Forest plot illustrating live birth…

Forest plot illustrating live birth rates and clinical pregnancy rates in patients over…

• Seshadri S, Morris G, Serhal P, Saab W. Assisted conception in women of advanced maternal age. Best Pract Res Clin Obstet Gynaecol. (2021) 70:10–20. doi: 10.1016/j.bpobgyn.2020.06.012 - DOI - PubMed
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• Research article
• Open access
• Published: 12 October 2016

Lifestyle and in vitro fertilization: what do patients believe?

• Brooke V. Rossi 1 , 4 ,
• Leah Hawkins Bressler 1 ,
• Katharine F. Correia 1 ,
• Shane Lipskind 1 ,
• Mark D. Hornstein 1 &
• Stacey A. Missmer 1 , 2 , 3  

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Patients have many beliefs regarding lifestyle factors and IVF outcomes.

Observational study of 208 IVF patients at an academic infertility center. Main outcome measures were perceived influence of various lifestyle factors assessed by multivariable logistic regression and p -value tests for linear trend (P t ).

A majority of participants believed that there were many women’s lifestyle choices that were influential, compared to fewer male factors (cessation of tobacco (72 %), alcohol (69 %), caffeine (62 %), and use of vitamins (88 %)). Compared to participants with less education, participants with a higher education level were less likely to believe vitamins were helpful and some alcohol use was not harmful. As income decreased, participants were less likely to consider dietary factors contributory to IVF success, such as women (p-trend, p  = 0.02) and men (p-trend, p  = 0.009) consuming a full-fat dairy diet. Participants’ beliefs were most commonly influenced by physicians (84 %) and the internet (71 %).

Conclusions

Patients believed many lifestyle factors are associated with IVF success. Understanding patients’ assumptions regarding the effect of lifestyle factors on IVF success may better allow physicians to counsel patients about IVF outcomes.

Several of the most influential factors on in vitro fertilization (IVF) success, such as age, are non-modifiable. Patients and providers, however, are interested in the effects of modifiable risk factors, such as lifestyle, on the success of IVF. There is considerable evidence that modifiable factors, like smoking and weight, have a negative effect on IVF [ 1 , 2 ]. Smoking negatively affects several outcomes and parameters in the IVF cycle and is associated with an increased risk of not conceiving [ 3 – 6 ]. In addition, body mass index (BMI) may affect a woman’s chance of successful of infertility treatment, as fecundity was found to be lower in underweight and obese women undergoing IVF compared to those with normal body weight [ 7 ]. Further, obese women were more likely to have IVF cycle cancellation, lower pregnancy, and live birth rates [ 8 – 12 ]. Overweight men also had a lower likelihood of pregnancy compared to men of a normal weight [ 13 ].

The effects of other factors such as psychological stress, caffeine, activity level, and environmental pollutants are less well-defined [ 1 , 2 , 14 ]. A prospective study of stress and IVF found that higher scores on positive affect scales were associated with a 7 % lower risk of not having a live birth and lowering stress with group intervention helped pregnancy rates [ 15 , 16 ]. Conversely, general anxiety and anxiety scores were not associated with IVF outcomes, such as live birth [ 17 ]. In regards to exercise, the associations are complex. While Morris et al. showed that women who exercised more than 4 h per week had a decreased likelihood of live birth [ 18 ], a more recent study demonstrated that those with higher active living and exercise/sports indices in the past year were more likely to have a clinical pregnancy [ 19 ].

There are many studies examining IVF and different lifestyle factors, but there exists a lack of data assessing patients’ knowledge and perception of which factors are truly associated with outcomes. Previous investigations demonstrate a poor understanding of the medical issues surrounding infertility and the chance of successful IVF [ 20 ]. For example, women were unable to identify which factors have an impact on fertility [ 21 , 22 ].

Finally, there are minimal data on the sources of the information and other characteristics that inform patient beliefs regarding lifestyle factors. In a study of infertility patients, participants felt that information-gathering and lifestyle change led to successful infertility treatment. Furthermore, some felt empowered by taking part in an activity they felt would impact their infertility [ 23 ]. However, after failure to conceive, others felt that their lack of lifestyle change was to blame for their infertility. To obtain information about lifestyle factors, infertility patients used the internet or books, and most spent hours on the internet. Nearly one-half of infertility patients use the internet for fertility related information [ 24 ]. Women, especially those over 35, were more likely to be influenced by on-line health information when seeking treatment.

No randomized controlled trials exist evaluating the effects of preconception advice regarding lifestyle factors on fertility outcomes in people who may have infertility [ 25 ]. One may hypothesize, however, that when patients are aware of how lifestyle factors may influence their reproductive outcome, they may be more motivated to make lifestyle changes that promote IVF success [ 1 ]. If patients are given health information, their behaviors may become healthier, as has been the case with infertile smokers [ 26 ].

In vitro fertilization is a resource-intensive treatment, often requiring a significant investment of time, money and emotional energy. Any lifestyles changes that could contribute to success, while reducing these burdens, would be significant. Our study aim was to determine which modifiable lifestyle factors patients believe to be associated with IVF success. Our primary hypothesis was that patients consider many modifiable lifestyle factors to be influential on IVF outcome. Our secondary hypotheses were that patients’ beliefs may vary based on demographics.

We used a cross-sectional survey to assess the perceived impact of lifestyle behaviors of couples undergoing IVF. We asked subjects their opinion on several lifestyle factors ( Appendix 1). Due to the large number of variables assessed, the results of the study were divided into 2 manuscripts; the current study and Hawkins et al. [ 27 ]. Couples presenting for fresh IVF cycles from 2011 through 2012 were screened for inclusion. English-speaking, heterosexual infertile couples undergoing a fresh, autologous IVF cycle with day 3 embryo transfer (cleavage transfer was standard at our institution at that time) were included. Enrolled, consenting participants were then asked questions on basic demographic information and medical history, as collected in prior studies in the IVF population [ 28 ]. We excluded donor oocyte, donor sperm, gestational carrier, and pre-implantation genetic diagnosis (PGD) cycles due to concern for subgroup heterogeneity and variability in the timing of embryo transfer. The protocol was approved by the Partners Human Research Committees. All patients were provided information on the study and completed online waivers of consent prior to beginning the survey.

Couples were screened for inclusion at the time of oocyte retrieval. They received an information packet including a one-page summary of the study and a separate document for interested participants to supply their and their partners’ email addresses. Patients who provided an email address(es) were subsequently emailed a link to the on-line survey and a login. This link directed participants to supply their login and a password to confirm eligibility.

Participants were considered enrolled after accessing the on-line study (Additional file 1 ). Consent was posted at the beginning of the survey. To ensure embryo transfer had occurred but serum pregnancy test had not at the time of survey completion, participants were allowed to supply responses to the survey only within a strict 11-day time window beginning three days after their egg retrieval and ending at the time of serum pregnancy test, 14 days after egg retrieval. Participants were emailed links to the survey the day of embryo transfer and before beginning the survey, participants were asked if they had undergone embryo transfer for this cycle and were denied access to the survey if they had not. To prevent responses submitted after serum pregnancy test, surveys were scheduled to expire 14 days after oocyte retrieval.

The remainder of the survey was presented with a Likert-type rating scale and included questions regarding participants’ perceived impact (very harmful, harmful, no effect, helpful, very helpful) of various lifestyle behaviors. For each of these questions, respondents were also provided the option of answering I don’t know/no opinion. The surveys were designed specifically for this study. The list of behaviors was created by considering: 1), the current evidence and literature on lifestyle factors and IVF and 2) feedback from IVF providers who reported their patients’ modification or questions about lifestyle factors and IVF. After answering these questions with regard to the perceived impact of their behavior, participants were then asked to answer these questions with regard to the perceived impact of their partner’s behavior. Lastly, participants were asked if a number of sources contributed to their beliefs about lifestyle (physician, nurse, book, internet, friends, family, and partner).

Participant responses were restricted by IP address to ensure participants did not complete the survey multiple times. Couples were not excluded if only one partner provided their email address. To comply with Institutional Review Board regulations regarding de-identification of participants completing online surveys through a third party, partners’ survey responses were not linked by couple. Responses were considered for inclusion in analysis from all submitted questionnaires in which a participant answered all demographic questions and at least part of the questions on lifestyle behaviors. Respondents who saved but did not submit responses, even in cases where participants completed the entire survey, were excluded from analysis due to concern that a participant’s non-submission represented indecision or discomfort with sharing responses. Responses from a total of 208 participants (45 % of invited, eligible participants) were included in analysis. Subject recruitment and outcomes are in Fig.  1 .

Subject recruitment and outcome

SAS 9.2 (SAS Institute Inc., Cary, NC) was used for all data analysis. Dichotomous outcomes were consolidated for analysis; helpful and very helpful versus harmful and very harmful. We excluded neutral responses, missing responses, and “no response/I don’t know” replies. All variables in Table  1 were considered and gender, age, and education level were found to be confounders. Multivariable logistic regression analyses adjusting for gender, age, and education were performed to estimate the effects of explanatory variables such as gender, infertility diagnosis, and duration of infertility on perceptions about lifestyle behaviors. Results are presented as adjusted odds ratios (OR) and 95 % confidence intervals (CI). Wald p-value tests for linear trend (for which statistical significance was assumed for p  < 0.05).

There were 208 participants, consisting of 138 (66.3 %) women and 70 (33.7 %) men, mostly age 35 or older and educated, with a variety of infertility diagnoses (Table  1 ). Due to the large amount of data collected and manuscript length limitations, we will only present data for the factors most respondents found important.

In regards to women, greater than 71.7 % of participants felt that women not smoking was helpful to the success of the IVF cycle, and 86.1 % believed daily second-hand smoke exposure was harmful. A majority of participants felt that avoiding alcohol (69.2 %) and caffeine (62.1 %) were helpful. Overall, vitamins were considered beneficial, including prenatal vitamins (88.3 %), multivitamins (81.6 %), vitamin C (66.1 %), vitamin E (65.2 %), and vitamin D (68.1 %). Most participants felt that an increase in fruits and vegetables (83.7 %) and an organic diet (57.6 %) was helpful; otherwise there were no consistent beliefs concerning diet or artificial sweeteners. Finally, many respondents felt that ibuprofen (74.7 %) and cold/allergy medicine (70.9 %) were harmful, and that Tylenol (79.0 %) use had no effect on IVF cycle success.

Considering men, 68.1 % felt not smoking was helpful and 76.0 % felt that daily second-hand smoke exposure was harmful. Most (65.4 %) considered no alcohol use helpful. However, when asked specifically about 1–4 drinks of beer, wine, or liquor per week, a majority believed this amount of alcohol to have no effect. Conversely, a majority felt >4 drinks of beer, wine, or liquor per week were harmful to IVF cycle success. Sixty-five percent felt that male use of multivitamins was helpful, but no other vitamin use was thought to be influential on IVF cycle outcome. Participants did not believe diet, caffeine, artificial sweeteners, or over-the-counter medicines were either helpful or harmful.

In general, participants felt that their own lifestyle choices were more influential than their partners believed them to be (Figs.  2 and 3 ). For example, compared to women, men were less likely to think that it was helpful for women to avoid artificial sweetener (OR 0.3; CI 0.2–0.7), smoking (OR 0.5; CI 0.2–0.9), alcohol (OR 0.4; CI 0.2–0.9), vitamins/herbal treatments (OR 0.2; 0.1–0.6), or over-the-counter medications (OR 0.4; CI 0.2–0.8). Similarly, compared to women, men were more likely to believe that it was helpful for a man to avoid caffeine (OR 1.8; CI 1.0–3.6), alcohol (OR 1.7; CI 0.9–3.3), or over-the-counter medications (OR 1.7; CI 0.8–3.5) (all not statistically significant).

Percent of women and men participants who believed that women avoiding these factors were helpful to IVF cycle success. Odd ratio and 95 % CI reported. Multivariate model includes gender, age (ordinal), and education (ordinal) in addition to the primary predictor

Percent of women and men participants who believed that men avoiding these factors were helpful to IVF cycle success. Odd ratio and 95 % CI reported. Multivariate model includes gender, age (ordinal), and education (ordinal) in addition to the primary predictor

Associations among the lifestyle factors and demographics were assessed. Education level and income were significantly associated with beliefs. Both men and women with doctorate degrees had approximately 30 % lower odds of believing vitamins were helpful or alcohol and caffeine were harmful. Trends were also seen among income, as men and women with a decreased income were less likely to feel that low carbohydrate, high protein, full-fat dairy diets were helpful to IVF success (all p t <0.05). Finally, when asked which sources led to their beliefs, participants felt physicians (84 %) and nurses (83 %) were influential or very influential [ 28 ]. Participants also considered the internet (71 %), books (65 %), and family (53 %) influential or very influential. In general, women considered more sources influential than men.

The present work characterizes patients’ beliefs surrounding lifestyle factors and IVF. A majority of patients did accurately recognize the harm of personal cigarette use and second-hand smoke exposure [ 3 , 6 , 29 , 30 ]. However, in general, patient beliefs were inconsistent with the current evidence surrounding lifestyle factors and IVF outcomes. There was concern for some amount of alcohol and caffeine, but they did not recognize that a minimal amount of either of these may be harmful [ 31 – 33 ]. Also, many patients considered certain lifestyle factors influential even though existing evidence is not strongly supportive of an association (vitamins, organic diet) [ 34 ]. While this over-cautiousness may not be harmful from a medical standpoint, we do need to consider the stress and financial impact of changing behaviors or lifestyles without scientific support. These overall beliefs measure physician success at patient education and highlight existing knowledge deficits.

One of the unique characteristics of this study is the assessment of the each member’s own lifestyle factors, as well as their beliefs about their partner’s lifestyle factors and IVF outcomes. In general, we observed that both men and women believed that their own gender’s lifestyle factors and behaviors were more influential than the opposite-sex’s behaviors. Patients may truly believe, based on what they have heard or learned, that their gender’s lifestyle factors are more important than their partners. It is also possible, however, that this finding suggests that patients are practicing self-blame. Self-blame is one of the coping mechanisms exhibited by infertile men and women, and this coping mechanism may be further increase their distress [ 35 ]. However, men and women manage the stress of infertility in different ways [ 36 ]. Women may be more likely to self-blame as a coping strategy [ 37 ]. This may explain that we had more significant variables for women’s’ beliefs of themselves than men’s. Better education of patients may help them understand which lifestyle factors may or may not have an impact and which are under their control. This may reduce self-blame and therefore reduce distress.

We noted several patient characteristics which correlated with beliefs, namely education and income level. The differences in education among patients using IVF are evident in many facets of infertility treatment, from attainment of care to beliefs. A higher education level (post-secondary degree) has been associated with a greater likelihood of having an infertility evaluation and treatment [ 38 ]. A survey of national infertility treatment use demonstrated that while 21–23 % of women aged 25–44 have used infertility treatment, only 10 % of women with a high-school diploma had treatment [ 39 ]. Our study demonstrated that participants with higher education believed vitamins were more influential, but did not feel that other habits, such as alcohol or caffeine were associated with IVF success. The potential effect of education level on IVF has not been extensively studied, however, one study did not demonstrate an association between education level and live birth rate [ 40 ]. Thus, the differences in lifestyle beliefs may lead patients to practice different behaviors or use different therapies (i.e. vitamins), but these changes may not influence IVF outcomes.

Similar trends were seen with income. As with education level, Chandra et al. also determined that infertility treatment was more prevalent for those with a household income above the poverty level (21 %) compared to below the poverty level (13 %) [ 39 ]. Even in a state with mandated IVF and infertility coverage, over 60 % had a household income of > $100,000 [ 41 ]. There are no studies evaluating the association between income level and IVF success. We found that those at a lower income level were more likely to incorrectly believe that certain dietary factors (alcohol, fat or carbohydrate composition) influenced IVF success, when they were not strongly supported in the literature.

Many patients seek information regarding lifestyle and infertility. Although a majority of our participants felt that care providers were influential, some patients felt that the information they received from their clinician was not sufficient and they sought other information [ 23 ]. The participants also noted that many of them had already made lifestyle changes that the clinicians discussed and they were seeking additional information, including that regarding complementary and alternative medicine treatments. Finally, participants reported that information gathering was empowering and provided emotional support though connections with other patients. Our study and others show that the internet is a popular way for patient to learn about infertility and IVF. As long ago as 2003, Haagen et al. demonstrated that 66 % of infertility participants surveyed used the internet for fertility-related problems [ 42 ]. In accord with our findings, more women than men used the internet, and education and household income was associated with amount of use.

Weaknesses of this study include issues related to the diversity of the study sample and that our survey was done in a single practice. Our practice is located in an academic medical center in a large Northeast city. Of course, any study done at one center may not be representative of the general population. For example, 88 % of our participants had a college degree or higher and only 24 % had an income of < $100,000. This is significantly different than the general US population in which 28 % have a college degree or higher and the median income is approximately $53,000, consistent with a large academic northeastern city [ 43 ]. The racial make-up of our study, however, was similar to the general population and our practice is in a state with mandated insurance coverage, which may allow for more patients to have access to IVF coverage compared to other states. Only 13 % of respondents were not of Caucasian or Asian ethnicity, and 88 % had at least a 4-year college education, whereas in the United States in general, only 31 % have a 4-year college degree. While this educational level, may be not in-line with the general population, it may be more typical of the general US IVF population, which tends to have a higher education level. Another weakness includes the inability to assess if one partner’s response was correlated to the other partner’s response. Each subject was independent and not linked to their partner. Future analyses could include tracking couple’s responses together to assess for correlations. Finally, our survey response rate was 45 %, which may limit generalizability to the overall IVF population.

We were also concerned that home pregnancy testing may influence results and took steps to minimize this potential source of bias. We advised patients to wait for their scheduled serum pregnancy test and only allowed access to the survey until the date of the test to decrease the risk that premature knowledge of their cycle outcome would influence their responses.

Our results demonstrate that IVF patients are aware of the established associations between lifestyle factors and cycle success. However, there is also a tendency for patients to ascribe importance to many factors that are not supported as influential by medical literature. Findings of our study may assist care providers with patient education and further help patients target their efforts towards meaningful lifestyle change. We advocate for better education about the impact of lifestyle on IVF for all, acknowledging the impact of socioeconomic status. Moreover, results highlight the need to tailor the education to appropriate sources, such as the internet, and recognize the importance of the care providers’ guidance and recommendations. Assessment of belief modification after an educational intervention about lifestyle factors and IVF outcomes is merited.

Abbreviations

Assisted reproductive technologies

In vitro fertilization

Body mass index

Preimplantation genetic diagnosis

Confidence interval

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BR- study design, data analysis, data interpretation, manuscript generation. LB- data collection, data analysis, data interpretation, manuscript generation. KC- data analysis, statistical analysis. SL- data collection, critical review of manuscript. MH- critical review of manuscript. SM- study design, data analysis, data interpretation, critical review of manuscript. All authors read and approved the final manuscript.

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MH is an author for UpToDate.com and is on the medical advisory board for WinFertility. No other authors state a conflict of interest.

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Brooke V. Rossi, Leah Hawkins Bressler, Katharine F. Correia, Shane Lipskind, Mark D. Hornstein & Stacey A. Missmer

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Stacey A. Missmer

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Rossi, B.V., Bressler, L.H., Correia, K.F. et al. Lifestyle and in vitro fertilization: what do patients believe?. Fertil Res and Pract 2 , 11 (2016). https://doi.org/10.1186/s40738-016-0026-5

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• Infertility
• Lifestyle factors
• Assisted reproductive technology (ART)
• In vitro fertilization (IVF)

Fertility Research and Practice

ISSN: 2054-7099

• Submission enquiries: [email protected]
• General enquiries: [email protected]

• Patient Care & Health Information
• Tests & Procedures
• In vitro fertilization (IVF)

• In vitro fertilization

During in vitro fertilization, eggs are removed from sacs called follicles within an ovary (A). An egg is fertilized by injecting a single sperm into the egg or mixing the egg with sperm in a petri dish (B). The fertilized egg, called an embryo, is transferred into the uterus (C).

In vitro fertilization, also called IVF, is a complex series of procedures that can lead to a pregnancy. It's a treatment for infertility, a condition in which you can't get pregnant after at least a year of trying for most couples. IVF also can be used to prevent passing on genetic problems to a child.

During in vitro fertilization, mature eggs are collected from ovaries and fertilized by sperm in a lab. Then a procedure is done to place one or more of the fertilized eggs, called embryos, in a uterus, which is where babies develop. One full cycle of IVF takes about 2 to 3 weeks. Sometimes these steps are split into different parts and the process can take longer.

In vitro fertilization is the most effective type of fertility treatment that involves the handling of eggs or embryos and sperm. Together, this group of treatments is called assisted reproductive technology.

IVF can be done using a couple's own eggs and sperm. Or it may involve eggs, sperm or embryos from a known or unknown donor. In some cases, a gestational carrier — someone who has an embryo implanted in the uterus — might be used.

Your chances of having a healthy baby using IVF depend on many factors, such as your age and the cause of infertility. What's more, IVF involves getting procedures that can be time-consuming, expensive and invasive. If more than one embryo is placed in the uterus, it can result in a pregnancy with more than one baby. This is called a multiple pregnancy.

Your health care team can help you understand how IVF works, what the risks are and whether it's right for you.

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Why it's done

In vitro fertilization is a treatment for infertility or genetic problems. Before you have IVF to treat infertility, you and your partner might be able to try other treatment options that involve fewer or no procedures that enter the body. For example, fertility drugs can help the ovaries make more eggs. And a procedure called intrauterine insemination places sperm directly in the uterus near the time when an ovary releases an egg, called ovulation.

Sometimes, IVF is offered as a main treatment for infertility in people over the age of 40. It also can be done if you have certain health conditions. For example, IVF may be an option if you or your partner has:

• Fallopian tube damage or blockage. Eggs move from the ovaries to the uterus through the fallopian tubes. If both tubes get damaged or blocked, that makes it hard for an egg to be fertilized or for an embryo to travel to the uterus.
• Ovulation disorders. If ovulation doesn't happen or doesn't occur often, fewer eggs are available to be fertilized by sperm.
• Endometriosis. This condition happens when tissue that's like the lining of the uterus grows outside of the uterus. Endometriosis often affects the ovaries, uterus and fallopian tubes.
• Uterine fibroids. Fibroids are tumors in the uterus. Most often, they're not cancer. They're common in people in their 30s and 40s. Fibroids can cause a fertilized egg to have trouble attaching to the lining of the uterus.
• Previous surgery to prevent pregnancy. An operation called tubal ligation involves having the fallopian tubes cut or blocked to prevent pregnancy for good. If you wish to conceive after tubal ligation, IVF may help. It might be an option if you don't want or can't get surgery to reverse tubal ligation.
• Issues with sperm. A low number of sperm or unusual changes in their movement, size or shape can make it hard for sperm to fertilize an egg. If medical tests find issues with sperm, a visit to an infertility specialist might be needed to see if there are treatable problems or other health concerns.
• Unexplained infertility. This is when tests can't find the reason for someone's infertility.
• A genetic disorder. If you or your partner is at risk of passing on a genetic disorder to your child, your health care team might recommend getting a procedure that involves IVF . It's called preimplantation genetic testing. After the eggs are harvested and fertilized, they're checked for certain genetic problems. Still, not all of these disorders can be found. Embryos that don't appear to contain a genetic problem can be placed in the uterus.

A desire to preserve fertility due to cancer or other health conditions. Cancer treatments such as radiation or chemotherapy can harm fertility. If you're about to start treatment for cancer, IVF could be a way to still have a baby in the future. Eggs can be harvested from their ovaries and frozen for later use. Or the eggs can be fertilized and frozen as embryos for future use.

People who don't have a working uterus or for whom pregnancy poses a serious health risk might choose IVF using another person to carry the pregnancy. The person is called a gestational carrier. In this case, your eggs are fertilized with sperm, but the embryos that result are placed in the gestational carrier's uterus.

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IVF raises the chances of certain health problems. From short term to longer term, these risks include:

• Stress. IVF can be draining for the body, mind and finances. Support from counselors, family and friends can help you and your partner through the ups and downs of infertility treatment.
• Complications from the procedure to retrieve eggs. After you take medicines to spur the growth of sacs in the ovaries that each contain an egg, a procedure is done to collect the eggs. This is called egg retrieval. Ultrasound images are used to guide a long, thin needle through the vagina and into the sacs, also called follicles, to harvest the eggs. The needle could cause bleeding, infection or damage to the bowel, bladder or a blood vessel. Risks are also linked with medicines that can help you sleep and prevent pain during the procedure, called anesthesia.

Ovarian hyperstimulation syndrome. This is a condition in which the ovaries become swollen and painful. It can be caused by receiving shots of fertility medicines, such as human chorionic gonadotropin (HCG), to trigger ovulation.

Symptoms often last up to a week. They include mild belly pain, bloating, upset stomach, vomiting and diarrhea. If you become pregnant, your symptoms might last a few weeks. Rarely, some people get a worse form of ovarian hyperstimulation syndrome that also can cause rapid weight gain and shortness of breath.

• Miscarriage. The rate of miscarriage for people who conceive using IVF with fresh embryos is similar to that of people who conceive naturally — about 15% for pregnant people in their 20s to over 50% for those in their 40s. The rate rises with the pregnant person's age.
• Ectopic pregnancy. This is a condition in which a fertilized egg attaches to tissue outside the uterus, often in a fallopian tube. The embryo can't survive outside the uterus, and there's no way to continue the pregnancy. A small percentage of people who use IVF will have an ectopic pregnancy.
• Multiple pregnancy. IVF raises the risk of having more than one baby. Becoming pregnant with multiple babies carries higher risks of pregnancy-related high blood pressure and diabetes, early labor and delivery, low birth weight, and birth defects than does pregnancy with a single baby.
• Birth defects. The age of the mother is the main risk factor for birth defects, no matter how the child is conceived. But assisted reproductive technologies such as IVF are linked with a slightly higher risk of a baby being born with heart issues, digestive problems or other conditions. More research is needed to find out if it's IVF that causes this raised risk or something else.
• Premature delivery and low birth weight. Research suggests that IVF slightly raises the risk that the baby will be born early or with a low birth weight.
• Cancer. Some early studies suggested that certain medicines used to stimulate egg growth might be linked with getting a specific type of ovarian tumor. But more-recent studies do not support these findings. There doesn't seem to be a significantly higher risk of breast, endometrial, cervical or ovarian cancer after IVF .

How you prepare

To get started, you'll want to find a reputable fertility clinic. If you live in the United States, the Centers for Disease Control and Prevention and the Society for Assisted Reproductive Technology provide information online about clinics' individual pregnancy and live birth rates.

A fertility clinic's success rate depends on many things. These include the ages and medical issues of people they treat, as well as the clinic's treatment approaches. When you talk with a representative at a clinic, also ask for detailed information about the costs of each step of the procedure.

Before you start a cycle of IVF using your own eggs and sperm, you and your partner will likely need various screening tests. These include:

• Ovarian reserve testing. This involves getting blood tests to find out how many eggs are available in the body. This is also called egg supply. The results of the blood tests, often used together with an ultrasound of the ovaries, can help predict how your ovaries will respond to fertility medicines.
• Semen analysis. Semen is the fluid that contains sperm. An analysis of it can check the amount of sperm, their shape and how they move. This testing may be part of an initial fertility evaluation. Or it might be done shortly before the start of an IVF treatment cycle.
• Infectious disease screening. You and your partner will both be screened for diseases such as HIV .
• Practice embryo transfer. This test doesn't place a real embryo in the uterus. It may be done to figure out the depth of your uterus. It also helps determine the technique that's most likely to work well when one or more actual embryos are inserted.
• Uterine exam. The inside lining of the uterus is checked before you start IVF . This might involve getting a test called sonohysterography. Fluid is sent through the cervix into the uterus using a thin plastic tube. The fluid helps make more-detailed ultrasound images of the uterine lining. Or the uterine exam might include a test called hysteroscopy. A thin, flexible, lighted telescope is inserted through the vagina and cervix into the uterus to see inside it.

Before you begin a cycle of IVF , think about some key questions, including:

How many embryos will be transferred? The number of embryos placed in the uterus often is based on age and the number of eggs collected. Since the rate of fertilized eggs attaching to the lining of uterus is lower for older people, usually more embryos are transferred — except for people who use donor eggs from a young person, genetically tested embryos or in certain other cases.

Most health care professionals follow specific guidelines to prevent a multiple pregnancy with triplets or more. In some countries, legislation limits the number of embryos that can be transferred. Make sure you and your care team agree on the number of embryos that will be placed in the uterus before the transfer procedure.

What will you do with any extra embryos? Extra embryos can be frozen and stored for future use for many years. Not all embryos will survive the freezing and thawing process, but most will.

Having frozen embryos can make future cycles of IVF less expensive and less invasive. Or you might be able to donate unused frozen embryos to another couple or a research facility. You also might choose to discard unused embryos. Make sure you feel comfortable making decisions about extra embryos before they are created.

• How will you handle a multiple pregnancy? If more than one embryo is placed in your uterus, IVF can cause you to have a multiple pregnancy. This poses health risks for you and your babies. In some cases, a surgery called fetal reduction can be used to help a person deliver fewer babies with lower health risks. Getting fetal reduction is a major decision with ethical, emotional and mental risks.
• Have you thought through the risks linked with using donor eggs, sperm or embryos, or a gestational carrier? A trained counselor with expertise in donor issues can help you understand the concerns, such as the legal rights of the donor. You also may need an attorney to file court papers to help you become legal parents of an embryo that's developing in the uterus.

What you can expect

After the preparations are completed, one cycle of IVF can take about 2 to 3 weeks. More than one cycle may be needed. The steps in a cycle go as follows:

Treatment to make mature eggs

The start of an IVF cycle begins by using lab-made hormones to help the ovaries to make eggs — rather than the single egg that usually develops each month. Multiple eggs are needed because some eggs won't fertilize or develop correctly after they're combined with sperm.

Certain medicines may be used to:

• Stimulate the ovaries. You might receive shots of hormones that help more than one egg develop at a time. The shot may contain a follicle-stimulating hormone (FSH), a luteinizing hormone (LH) or both.
• Help eggs mature. A hormone called human chorionic gonadotropin (HCG), or other medicines, can help the eggs ripen and get ready to be released from their sacs, called follicles, in the ovaries.
• Delay ovulation. These medicines prevent the body from releasing the developing eggs too soon.
• Prepare the lining of the uterus. You might start to take supplements of the hormone progesterone on the day of the procedure to collect your eggs. Or you might take these supplements around the time an embryo is placed in the uterus. They improve the odds that a fertilized egg attaches to the lining of your uterus.

Your doctor decides which medicines to use and when to use them.

Most often, you'll need 1 to 2 weeks of ovarian stimulation before your eggs are ready to be collected with the egg retrieval procedure. To figure out when the eggs are ready, you may need:

• Vaginal ultrasound, an imaging exam of the ovaries to track the developing follicles. Those are the fluid-filled sacs in the ovaries where eggs mature.
• Blood tests, to check on how you respond to ovarian stimulation medicines. Estrogen levels often rise as follicles develop. Progesterone levels remain low until after ovulation.

Sometimes, IVF cycles need to be canceled before the eggs are collected. Reasons for this include:

• Not enough follicles develop.
• Ovulation happens too soon.
• Too many follicles develop, raising the risk of ovarian hyperstimulation syndrome.
• Other medical issues happen.

If your cycle is canceled, your care team might recommend changing medicines or the amounts you take, called doses. This might lead to a better response during future IVF cycles. Or you may be advised that you need an egg donor.

Egg retrieval

This is the procedure to collect the eggs from one or both ovaries. It takes place in your doctor's office or a clinic. The procedure is done 34 to 36 hours after the final shot of fertility medicine and before ovulation.

• Before egg retrieval, you'll be given medicine to help you relax and keep you from feeling pain.
• An ultrasound device is placed into the vagina to find follicles. Those are the sacs in the ovaries that each contain an egg. Then a thin needle is inserted into an ultrasound guide to go through the vagina and into the follicles to collect the eggs. This process is called transvaginal ultrasound aspiration.
• If your ovaries can't be reached through the vagina this way, an ultrasound of the stomach area may be used to guide the needle through the stomach and into the ovaries.
• The eggs are removed from the follicles through a needle connected to a suction device. Multiple eggs can be removed in about 20 minutes.
• After the procedure, you may have cramping and feelings of fullness or pressure.
• Mature eggs are placed in a liquid that helps them develop. Eggs that appear healthy and mature will be mixed with sperm to attempt to create embryos. But not all eggs are able to be fertilized with success.

Sperm retrieval

If you're using your partner's sperm, a semen sample needs to be collected at your doctor's office or clinic the morning of egg retrieval. Or sperm can be collected ahead of time and frozen.

Most often, the semen sample is collected through masturbation. Other methods can be used if a person can't ejaculate or has no sperm in the semen. For example, a procedure called testicular aspiration uses a needle or surgery to collect sperm directly from the testicle. Sperm from a donor also can be used. Sperm are separated from the semen fluid in the lab.

Fertilization

Two common methods can be used to try to fertilize eggs with sperm:

• Conventional insemination. Healthy sperm and mature eggs are mixed and kept in a controlled environment called an incubator.
• Intracytoplasmic sperm injection (ICSI). A single healthy sperm is injected right into each mature egg. Often, ICSI is used when semen quality or number is an issue. Or it might be used if fertilization attempts during prior IVF cycles didn't work.

In certain situations, other procedures may be recommended before embryos are placed in the uterus. These include:

Assisted hatching. About 5 to 6 days after fertilization, an embryo "hatches" from the thin layer that surrounds it, called a membrane. This lets the embryo attach to the lining of the uterus.

If you're older and you want to get pregnant, or if you have had past IVF attempts that didn't work, a technique called assisted hatching might be recommended. With this procedure, a hole is made in the embryo's membrane just before the embryo is placed in the uterus. This helps the embryo hatch and attach to the lining of the uterus. Assisted hatching is also useful for eggs or embryos that were frozen, as that process can harden the membrane.

Preimplantation genetic testing. Embryos are allowed to develop in the incubator until they reach a stage where a small sample can be removed. The sample is tested for certain genetic diseases or the correct number of threadlike structures of DNA, called chromosomes. There are usually 46 chromosomes in each cell. Embryos that don't contain affected genes or chromosomes can be transferred to the uterus.

Preimplantation genetic testing can lower the chances that a parent will pass on a genetic problem. It can't get rid of the risk completely. Prenatal testing may still be recommended during pregnancy.

Embryo transfer

Egg-retrieval technique

Typically, transvaginal ultrasound aspiration is used to retrieve eggs. During this procedure, an ultrasound probe is inserted into the vagina to identify follicles. A needle is guided through the vagina and into the follicles. The eggs are removed from the follicles through the needle, which is connected to a suction device.

In intracytoplasmic sperm injection (ICSI), a single healthy sperm is injected directly into each mature egg. ICSI often is used when semen quality or number is a problem or if fertilization attempts during prior in vitro fertilization cycles failed.

Three days after fertilization, a healthy embryo will contain about 6 to 10 cells. By the fifth or sixth day, the fertilized egg is known as a blastocyst — a rapidly dividing ball of cells. The inner group of cells will become the embryo. The outer group will become the cells that nourish and protect it.

The procedure to place one or more embryos in the uterus is done at your doctor's office or a clinic. It often takes place 2 to 6 days after eggs are collected.

• You might be given a mild sedative to help you relax. The procedure is often painless, but you might have mild cramping.
• A long, thin, flexible tube called a catheter is placed into the vagina, through the cervix and into the uterus.
• A syringe that contains one or more embryos in a small amount of fluid is attached to the end of the catheter.
• Using the syringe, the embryo or embryos are placed into the uterus.

If the procedure works, an embryo will attach to the lining of your uterus about 6 to 10 days after egg retrieval.

After the procedure

After the embryo transfer, you can get back to your usual daily routine. Your ovaries may still be enlarged, so vigorous activities or sex might cause discomfort. Ask your care team how long you should stay away from these.

Typical side effects include:

• Passing a small amount of clear or bloody fluid shortly after the procedure. This is due to the swabbing of the cervix before the embryo transfer.
• Breast tenderness due to high estrogen levels.
• Mild bloating.
• Mild cramping.
• Constipation.

Call your care team if you have moderate or severe pain, or heavy bleeding from the vagina after the embryo transfer. You'll likely to need to get checked for complications such as infection, twisting of an ovary and ovarian hyperstimulation syndrome.

At least 12 days after egg retrieval, you get a blood test to find out whether you're pregnant.

• If you're pregnant, you'll likely be referred to an obstetrician or other pregnancy specialist for prenatal care.
• If you're not pregnant, you'll stop taking progesterone and likely get your period within a week. Call your care team if you don't get your period or if you have unusual bleeding. If you'd like to try another cycle of IVF , your care team might suggest steps you can take to improve your chances of getting pregnant next time.

The chances of giving birth to a healthy baby after using IVF depend on various factors, including:

• Maternal age. The younger you are, the more likely you are to get pregnant and give birth to a healthy baby using your own eggs during IVF . Often, people 40 and older are counseled to think about using donor eggs during IVF to boost the chances of success.
• Embryo status. Transfer of embryos that are more developed is linked with higher pregnancy rates compared with less-developed embryos. But not all embryos survive the development process. Talk with your care team about your specific situation.
• Reproductive history. People who've given birth before are more likely to be able to get pregnant using IVF than are people who've never given birth. Success rates are lower for people who've already tried IVF multiple times but didn't get pregnant.
• Cause of infertility. Having an average supply of eggs raises your chances of being able to get pregnant using IVF . People who have severe endometriosis are less likely to be able to get pregnant using IVF than are those who have infertility without a clear cause.
• Lifestyle factors. Smoking can lower the chance of success with IVF . Often, people who smoke have fewer eggs retrieved during IVF and may miscarry more often. Obesity also can lower the chances of getting pregnant and having a baby. Use of alcohol, drugs, too much caffeine and certain medicines also can be harmful.

Talk with your care team about any factors that apply to you and how they may affect your chances of a successful pregnancy.

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• ART: Step-by-step guide. American Society for Reproductive Medicine. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/art-step-by-step-guide/. Accessed Feb. 27, 2023.
• Anchan RM, et al. Gestational carrier pregnancy. https://www.uptodate.com/contents/search. Accessed Feb. 23, 2023.
• Infertility fact sheet. Office on Women's Health. http://www.womenshealth.gov/publications/our-publications/fact-sheet/infertility.html. Accessed Feb. 23, 2023.
• Ho J. In vitro fertilization. https://www.uptodate.com/contents/search. Accessed Feb. 23, 2023.
• FAQs: IVF. Society for Assisted Reproductive Technology. https://www.sart.org/patients/frequently-asked-questions/. Accessed Feb. 23, 2023.
• FAQs: Infertility. Centers for Disease Control and Prevention. http://www.cdc.gov/reproductivehealth/Infertility/. Accessed Feb. 23, 2023.
• FAQs: Evaluating infertility. American College of Obstetricians and Gynecologists. https://www.acog.org/Patients/FAQs/Evaluating-Infertility. Accessed Feb. 23, 2023.
• Ovarian hyperstimulation. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/stimulation/ovarian-hyperstimulation-syndrome/. Accessed Feb. 23, 2023.
• Guidance on the limits to the number of embryos to transfer: A committee opinion. Practice Committee of the American Society for Reproductive Medicine and the Practice Committee for the Society for Assisted Reproductive Technologies. https://www.asrm.org/news-and-publications/practice-committee-documents/. Accessed March 1, 2023.
• In vitro fertilization (IVF): What are the risks? American Society for Reproductive Medicine. https://www.sart.org/patients/risks-of-ivf/ Accessed Feb. 2, 2024.
• Preparing for IVF: Emotional considerations. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/preparing-for-ivf-emotional-considerations/. Accessed March 1, 2023.
• Micromanipulation. Society for Assisted Reproductive Technology. https://www.sart.org/patients/a-patients-guide-to-assisted-reproductive-technology/general-information/micromanipulation/. Accessed March 1, 2023.
• Preparing for in vitro fertilization (IVF): Lifestyle factors. Society for Assisted Reproductive Technology. https://www.sart.org/patients/fyi-videos/preparing-for-in-vitro-fertilization-ivf-lifestyle-factors/. Accessed March 1, 2023.
• Ubaldi FM, et al. Advanced maternal age in IVF: Still a challenge? The present and the future of its treatment. Frontiers in Endocrinology. 2019;10:94.
• Can I freeze my eggs to use later if I'm not sick? American Society for Reproductive Medicine. https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/can-i-freeze-my-eggs-to-use-later-if-im-not-sick/. Accessed Feb. 24, 2023.
• Medications for inducing ovulation: A guide for patients. American Society for Reproductive Medicine. https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/medications-for-inducing-ovulation-booklet/. Accessed Feb. 24, 2023.
• In vitro fertilization (IVF): What are the risks? American Society for Reproductive Medicine. https://www.reproductivefacts.org/news-and-publications/patient-fact-sheets-and-booklets/documents/fact-sheets-and-info-booklets/in-vitro-fertilization-ivf-what-are-the-risks/. Accessed Feb. 24, 2023.
• Commonly asked questions about the US national ART surveillance system. Centers for Disease Control and Prevention. https://www.cdc.gov/art/reports/2019/commonly-asked-questions.html. Accessed Feb. 27, 2023.
• Evaluation before IVF. Society for Assisted Reproductive Technology. https://www.sart.org/patients/sart-patient-evaluation/. Accessed Feb. 27, 2023.
• Multifetal pregnancy reduction. The American College of Obstetricians and Gynecologists. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/09/multifetal-pregnancy-reduction. Accessed Feb. 27, 2023.
• Third party reproduction. Society for Assisted Reproductive Technology. https://www.sart.org/patients/third-party-reproduction/. Accessed Feb. 27, 2023.
• Ho J. In vitro fertilization: Overview of clinical issues and questions. https://www.uptodate.com/contents/search. Accessed Feb. 27, 2023.
• American Society for Reproductive Medicine. Fertility drugs and cancer: A guideline. Fertility and Sterility. 2016; doi:10.1016/j.fertnstert.2016.08.035.
• Bart CJM. Overview of ovulation induction. https://www.uptodate.com/contents/search. Accessed March 2, 2023.
• Gershenson DM, et al. In vitro fertilization. In: Comprehensive Gynecology. 8th ed. Elsevier; 2022. https://www.clinicalkey.com. Accessed March 2, 2023.
• Barcroft JF, et al. Fertility treatment and cancers-the eternal conundrum: A systematic review and meta-analysis. Human Reproduction. 2021; doi:10.1093/humrep/deaa293.
• Hornstein MD, et al. Endometriosis: Treatment of infertility in females. https://www.uptodate.com/contents/search. Accessed March 2, 2023.
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Information for the public: the nobel prize in physiology or medicine 2010 (pdf), populärvetenskaplig information: nobelpriset i fysiologi eller medicin år 2010 (pdf).

The Nobel Prize in Physiology or Medicine 2010 is awarded to Robert G. Edwards “for the development of in vitro fertilization”

Robert Edwards is awarded the 2010 Nobel Prize for the development of human in vitro fertilization (IVF) therapy. His achievements have made it possible to treat infertility, a medical condition afflicting a large proportion of humanity including more than ten percent of all couples worldwide.

A newborn baby appeared on the front pages of newspapers all over the world 27 July 1978. A baby girl in perfect health who was going to be named Louise: what was so sensational about that? It was the way she had been conceived. For the first time ever, a child had been born after “test tube fertilization” of a woman who had been diagnosed as infertile.

Until then the possibilities of treating infertility had been limited. The understanding of the fertilization process was incomplete and those who suffered an inability to conceive a child usually faced life-long disappointment.

Infertility – a medical and psychological problem

A question of timing

At the beginning of the 1950s Robert Edwards was working on his doctoral thesis at the University of Edinburgh in Scotland. His topic was reproduction in mice. He spent many hours in the laboratory – frequently at night, because that was when the mice usually ovulated. It was there he got his idea for future treatment of infertility: maybe the problem could be solved by lifting human fertilization from inside the body out into a Petri dish? In that way the fertilization process could be helped along and the obstacles that most frequently cause infertility could be circumvented.

After moving to London at the end of the 1950s and starting to do research on human reproduction, Robert Edwards found an opportunity to test his ideas. With the help of a gynaecologist he gained access to small pieces of ovarian tissue from which he could isolate a few undeveloped egg cells, oocytes. If the oocytes were to be fertilized, he first needed to get them to mature – a process that occurs naturally inside a woman’s body every month but that would turn out to be difficult to replicate in the laboratory.

Other researchers had succeeded in getting oocytes from rabbits to mature and had also managed to fertilize them. But these methods did not work on human oocytes, which clearly followed a different life cycle. Robert Edwards tried everything, repeatedly adjusting hormone levels, culture media and time schedules, but the precious oocytes refused to emerge from their quiescent state and become receptive to fertilization. The work was also impeded by a constant lack of oocytes. After several years’ work and a move to Cambridge, Edwards finally found the decisive piece of the puzzle. One problem had been that human oocyte development followed an unknown schedule that differed from those of all the other animal species he had studied. It dawned on Edwards that human egg cells required an entire day and night to mature – twice as long as rabbit oocytes. He had now discovered the window of opportunity during which fertilization was possible.

The first test tube fertilization

With this discovery, the way to IVF lay open. Robert Edwards, in collaboration with various colleagues, had learned to control the oocyte’s maturation so that it would be ready for fertilization outside the body. He had also defined under which conditions spermatozoa become activated and can fertilize the egg. On 15 February 1969 the results were presented in an article in the journal Nature, authored by Robert Edwards and his co-workers. The summary on the first page of the article stated modestly: “Human oocytes have been matured and fertilized by spermatozoa in vitro. There may be certain clinical and scientific use for human eggs fertilized by this procedure.”

The reactions, however, were anything but modest. At the time, this research and the plans for IVF treatment aroused fascination but also public debate, and the Physiology laboratory at the University of Cambridge was invaded by journalists who wanted to interview Robert Edwards.

Fruitful collaboration

Though advances had been made, a problem remained: fertilized eggs stopped developing after a single cell division, and this probably had something to do with the oocytes having matured in the laboratory. Robert Edwards realized that the only way forward would be to use eggs that had been allowed to mature in the ovary before being taken out. To get hold of such cells he initiated collaboration with gynaecologist Patrick Steptoe at the district hospital in Oldham. Steptoe was a pioneer in the new field of laparoscopic surgery, which appeared ideal for Edwards’ purpose.

Patrick Steptoe was the clinician who worked with Robert Edwards to develop IVF from experimental technique to medical therapy. Women were first treated with hormones to stimulate maturation of several eggs in their ovaries. Then, using laparoscopic techniques, Patrick Steptoe extracted several eggs from the ovaries; Robert Edwards put these oocytes in culture dishes and mixed them with spermatozoa. The fertilized eggs now divided several times and developed into early embryos consisting of eight cells.

Research against the wind

Everything looked promising but the research grew increasingly controversial. Several bishops and ethicists demanded that the project be stopped, whereas others supported it. Critics considered the research ethically questionable; one of their concerns was that children conceived through IVF might have birth defects. Large parts of the scientific establishment also disapproved of the research. The British Medical Research Council questioned both the safety and the long-term usefulness of infertility treatment and turned down an application for research funding.

Robert Edwards viewed these ethical questions with profound earnestness. Early on, he wrote articles about the issue and advocated implementation of strict ethical guidelines for research on human stem cells and embryos. However, he considered the risks of IVF to be small and was determined to bring his work to fruition. A private donation enabled the project to continue after other funding had been withdrawn.

The birth of Louise Brown

Robert Edwards and Patrick Steptoe were now working hard to get past the last obstacle: transferring the fertilized egg back into the woman so a pregnancy could be established. At this time Robert Edwards travelled constantly back and forth between Cambridge and Patrick Steptoe’s workplace at the hospital in Oldham, nearly 300 km away. After more than a hundred failed attempts to establish a pregnancy, they decided to skip the hormone treatment aimed to stimulate the woman’s ovaries to produce several mature oocytes. Instead, they would rely on the single oocyte that matures in the course of a natural menstrual cycle. By analysing the patient’s hormone levels they were able to pinpoint the optimal time for fertilization and increase the likelihood that a child would be conceived.

In November 1977, Lesley and John Brown came to the clinic after nine years of unsuccessful attempts to have a child. An oocyte was fertilized in the test tube and when it had developed into an embryo with eight cells, it was reimplanted in the mother-to-be. The resulting pregnancy went to term and the world’s first test tube baby, Louise Brown, was born by caesarean section 25 July 1978.

The world’s first IVF centre

To everyone’s relief, Louise Brown was in perfect health. On 4 July 1979 the feat was repeated with the birth of the world’s second IVF baby, a boy. But the research granting agencies were still sceptical and reluctant to help Robert Edwards and Patrick Steptoe open a clinic where the technique could be refined. Once again, they moved forward with private financing.

In an idyllic manor house in the village of Bourn on the outskirts of Cambridge they now opened Bourn Hall Clinic – the world’s first IVF centre. At Bourn Hall, Robert Edwards and Patrick Steptoe were to develop their techniques, simultaneously training gynaecologists and cell biologists from all over the world. The world’s first ethical committee for issues related to assisted conception was also established to serve as a sounding board for these activities. In the 1980s the IVF technique gained wider acceptance and the number of IVF babies grew ever larger. In 1986, one thousand children had been born after IVF at Bourn Hall: about half of all the IVF babies in the world. Patrick Steptoe remained Medical Director of Bourn Hall Clinic until his death in 1988, and Robert Edwards was its Research Director until he retired.

IVF is improved and spreads around the world

The IVF technique is now established worldwide and has undergone several important improvements. For one thing, individual spermatozoa can now be injected directly into an oocyte in the culture dish, which gives men with defective sperm production a better chance of having children. Ultrasound is used to identify egg follicles that may contain mature eggs, and eggs are now removed from the follicles through a fine needle rather than laparoscopically.

Oocytes and embryos produced with IVF can now be frozen and saved for later use. Scientists are currently developing techniques that enable use of immature or mature frozen oocytes for IVF, a method that would help ensure that women at risk of ovary damage (e.g. because of cancer therapy) will be able to have children later in life.

IVF is a safe and effective treatment. Between 20 and 30 percent of the fertilized eggs eventually develop into live-born children and the majority of all infertile women treated with IVF succeed in having a child. The risk of complications, such as premature birth, is small provided only one egg is implanted. Long-term follow-up of IVF children has shown them to be just as healthy as other children. So far, around four million children have been born thanks to IVF. Louise Brown and other IVF children have given birth to healthy children of their own, and this is perhaps the best proof of the success and safety of the IVF technique.

Millions have benefitted

It is not always immediately obvious how society will benefit from scientific discoveries. But Robert Edwards’ research attracted public attention right from the start and its positive impact on people’s lives is now almost unparalleled. Millions of people would not even exist were it not for Robert Edwards’ contributions, and even more owe him thanks for a long-awaited child or a cherished sibling.

The Laureate

Robert g. edwards robert g. edwards was born in 1925 in batley, yorkshire, uk. for most of his academic career in reproductive physiology, he worked in cambridge, england, where he and his co-workers also established the world’s first ivf centre, bourn hall clinic. robert edwards is now emeritus professor at the university of cambridge., the editorial committee for this year’s popular presentation of the nobel prize in physiology or medicine included the following scientific advisors, all professors at karolinska institutet: göran k hansson, medicine, secretary of the nobel assembly; outi hovatta, obstetrics and gynaecology; christer höög, genetics; klas kärre, immunology, chairman of the nobel committee; hugo lagercrantz, paediatrics; urban lendahl, genetics., text: ola danielsson, medical journalist translation: janet holmén, editor illustrations and layout: mattias karlén, © the nobel committee for physiology or medicine, karolinska institutet, nobel prizes and laureates, nobel prizes 2023.

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Harris Is Good on Abortion Rights. Now She Needs to Take It to 11.

By Cecile Richards

Ms. Richards is a former president of Planned Parenthood.

Among the many critical issues at stake in the 2024 election, one will be central for many Americans: Whom do you trust to make medical decisions — women and their doctors, or Donald Trump and JD Vance?

Vice President Kamala Harris cast the issue of abortion in stark relief in her first debate with former President Trump last week, striking a chord with voters across political lines . Ms. Harris’s answers on abortion emerged as her strongest moments onstage in a strong night for her overall — and provided a glimpse of a winning strategy for this election.

That involves the Harris-Walz ticket turning the volume up to 11 on abortion. Ms. Harris, Gov. Tim Walz and their campaign surrogates must keep emphasizing — on the stump, in ads and at every chance they get — how Mr. Trump and Mr. Vance are impossible to trust on these issues.

They must refuse to let Mr. Trump and other Republicans suggest that leaving decisions about abortion up to the states is a benign proposition and continue to point to the wide-ranging impact of abortion bans on pregnancy care , miscarriage treatment and training opportunities for an entire generation of doctors.

Ms. Harris would do well, even, to devote an entire speech to the issue, laying out her plan to take action in support of abortion rights, with or without Congress.

At the same time, she should keep deploying campaign surrogates such as Kaitlyn Joshua , a mother from Baton Rouge, La., who described being denied care at not one but two emergency rooms in the midst of a painful miscarriage because of her state’s abortion ban. Personal stories like these can break through and reach voters more effectively than any campaign talking point. According to PerryUndem , a research and polling firm, exposure to these stories is helping to shift public opinion in support of reproductive rights — an imperative in this election and beyond.

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Use of in vitro fertilization—ethical issues

Kjell asplund.

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

This report is an ethical analysis based on both facts and values. In in vitro fertilization (IVF), there is an intricate interaction between rapid scientific development and changing societal values. In most countries, the ethical discussion is no longer on whether or not IVF in itself is ethically justifiable. Therefore, in this review, I discuss other ethical aspects that have emerged since IVF was first introduced, such as upper age limits, ‘ownership’ of gametes and embryos, IVF in single women and same-sex couples, preimplantatory genetic testing, social egg freezing, commercialization, public funding, and prioritization of IVF. Despite secularization, since religion still plays an important role in regulation and practices of IVF in many countries, positions on IVF among the world religions are summarized. Decision-making concerning IVF cannot be based only on clinical and economic considerations; these cannot be disentangled from ethical principles. Many concerns regarding the costs, effects, and safety of IVF subtly transcend into more complex questions about what it means to society to bear and give birth to children.

Introduction

Ethics is about the systematic reflection on human values and actions. Simplistically, the two principal components of an ethical analysis are facts and values. When facts and values change, the ethical analysis must be revised.

In vitro fertilization (IVF) is an illustrative case of this dynamic process. In some aspects, the expansion of scientific information has made decision-making easier; it has left less room for opinions and speculations, and facilitated evidence-based regulations and clinical recommendations. On the other hand, rapid technological development has implied a number of new ethical challenges.

Since medical ethics has a history that goes back to the Hippocratic principles, it would be easy to conclude that values are, or should be, unwavering. It is then thought-provoking to view IVF as an example of how radically societal values and attitudes have changed over the last four decades.

Given the changes in facts and values, the prerequisites for an ethical analysis of IVF are under ongoing evolution. In most countries, the ethical discussion is no longer on whether or not IVF in itself is ethically justifiable. Therefore, the major focus of this article is on new ethical questions that are invoked by biotechnological development or changes in societal values.

The focus of this article is on IVF practices and ethical discussions in Europe and English-speaking countries. This is where most of the scientific literature on ethical issues on IVF originates, but it inevitably means that this article is ethnocentric. Several examples of ethical analyses are taken from my work as Chair of the Swedish Council on Medical Ethics, which advises the Swedish Government and Parliament on medical ethics issues.

I will discuss ethical aspects on upper age limits, ‘ownership’ of stored gametes and embryos, IVF in single women and same-sex couples, preimplantatory genetic diagnosis, social egg freezing, egg sharing, surrogacy, commercialization, public funding, and prioritization of IVF. Finally, despite secularization, since religion still plays an important role in the regulation and practices of IVF in many countries, positions on IVF among the world religions are summarized.

Brief historical notes

The ethical controversy over IVF had already started when the results of the first animal IVF experiments were published in the mid-1930s (the results were later contested). While some commentators saw it as a promising development to help infertile couples, others were critical, saying that the scientists were playing God ( 1 ). It is interesting to note that the animal experiments evoked eugenic questions that were in focus at the time. In a 1936 article in New York Times , it was stated: ‘Advocates of “race betterment” might urge such procedures for men and women of special aptitudes, physical, mental, or spiritual’ (cited by Biggers ( 1 )). In the press, there was speculation, repulsive in nature, on both surrogacy and a world where men were not needed for reproduction: ‘The mythical land of the Amazons would then come to life’ ( 1 ).

In 1978, when the first child was born after IVF in the UK, the negative ethical comments of the 1930s were reiterated with more fervour. The protests seem to have been particularly strong when attempts were made to introduce IVF in the USA. John Biggers, one of the IVF pioneers, recalled memories from a public hearing arranged by the state of Virginia: ‘The entire meeting turned out to be a shouting match, the two groups [“pro-lifers” and IVF proponents] hurling insults at each other’ ( 1 ).

In the 40 years since the first successful human IVF, enormous experience and scientific knowledge have accumulated. Few of the fears of negative effects have been met. Values have changed, partly because more facts are available, but also due to general trends in values in many populations, secularization perhaps being the most important. Today, the principal resistance to IVF as such rests mainly in Catholic and Orthodox Christian settings. The philosophical argument that being born is better than not being born has also been invoked in the IVF debate (the opposing view is abundantly present in philosophy as well as religion, for example elaborated by the philosopher David Benatar in his book Better Never to Have Been: The Harm of Coming into Existence ( 2 )).

Upper-middle-age women who give birth to a child after IVF are often subject to public opinion on how ‘unfitting’, ‘unnatural’, and even ‘repulsive’ this is. Table 1 summarizes the principal arguments for and against a fixed upper age limit for IVF in older women. In the public debate, the age limit discussed is usually in the 40–50-year age range.

Four common arguments supporting and four arguments against an upper maternal age limit for IVF.

Thus, the arguments concern both facts and values. The likelihood of outcomes such as successful pregnancy or the death of the mother before the child is able to support itself are examples of fact-based arguments, as are the consequences of the outcomes. The most obvious value-based arguments are the right of children to be brought up under safe conditions and women’s reproductive autonomy.

Some arguments are based on both facts and values. Are older women as good mothers as younger women? The answer may be value-based, but it may also be based on the scientific information available. There have been reports that children born to mothers above the age of 35 or 40 do not have increased physical or mental vulnerability, but a modest increase in vulnerability has also been reported at maternal ages above 35 ( 3 ). Yet, at maternal ages above 35 or 40 years, child vulnerability still seems to be consistently lower than that in children born to very young mothers ( 3 ).

Compared to upper age limits for the mother, there has been little discussion on age limits for the father. Men are, on average, older than women when they become parents and have a somewhat shorter life expectancy than women. Therefore, the argument of being able to take responsibility for a child until adulthood would apply equally, if not more, to men as to women.

After considering basic ethical principles and the large variations in individual prerequisites, both medically and socially, the Swedish Council on Medical Ethics has recommended that there should be no strict upper age limit for publicly funded IVF ( 4 ). Instead, individual assessments should be made, taking into consideration biological rather than chronological age. The needs of the child are emphasized: at least one parent should be young enough to take responsibility for the child until adulthood.

When political decisions are made, other ethical values and non-ethical factors may play a major role. In 2016, public healthcare providers in Sweden agreed to apply a national upper age limit for publicly funded IVF ( 5 ). The age limit was set at 40 years in women and 56 years in men. Stored embryos could be used up to a maternal age of 45. A major reason for this decision was to eliminate the then-existing regional variations in age limits. The principles of fairness, cost-effectiveness, and simplicity in decision-making seem to have overridden other ethical principles, most importantly reproductive autonomy and non-discrimination by age. In Swedish private practice with out-of-pocket payments, more variable age limits are applied, usually well above 40 years.

In most countries, there are no national age limits for IVF, and practices vary. In the UK, for instance, public funding is decided locally by Clinical Commissioning Groups (CCGs), with different practices across the country. There are, however, healthcare professionals’ guidelines that recommend that women up to the age of 40 should be offered three cycles of IVF and women up to the age of 42 one cycle of IVF ( 6 ).

Single women and same-sex couples

The major ethical questions about providing IVF or other forms of assisted reproduction for single women and same-sex couples have concerned the welfare of the child. Ethical arguments for and against IVF in singles and homosexuals that have been discussed are those of fairness, non-discrimination, reproductive autonomy, and children’s well-being.

A systematic literature review (with methodological problems in most of the included studies) compared adolescents born through IVF for single women or women in same-sex partnerships with naturally conceived adolescents. There were no differences in psychological adjustment or parent–adolescent relationships ( 7 ).

Not surprisingly, legal restrictions on IVF and other forms of assisted reproduction for singles and same-sex couples vary between countries. In a survey of legislation in the 28 EU countries published in 2014, medically assisted reproduction (including IVF) for single women was permitted in 11 countries and not allowed in 11 countries, whereas the legal status was undefined in the remaining 6 countries ( 8 ). Since 2014, some countries with a previous ban have modified the legislation to permit IVF for single women. It is difficult to discern a distinct pattern of countries permitting or prohibiting IVF as to traditional values, level of secularity, or extent of self-expression in the population [see World Values Survey ( 9 )].

Some regulatory differences exist even between countries where assisted reproduction is permitted for single women. In Sweden, a child born through gamete donation has the right to know how it was conceived and who is the genetic father and mother; this is based on the principle of autonomy. Some Swedish women prefer to have IVF performed in Denmark, where the anonymity of the sperm donor is ensured.

For female same-sex couples, there is usually no specific legislation; when IVF for single women is allowed, this would also cover female same-sex couples. In a 2013 statement by its ethics committee, the American Society for Reproductive Medicine called for programmes providing IVF and other fertility services to ‘treat all requests for assisted reproduction equally without regard to marital/partner status or sexual orientation’ ( 10 ). In most countries where surrogacy is allowed (or not prohibited by law), IVF with sperm from a homosexual father-to-be may be used for conception of the surrogate mother.

Who ‘owns’ stored gametes and embryos?

Humans have always strived for a form of immortality through our genetic offspring ( 11 ). Gamete storage has now enabled us to plan prospectively, allowing for untimely demise or social reproductive choices. The aim is that our genetic ‘identity’ should continue after our death. Aside from what the deceased person may have wanted, it is often a wish of the family to immortalize their loved one. For the family, use of stored gametes (or embryos) may be a relief from part of the sorrow ( 11 ).

Thus, when gametes are collected and stored before cancer treatment and the patient dies, should the remaining partner have a right to use them for IVF? In practice, this issue occurs when the remaining partner is a woman, but hypothetically a remaining male partner could request to use an egg from a deceased female partner to engage a surrogate mother.

Would a person who stores sperm, eggs, or embryos choose to reproduce after death? Anyone who has decided to store them for future reproduction could perhaps be presumed to have consented. Usually, however, the consent does not involve the event that the person dies. Use of gametes from deceased individuals is currently prohibited by law in France, Germany, Sweden, and other countries, even when there is written consent from the deceased. In the UK, sperm from a deceased person can be used for IVF if there is written consent before death. In the USA, practices vary from clinic to clinic, and written consent is not always required ( 12 ).

Postmortem sperm retrieval (PMSR) raises significant ethical and legal concerns, including issues of implied/presumed consent and the designation of sperm as property. In many countries, the legal situation is not clear. Most commentators seem to agree that a core principle is not to reproduce anyone without his or her permission ( 12 ). Thus, consent should be obtained. In countries where the use of gametes from deceased individuals is prohibited (see above), any use of PMSR would require a modification of the legislation.

Grieving family members are not always in the position to make rational choices. Therefore, some experts have recommended compulsory wait times (up to one year) before using the retrieved sperm for conception.

If a couple who have decided to store embryos for future use splits up and only one of the partners wants to use them (in a hypothetical case, the male partner may want to use the embryos for surrogacy), who ‘owns’ the embryos and has the right to decide (it would be more appropriate to talk about disposal than strict ownership)?

A UK case attracting much public attention may illustrate the ethical and legal complexity. Embryos were stored before oophorectomy in a woman with ovarian cancer ( 13 ). When the couple split up half a year later, the man wanted the embryos to be destroyed. The clinic informed the woman that UK laws requested consent from both partners for storage to continue. The woman brought the case to court, all the way to the Grand Chamber of the European Court of Human Rights. The courts, both British and European, decided against the woman’s wishes (but the decisions were not always unanimous). The legal—and ethical—dilemma was: how to weigh the need for consent from both partners against the right to a family life as enshrined in the European Convention of Human Rights. The Grand Chamber decided that the right to a family life could not override the male partner’s withdrawal of consent ( 13 ). Thus, the principle of consent has strong legal support of the European Court.

IVF and preimplantatory genetic testing (PGT)

The fact that IVF may be used for purposes other than the treatment of infertility evokes additional ethical questions and dilemmas.

In families in which a child with a severe monogenetic disease has previously been born or if there is a high risk of aneuploidy, preimplantation genetic testing (PGT; previously PGD, preimplantation genetic diagnosis) offers a way to escape a pregnancy with a severely diseased child. A possible late-term abortion or the birth and early death of an infant may be avoided. For early-onset severe or lethal monogenetic diseases and structural chromosome rearrangements, the use of PGT is relatively non-controversial ethically.

Other applications of PGT have raised ethical concerns. The most obvious question is: What diseases and aneuploidies should be assessed? Increasingly, PGT is being considered for late-onset, variably penetrant, and less severe conditions.

Even more ethically challenging: could testing be based on non-disease characteristics with genetic influences, such as intelligence and beauty (what has been called ‘preimplantatory genetic profiling’)? The concern that such testing would lead to choosing a child to order, as a commodity that has been designed simply to meet the needs and desires of the parents (‘catalogue babies’), was raised already when PGT was introduced in the 1990s ( 14 ). This prospect has created fears that the increasing frequency of ‘genetic profiling’ will move toward a modern eugenics movement ( 15 ).

PGT can also be used to select embryos by sex and thus reach what has been referred to as ‘family balancing’. Particular concern has arisen when IVF has been used for selection by sex in populations where male offspring are favoured over female offspring for cultural and economic reasons. In the UK, the use of PGT for sex selection of embryos for non-medical reasons is explicitly forbidden ( 16 ).

Highly publicized cases of ‘savior siblings’ have concerned the use of preimplantation tissue typing (PTT) to select embryos that could produce children suitable to become donors of stem cells or tissues for siblings who suffer from severe diseases ( 17 ). The merits of saving a sibling can be rationalized and commended. However, in other organ and tissue donation, treatment of a person solely for the purpose of becoming a donor is rejected. In PTT, questions on consent and the protection of children’s autonomy become paramount.

The regulation of PGT and PTT varies between countries, often also between regions in the same country. In most EU countries, PGT is allowed, either by legislation or because there is no explicit prohibition ( 18 ). The most detailed regulation is probably in the UK, where the Human Fertilization and Embryology Authority (HFEA) lists more than 600 genetic conditions for which PGT is allowed. These conditions have also been approved for use in cases involving PTT. However, unlike PGT, PTT requires additional approval on a case-by-case basis for specific patients ( 19 ).

There are attempts to harmonize the use of PGT in EU countries. The European Court of Human Rights has sanctioned Italy and Latvia for refusing access to PGT. The Court refers to the right to bring a child into the world who is not affected by the illness that they carry ( 20 , 21 ). In other countries, such as Canada and the USA, there is no national regulation of PGT. It has been argued that not regulating PGT also involves taking a moral position ( 22 ).

Storage of oocytes for social reasons

Since the success rate of IVF declines rapidly in ages above 35 years when the woman uses her own eggs, social egg freezing (oocyte cryopreservation) has been introduced as a means to preserve and store oocytes retrieved at an earlier age. Stored oocytes are used in IVF at a time when the social circumstances for having a child would be preferable ( 23 ).

Ethical considerations that have evolved in the discussions on social oocyte cryopreservation have concerned reproductive autonomy, risks involved in egg retrieval, undue hope, risk of failure, and the need for truly informed consent. To this end, the pros and cons of an upper age limit for IVF have been added (see above).

Most countries do not have national regulations on social oocyte cryopreservation. One exception is Israel, where the procedure has been regulated and authorized for public support. The main justification has been that of promoting individual autonomy ( 24 ). When the Swedish Council on Medical Ethics reviewed social egg freezing, the medical problems with delayed motherhood were weighed against reproductive autonomy. The Council found no convincing ethical arguments for a ban on social egg freezing, but concluded that the costs should not be covered by public funding ( 4 ).

Egg sharing

The term egg sharing is used when a woman who is already having IVF donates some of her eggs to other women. This may be done as an entirely altruistic act, but the eggs may also be donated to the clinic where she is having treatment in return for free or discounted treatment. If so, an indirect form of economic incentive is introduced. This is accepted in some countries, whereas other countries have taken a universal position against commercialization of organ or tissue donation, including donation of gametes; only modest reimbursement for expenses is allowed.

In the UK, where egg sharing in return for free treatment is allowed, The Human Fertilization and Embryology Authority emphasizes that the woman should never be put under any pressure to share her eggs. She should be informed that egg sharing is a big decision with serious implications, and she should receive professional counselling before going ahead. In the UK, as in some other countries, this includes information about the right of children conceived by egg sharing to know about their genetic origin when they turn 18 ( 25 ).

The term surrogacy has in itself a judgmental connotation (and the term surrogate children is even more objectionable). But since the terminology battle now seems to be over (even among healthcare professionals), I am, somewhat reluctantly, using surrogacy here.

Surrogacy may either be partial, when pregnancy is initiated through insemination, or full, involving eggs from another woman than the surrogate mother. In full surrogacy, eggs and sperm may come from the intended parents or from external donors. Full surrogacy thus involves IVF with no genetic link to the surrogate mother but with genetic link(s) to two, one, or none of the intended parents.

The ethics of surrogacy, whether partial or full, is covered by an abundance of analyses and debate articles ( 26 ). Much of the ethics debate is on altruistic versus commercial surrogacy, autonomy versus exploitation of women, human dignity, medical risks, balancing interests of the persons involved and the long-term well-being of surrogate mothers, children, and their families.

However, the ethical debate has only rarely distinguished between partial and full surrogacy. Most intended parents seem to prefer to maximize the genetic linkage to the extent that is medically feasible. IVF then becomes the method of choice for conception, and this may be regarded as catering for the principle of autonomy. An additional possible argument for full surrogacy is that the psychological impact would conceivably be less if the surrogate mother knows that she is not genetically related to the child she is carrying and will be separated from.

Commercialization of IVF

With the increasing demand for IVF, the economic impact of the IVF sector has come into focus highlighting the possible negative aspects of the commercialization of IVF. Ethical questions that are often raised in the debate include equity, possible exploitation of need and hope, consent that is truly informed, and the many components of marketing ethics.

The ‘IVF industry’ has been seen as an example of what social scientists describe as an increasing trend toward a market-driven construction of health, medicine, and the human body ( 27 ). Most of the public debate on commercialization of IVF has not, however, concerned IVF as such but the reimbursement of gamete donors (egg donors in particular), the selling of embryos, and the use of IVF for commercial surrogacy.

Public funding of IVF and prioritization

Whether or not IVF should be funded publicly is, to a large extent, a matter of priority ethics. The Swedish model for priority-setting in healthcare may serve as an example. It is based on three ethical principles ( 28 ).

The human dignity principle

This is basically a principle of equal value, equal human rights, and non-discrimination. All people have human dignity simply by being human and not for what they have or do. Access to healthcare services should not depend on sex, social or economic background, religion, sexual orientation, or cognitive function, among others.

According to this principle, singles and homosexuals should have the same right to IVF as infertile heterosexual couples in need of sperm or egg donation. Regional and socioeconomic differences in access to public funding of IVF are not in accordance with the principle of human dignity. It has been argued that the right to health, as defined by the World Health Organization, includes the right to have children. Even if this perspective is accepted, it does not necessarily translate into a right to public funding of IVF ( 29 ).

The needs and solidarity principle

Resources should be allocated to patients who have the greatest need. Need is assessed by (a) the severity of the health problem; (b) the potential health improvement that would be brought about by a healthcare intervention; and (c) the scientific support for a favourable benefit–risk ratio. The solidarity component means that special attention should be paid to those who cannot themselves express their needs, such as children, people with dementia, or patients with severe mental disorders. The principle of needs and solidarity contrasts with requests for healthcare, often not equalling needs.

The main ethical debate in the treatment of infertility concerns need. There are many individual variations in how involuntary childlessness is perceived, and these may be affected by societal norms, attitudes of next-of-kin and friends, how childlessness is presented in the media, and other factors. Decisions on public funding of IVF are, however, not made at the individual level but at group levels.

The cost-effectiveness principle

According to this principle, the healthcare system has a duty to utilize its resources as effectively as possible, and there should be a reasonable balance between the costs and effects of an intervention. This principle is subordinate to the other two principles.

The cost-effectiveness of IVF primarily depends on three factors: (a) treatment success rates; (b) multiple pregnancies; and (c) the cost of treatment ( 29 ). The cost-effectiveness has been estimated to be notably lower in older than in younger women ( 30 ), so the (subordinate) cost-effectiveness principle may conflict with the human dignity principle. A weakness in the cost-effectiveness studies is that costs are usually measured per successful outcome such as live births or ‘take-home babies’. In other medical areas, costs are usually expressed as costs per quality-adjusted (QALYs) or disability-adjusted life years (DALYs) gained. The different denominators make it difficult to prioritize IVF versus other healthcare interventions (horizontal priority-setting).

The three principles for priority-setting provide an ethical platform, but they do not resolve all issues regarding the prioritization of IVF. A frequent question is: Should women and men with an established medical cause of infertility have a higher priority for assisted reproduction than those with unexplained infertility? Since the medical preconditions may differ, the need can, at least to some extent, be expressed in term of effects, adverse effects, and the strength of scientific documentation. But usually, needs in terms of distress and suffering do not differ by cause of infertility; the existential burden remains the same. Therefore, it would not be acceptable to prioritize IVF solely based on the presence or absence of an established medical cause of infertility. It has also been argued that women with age-related infertility have a greater need for IVF since they are more likely to be permanently infertile and their time to become pregnant is running out.

Public funding of IVF varies between countries. In North America, payment for IVF is usually through private health insurance or out-of-pocket funds. In the USA, high costs have generated ‘reproductive tourism’ to countries with lower fees but also with safety concerns ( 31 ). In many European countries, there are programmes for public funding but with considerable variations in the number of cycles that are funded, age limits, and the proportion of the total cost that is paid for, among other factors ( 29 , 32 ). Public funding is often restricted to IVF performed in public hospitals and clinics ( 29 ).

In public funding, equity is an important aspect of the human dignity principle. It has repeatedly been shown that socioeconomically disadvantaged groups have less access to assisted reproduction services than more privileged groups. Socioeconomic disparities persist after adjusting for several confounding factors, including age at first birth and geographic remoteness ( 33 ). In Finland, where IVF is publicly funded whether performed in public or private clinics, socioeconomic inequities have been observed in private but not public clinics ( 34 ).

IVF and religion

While academic bioethics usually considers both facts and values when performing ethical analyses, religions rely principally on values. Religious beliefs may be decisive when infertile women and men consider the IVF option. They may also impact law-making and other regulations in a country.

IVF and procedures associated with IVF are summarized by religion in Table 2 . By necessity, the table gives a very simplified view. Within one religion, different sects have diverse interpretations and have reached varying conclusions. Some of the information in the table is from unofficial Internet sources; the summary should therefore be regarded as provisional. The text below comments on the religions’ positions on IVF.

IVF by religion and cultural tradition.

The Roman Catholic Church opposes IVF. In 2007, Pope Benedict XVI declared that IVF and other forms of assisted reproduction are unworthy methods of conception, since they separate the procreative goal of marital sex from the goal of uniting a married couple. An additional reason for the resistance against IVF is that some embryos (beginnings of a new lives) are discarded ( 35 ).

The position of the Eastern Orthodox Churches on IVF seems to be somewhat less restrictive than that of the Catholic Church. Under some circumstances, the Eastern Orthodox Church permits the use of parents’ gametes for IVF, fertilising only as many embryos as will be implanted, thus avoiding scenarios under which embryos are discarded ( 36 ).

Among the Protestant Churches, there is no common statement on IVF. In most Protestant countries, IVF as such is no longer disputed, but some of the applications are questioned. For instance, the Church of England has expressed profound concern at offering fertility treatments to single women and gay couples ( 36 ).

Followers of the Jewish faith are encouraged to have children (‘Be fruitful and multiply, fill the earth and subdue it’, Genesis 1:28). IVF is allowed, and in Israel it is encouraged. Certain aspects of assisted reproduction are still controversial among Orthodox Jews, for example the collection of sperm (the ‘spilling of seed’ is prohibited) and donation of gametes and embryos ( 36 ).

Islamic jurisprudence states that any act is permissible unless prohibited by a text in the Quran. Islam affirms the importance of marriage, family formation, and procreation. According to Sunni Islam fatwas (religious opinions/rulings), all forms of assisted reproduction are allowed as long as the sperm and oocyte are those of the husband and his wife ( 37 ). A third party cannot be involved in the conception; that is, gamete or embryo donation is not allowed. Most Sunni Muslims accept surrogacy, provided that the gametes come from the prospective parents ( 37 ).

Shi’a principles and practices are similar to those in the Sunni fatwas, except that Shi’as permit gamete donation, the rationale being that it does not involve sexual intercourse with someone outside the family. Gestational surrogacy using IVF is accepted by Shi’a Muslims ( 36 ).

Hinduism is liberal with most assisted reproduction procedures, but demands that the egg and sperm come from a married couple. There are, however, exceptions: the sperm may also come from a close relative of an infertile man ( 36 ).

Buddhism is very permissive regarding IVF. It does not restrict the use of IVF to married couples, and sperm donation is permitted.

In Chinese and Japanese societies, there are influences from several religions, such as Buddhism, Confucianism, Taoism, and Shintoism. In addition, Japan is a highly secularized country, and in China it is common that several beliefs are practiced at the same time (it has been suggested that this should not be called ‘religion’ but rather ‘cultural practices’, ‘thought systems’, or ‘philosophies’ ( 36 )). It is thus difficult to estimate to what extent religious beliefs have influenced the regulation of IVF and other forms of assisted reproduction in these countries. In China, IVF as such is permitted, but sex selection without medical indication, surrogacy, and gamete and embryo donation are prohibited ( 36 ). Japanese law permits IVF and sperm donation but not oocyte donation and surrogacy ( 36 ). After several landmark rulings by Japan’s Supreme Court, the Japan Society of Obstetrics and Gynecology has allowed unmarried couples access to IVF. Permission does not include single women or same-sex couples.

Concluding remarks

This review has focussed on the individual woman and her partner. It should be added that, in some countries, IVF is used as a part of national policy to increase birth rates. South Korea ( 38 ) and Israel ( 39 ) have been exemplified as such pronatalist countries. If a pronatalist policy involves IVF promotion combined with a ban on abortions, as in South Korea, women’s reproductive health and rights are at stake ( 38 ).

This review has also aimed at showing that decision-making concerning IVF cannot be based only on clinical and economic considerations; they cannot be disentangled from ethical principles, nor from social, political, and philosophical considerations. As noted by Mladovsky and Sorenson ( 29 ), many concerns regarding the costs, effects, and safety of IVF subtly raise more complex questions about what it means to society to bear children.

Kjell Asplund , MD, PhD, Professor emeritus of Medicine, Umeå University, Sweden. Former Director General of the National Board of Health and Welfare and Chief Medical Officer of Sweden. Former Chair of the Swedish Council on Medical Ethics.

Disclosure statement

No potential conflict of interest was reported by the authors.