Preimplantation Genetic Testing for Polygenetic Conditions: A Legal, Ethical, and Scientific Challenge.

The recent commercialization of the Embryo Health Score (EHS), determined through preimplantation genetic testing for polygenic conditions, offers the potential to select embryos with lower disease risk, thus potentially enhancing offspring longevity and health. Lately, Orchid Health company increased testing from less than 20 diseases to more than 900+ conditions for birth defects. However, the "geneticization" of phenotype estimates to a health state erases the environmental part, including the in vitro fertilization potential risks, questioning its scientific usefulness. EHS is utilized in countries with minimal regulatory oversight and will likely expand, while it remains illegal in other countries due to ethical and legal dilemmas it raises about reproductive autonomy, discrimination, impacts on family dynamics, and genetic diversity. The shift toward commercialized polygenic embryo screening (PES) redefines healthcare relationships, turning prospective parents into consumers and altering the physician's role. Moreover, PES could increase social inequalities, stigmatize those not born following PES, and encourage "desirable" phenotypic or behavioral traits selection, leading to ethical drift. Addressing these issues is essential before further implementation and requires a collaborative approach involving political, governmental, and public health, alongside geneticists, ethicists, and fertility specialists, focusing on the societal implications and acceptability of testing for polygenic traits for embryo selection.

Polygenic embryo screening: are there potential maternal and fetal harms?

Polygenic embryo screening (PES) and its derivate the Embryo Health Score (EHS) have generated interest in both infertile and fertile populations due to their potential ability to select embryos with a reduced risk of disease and improved long-term health outcomes. Concerns have been raised regarding the potential harms of IVF itself, including possible epigenetic changes that may affect the health of the offspring in late adulthood, which are not fully captured in the EHS calculation. Knowledge of the potential impacts of the trophectoderm biopsy, which is a key component of the PES procedure, on the offsprings' health is limited by the heterogeneity of the population characteristics used in the published studies. Nonetheless, the literature suggests a possible increased risk of preterm delivery, birth defects and pre-eclampsia after trophectoderm biopsy. Overall, the risks of PES for prenatal and postnatal health remain uncertain, and further research is needed. Counselling patients regarding these risks before considering PES is important, to provide an understanding of the risks and benefits. This review aims to highlight some of these issues, the need for continued investigation in this area, and the importance of informed decision-making in the context of PES.

Does underlying infertility in natural conception modify the epigenetic control of imprinted genes and transposable elements in newborns?

RESEARCH QUESTION: Does the epigenetic control of imprinted genes and transposable elements at birth differ according to time to conception in natural conception and after intrauterine insemination (IUI)? DESIGN: A total of 144 singletons were included in four groups: 50 natural pregnancies obtained within 6 months after stopping contraception (group 1); 34 natural pregnancies with infertility period between 6 and 12 months (group 2); 36 pregnancies with an infertility period of more than 12 months (group 3) and 24 pregnancies obtained after IUI (group 4). RESULTS: The placental DNA methylation levels of H19/IGF2 and KCNQ1OT1 were lower in groups 2, 3 and 4 than in group 1 (P = 0.025 in the overall comparison). The DNA methylation rate for LINE-1 was higher in placentas from group 2 than in group 1 (P = 0.022). In cord blood, DNA methylation levels were not significantly different between groups except for H19/IGF2 for which the DNA methylation levels were higher in group 2 than in group 1 (H19/IGF2-seq1 and seq2: P = 0.023 and P = 0.002, respectively). In placenta tissue, compared with group 1, relative expression for SNRPN and for LINE-1 was significantly higher in group 2 (P = 0.002 and P < 0.001, respectively). The relative expression of KCNQ1 in placenta was lower in group 4 than in group 1 (P = 0.013). In cord blood, compared with group 1, the relative expression for H19 was significantly higher in group 3 (P = 0.026), and the relative expression of LINE-1 was higher in groups 2 and 3 and in group 4 (P < 0.001). CONCLUSIONS: Infertility itself, and not only ART techniques, could contribute to potential epigenetic risks for children.

Analysis and quantification of female and male contributions to the first stages of embryonic kinetics: study from a time-lapse system.

PURPOSE: The few studies that examined the effect of male and/or female features on early embryo development, notably using the time-lapse system (TL), reported conflicting results. This can be explained by the small number of studies using an adapted model. METHODS: We used two original designs to study the female and male effects on embryo development: (1) based on embryos from donor oocytes (TL-DO), and (2) from donor sperm (TL-DS). Firstly, we analyzed the female and male similarities using an ad hoc intraclass correlation coefficient (ICC), then we completed the analysis with a multivariable model to assess the association between both male and female factors, and early embryo kinetics. A total of 572 mature oocytes (TL-DO: 293; TL-DS: 279), fertilized by intracytoplasmic sperm injection (ICSI) and incubated in a TL (Embryoscope®) were included from March 2013 to April 2019; 429 fertilized oocytes (TL-DO: 212; TL-DS: 217) were assessed. The timings of the first 48 h have been analyzed. RESULTS: The similarities in the timings thought to be related to the female component were significant: (ICC in both DO-DS designs respectively: tPB2: 9-18%; tPNa: 16-21%; tPNf: 40-26%; t2: 38-24%; t3: 15-20%; t4: 21-32%). Comparatively, those related to male were lower. Surprisingly after multivariable analyses, no intrinsic female factors were clearly identified. However, in TL-DO design, oligozoospermia was associated with a tendency to longer timings, notably for tPB2 (p = 0.026). CONCLUSION: This study quantifies the role of the oocyte in the first embryo cleavages, but without identified specific female factors. However, it also highlights that sperm may have an early embryonic effect.

Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?

OBJECTIVE: To determine whether the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) differs at birth between fresh or frozen embryo transfers and natural conceptions. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): A total of 202 singleton births were divided into three groups: 84 natural pregnancies (controls), 66 in vitro fertilization/intracytoplasmic sperm injection with fresh embryo transfers, and 52 vitro fertilization/intracytoplasmic sperm injection with frozen embryo transfers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pyrosequencing was used to assess the DNA methylation profiles of three IGs (H19/IGF2:IG-DMR [two sequences], KCNQ1OT1:TSS-DMR, and SNURF:TSS-DMR) and two TEs (LINE-1 and HERV-FRD) in cord blood and placenta. The quantitative reverse transcriptase polymerase chain reaction was used to study the transcription of three IGs (H19, KCNQ1, and SNRPN) and two TEs (LINE-1 and ORF2). RESULT(S): After adjustment, the placental DNA methylation levels of H19/IGF2 were lower in the fresh embryo transfer group than in the control (H19/IGF2-seq1) and frozen embryo transfer (H19/IGF2-seq2) groups. The DNA methylation rate for LINE-1 was lower in placentas from the fresh embryo transfer group than in placentas from the control and frozen embryo transfer groups and for HERV-FRD compared with controls. In cord blood, DNA methylation levels were not significantly associated with the mode of conception. The relative expression of LINE-1 and ORF2 was decreased in both cord blood and placental tissues from fresh embryo transfer conceptions compared with natural conceptions and frozen embryo transfer conceptions. CONCLUSION(S): Compared with natural conceptions and frozen embryo transfers, fresh embryo transfers were associated with methylation and/or transcription changes in some TEs and IGs, mostly in placental samples, which could indicate altered placental epigenetic regulation resulting from ovarian stimulation protocols.

Placental volume and other first-trimester outcomes: are there differences between fresh embryo transfer, frozen-thawed embryo transfer and natural conception?

RESEARCH QUESTION: Does mode of conception influence placental volume and other first-trimester outcomes? DESIGN: This retrospective single-centre case-control study led in Dijon University Hospital included 252 singleton pregnancies (84 IVF with either fresh embryo transfer or frozen-thawed embryo transfer [FET] and 168 natural conceptions). First-trimester placental volume, uterine artery pulsatility index and maternal serum PAPP-A and beta-HCG were measured. Statistical analyses were adjusted for gestational age, the newborn's gender, maternal age, parity, body mass index and smoking status. RESULTS: Placental volume was significantly greater in the FET group than in the control group (P = 0.043) and fresh embryo transfer (P = 0.023) groups. At birth, fresh embryo transfer newborns were significantly smaller than controls (P = 0.01) and FET newborns (P = 0.008). Postpartum haemorrhage was far more frequent in FET than in controls and fresh embryo transfer group (38.1%, 2.6% and 1.9%, respectively; P < 0.0001). Placental volume positively correlated with PAPP-A, beta-HCG and the newborn's birth weight, and negatively correlated with uterine artery pulsatility index. CONCLUSIONS: Placental volume and other first-trimester parameters are modified by IVF with fresh embryo transfer and FET compared with natural conception, but with opposite trends. Given the different protocols used for these techniques, hormonal treatment per se may have a major effect on pregnancy outcomes through the modification of placental invasiveness.

Singleton fetal growth kinetics depend on the mode of conception.

OBJECTIVE: To study the impact of in vitro fertilization, with or without intracytoplasmic sperm injection (IVF/ICSI), frozen-embryo transfer (FET), and intrauterine insemination (IUI) on fetal growth kinetics throughout pregnancy and to compare the different modes of conception. DESIGN: Retrospective cohort study. SETTING: University. PATIENT(S): A total of 560 singleton pregnancies were included (96 IVF, 210 ICSI, 121 FET, and 133 IUI). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We compared crown-rump length (CRL) at the first trimester (T1: 11-13 weeks of gestation [WG] + 6 days), estimated fetal weight (EFW) at the second (T2: 21-23 WG + 6 days) and third (T3: 31-33 WG + 6 days) trimesters, and birth weight (BW) z-scores with those in the reference curves (Papageorghiou for T1, and Ego M2 for T2, T3, and birth). Multivariate analyses were performed. RESULT(S): For T1, the CRL was longer than the reference curve whatever the assisted reproductive technique (ART). For T2, EFW was significantly greater for all groups compared with the reference curve, and for T3 only FET singletons had a greater EFW. ICSI, IVF, and IUI singletons had a significantly lower BW compared with reference curves. For all ART fetuses, growth kinetics differed from T2. Only FET fetuses maintained their significantly above-reference growth values. The proportion of fetuses for which at least one period of growth loss was observed from T2 to birth was higher after IVF, ICSI, and IUI than after FET. CONCLUSION(S): For the first time, we have highlighted that fetal growth kinetics differed from T2 depending on the ART protocols used. They could have an impact on trophoblastic invasiveness and might lead to long-term health effects.

Severe ovarian hyperstimulation syndrome modifies early maternal serum beta-human chorionic gonadotropin kinetics, but obstetrical and neonatal outcomes are not impacted.

OBJECTIVE: To study the impact of severe ovarian hyperstimulation syndrome (OHSS) on beta-hCG kinetics and obstetrical and neonatal outcomes. DESIGN: Retrospective single-center case-control study. SETTING: University tertiary referral center. PATIENT(S): A total of 77 patients who presented a clinical pregnancy after IVF and had been hospitalized for severe OHSS were included in this study and compared with 231 controls presenting an IVF-induced clinical pregnancy without OHSS and matched for the year of pregnancy and the number of gestational sacs. INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): The outcome of pregnancy (miscarriage, medical abortion, or delivery), beta-hCG values, obstetrical, and neonatal outcomes. RESULT(S): After multivariate analysis adjusted for parity, tobacco smoking, presence of polycystic ovary syndrome, age, and body mass index, outcomes of pregnancies were not altered by OHSS. However, there was a trend toward a lower early miscarriage rate in the OHSS group (7.8%) than in the control group (16%). Maternal serum beta-hCG values at different time points of the pregnancy and fold changes of beta-hCG values were lower in OHSS than in controls (268 ± 160 vs. 389 ± 215 IU/L at day 16; and 4.8 ± 1.5 vs. 5.4 ± 1.4 fold change between day 16 and day 20). Beta-hCG also correlated negatively with the number of oocytes retrieved. Incidence of gestational diabetes, gestational hypertension, intrauterine growth restriction, premature birth, and low birth weight did not differ between groups. CONCLUSION(S): Although early maternal serum beta-hCG kinetics were modified in women after severe OHSS, the outcomes of these pregnancies remained comparable to those of IVF pregnancies without OHSS. According to these data, pregnancies after severe OHSS do not require particular care compared with IVF pregnancies, but differences in beta-hCG levels and kinetics should be taken into account when interpreting these results.