The Effects Of Maternal Premature Ovarian Insufficiency On The Development And Reproductive Health In The Next Generation

Background:Premature ovarian insufficiency(POI)is characterized by cessation of ovarian function before the age of 40 years.It could not only threat to the reproductive health of women of childbearing age,but also lead to a serious social and economic burden.Both family aggregation phenomenon and genome-wide association studies(GWAS)in spontaneous patients have demonstrated that women with POI carry specific genetic susceptibility.Moreover,deregulation of the hypothalamus-pituitary-ovarian axis(HPO axis)was associated with steroidal hormone deficiency in mothers with POI or even in the biochemical stage(bPOI).Previous population studies showed that estradiol(E2)or testosterone(T)deficiency during pregnancy may have an adverse impact on the health of offspring,including growth and development,neural system development,and reproductive system development.All these clues imply possible development and reproductive health changes in offspring born to mothers with POI but not confirmed before.Objective:1.To explore the impact of maternal POI and bPOI on the health of their offspring,including neonatal outcomes,growth and development,as well as reproductive endocrine status in childhood.2.To further elucidate the potential mechanism and target by hormonal detections of the affected mothers during the first trimester.Methods:A nested case-control study was conducted based on an assisted reproductive technologies birth cohort.Overall,61 offspring born to mothers with POI using donor oocytes(DOs),453 offspring born to mothers with bPOI using autologous oocytes and 2652 control offspring were enrolled.Offspring included in this study were all singleton using in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).The age of offspring ranged from 1 to 4 years old during long-term visits.Parental characteristics were collected before IVF/ICSI treatment.Blood was resampled at the end of the first trimester(11 to 13 gestational weeks)for hormone tests in mothers(E2、DHEA-S、T).Follow-up visits including neonatal outcomes(birth weight,gestational age),growth measurement(height,weight,penile length,testicular volume),age and stage questionnaires(Scores of communication,gross motor,fine motor,problem-solving,and personal-social skills domains),and reproductive endocrinal profiles tests(FSH、LH、E2、T、PRL、DHEA-S、AMH)were performed in the offspring during childhood.The effect of maternal POI and bPOI on offspring health was analyzed by the linear mixed regression model.Results:1.The typical hormonal changes of POI would consist during pregnancy in the mothers.Compared to the control mothers,bPOI mothers had significant lower levels of E2,T,and dehydroepiandrosterone sulfate(DHEA-S)[E2:3104(2342,4238)vs.3774(2790,5261),P<0.001;T:49.2(30.4,69.5)vs.76.3(53.5,109.5),P<0.001;DHEA-S:190.7(125.8,258)vs.232.4(160.8,311.2),P<0.001].However,POI mothers only showed lower T but comparable E2 and DHEA-S[T:41.9(25.3,54.5)vs.76.3(53.5,109.5),P<0.001].2.For neonatal outcomes,male offspring born to bPOI mothers showed lower birth weight[birth weight,adjusted mean difference(AMD)(95%CI):-81.60(-150.00,-12.80),P=0.020;birth weight z-score:-0.19(-0.34,-0.05),P=0.010].Lower LG A risk was also found in male offspring with maternal bPOI compared with the controls[adjusted odds ratio(95%CI):0.56(0.37,0.81),P=0.003)].No differences were found in male offspring born to POI.Female offspring of the two case groups showed similar neonatal outcomes to the controls.3.Growth and developmental parameters in all offspring were comparable between the case groups and the control group,including general growth measurement and scores of five domains of age and stage questionnaires.4.Female offspring born to bPOI mothers manifested declined anti-müllerian hormone(AMH)and prolactin(PRL)compared with the control girls in childhood[AMD(95%CI):loge PRL,0.15(-0.28,-0.03),P=0.018;loge AMH,-0.36(-0.59,-0.14),P=0.002].Male offspring born to POI mothers showed lower penile length and mean testicular volume in childhood[AMD(95%CI),penile length in 0-2 years:0.17(-0.31,-0.02),P=0.024;mean testicular volume in 2-4 years:-0.15(-0.28,-0.03),P=0.016].Reproductive hormone profiles in male offspring were comparable between the case groups and the control group.Conclusion:Maternal bPOI or POI showed effects on neonatal outcomes and long-term reproductive health in the next generation in differential sex-specific ways.Deregulation of steroid hormones during pregnancy was identified as an important factor besides genetic predisposition.These findings suggested hormone replacement might be the interventional target in mothers with bPOI and POI,and provide valuable guidance for reproductive counselling for them.