Effect Of Maternal Infertility Etiology On Birth Outcomes Of Assisted Reproductive Technology Offspring

Background:Infertility affects nearly 8%-12%couples around the world.Its main causes include tubal factors,ovulatory disorders,endometriosis,unexplained infertility,and male factors.Assisted reproductive technology(ART),as a reliable treatment for infertile patients to overcome infertility and obtain offspring,its influence on offspring has become a research hot spot in the field of reproductive medicine.More and more studies have shown that compared to neonates of natural conceived women,ART offspring has an increased risk of adverse birth outcomes such as preterm birth(PTB),low birth weight(LBW),and small for gestational age(SGA).Some scholars believe that the ART treatment as an additional exposure may have adverse effects on the offspring,while others believe that the pathophysiological changes related to infertility may increase the risk of adverse birth outcomes,but the relationship between the two has not been well explained.Studying the impact of ART treatment and different pathophysiological changes related to maternal infertility on offspring will help to provide a more personalized risk assessment of ART treatment for infertility patients with different causes,promote pre-pregnancy health care and pregnancy management of high-risk groups,and reduce the occurrence of adverse events.Objective:The purpose of this study is to explore the risk of adverse birth outcomes of ART offspring compared with natural pregnancy offspring,analyze the effects of different infertility causes and ART treatment on the birth outcomes of offspring,and clarify the relationship between the maternal pathophysiological changes and artificial intervention in the occurrence and development of adverse birth outcomes of offspring.Methods:We conducted a prospective cohort study at the Hospital for Reproductive Medicine Affiliated to Shandong University.Recruitment started in July 2014 and ended in December 2017.Women who had registered in our reproductive center and planned a pregnancy were invited into our research.During the same period,fertile women were recruited in the first trimester from the obstetrics clinic.The eligible participants were Chinese residents over the age of 20;the pre-pregnancy examination showed normal fertility,or had single infertility related diagnosis including tubal factor,ovulatory dysfunction,endometriosis,unexplained infertility,and male factor infertility;willing to complete the whole follow-up.The exclusion criteria were:no live fetus was delivered at the end of follow-up;multiple births;incomplete medical records;the gestational week of the newborn is less than 22 weeks or the birth weight is less than 500g.All participants were divided into four groups according to infertility diagnosis and ART treatment:fertile natural conceived(NC)women,infertile NC women,female factor ART treated women,and male factor ART treated women.Collect the baseline information and follow up the incidence of pregnancy complications and neonatal information through medical records,questionnaire survey and telephone follow-up.The birth outcomes of offspring include neonatal gestational age(GA),birth weight(BW),and birth weight Z score.Adverse birth outcomes include preterm birth(PTB),low birth weight(LBW),small for gestational age(SGA),and large for gestational age(LGA).SPSS24 was used to describe the baseline characteristics of the subjects,the birth outcomes of their offspring,and the incidence of adverse birth outcomes.Interaction analysis and logistic regression analysis were also carried out.Result(s):Follow-up results of the cohort:Up to March 2019,a total of 9894 women with live births were included in our study,including 1577 fertile NC women,181 infertile NC women,6335 female factor ART women and 1801 male factor ART women.Baseline characters of couples:There were significant differences in age,BMI,the incidence of gestational diabetes mellitus(GDM)and hypertensive disorders complicating pregnancy(HDCP)between the four groups.Among the four groups,the fertile NC group had the longest GA(39.3±1.5 weeks)and the lowest BW(3405 ± 494 g).Although there was a significant difference in the proportion of women with two or more births in each group(P=0.021),there was no significant difference in the proportion of primiparas or women with a previous history of PTB in each group(primiparas:P=0.489,previous history of preterm birth:P=0.564).Birth outcomes of offspring:Among the four groups,the fertile NC group had the longest GA(39.3 ± 1.5 weeks)and the lowest BW(3405 ± 494 g).Compared to the fertile NC group,the female factor ART group had a shorter GA(39.0±1.6 weeks vs.39.3±1.5 weeks,P<0.05)and higher BW(3443±526g vs.3405 ±494g,P<0.05).The incidence of LBW and SGA was comparable in the four groups,and the difference was not statistically significant(P>0.05).The incidence of PTB in the female factor ART group was the highest,which was 6.5%.Compared to the fertile NC group,The incidence of PTB in the female factor ART group was significant higher(6.5%vs.4.0%,P<0.05).The incidence of LGA in the female factor ART group was also the highest,and the difference was statistically significant compared with the fertile NC group(24.2%vs.20.4%,P<0.05).When compared to the infertile NC group,female factor ART group and male factor ART group and infertile NC group showed no significant difference in the above four adverse birth outcomes(All P>0.05).Interaction test between female infertility and ART treatment:In the pairwise comparison among fertile NC group,infertile NC group,and female factor infertile group,the differences of birth outcomes only appeared in the comparison between the female factor ART group and the fertile NC group.Since these results suggested the adverse effect of the combination of female infertility and ART treatment,we conducted the interaction test to identify their influence on GA and BW.The interaction between female infertility and ART treatment was significant for GA(P=0.023),but was not statistically significant for BW(P=0.976).Risk of adverse birth outcomes of offspring under different causes of infertility:Compared to the fertile NC group,the risk of PTB(OR=1.56,95%CI=1.18-2.07)and LGA(OR=1.27,95%CI=1.10-1.47)in the female factor ART group was significantly increased.The female factor ART group was further divided into four subgroups according to the causes of female infertility:tube factor ART group,ovulation dysfunction ART group,endometriosis ART group and unexplained infertility ART group.After adjusted for co-founding factors including female age,female BMI,and pregnancy complications,compared to the fertile NC group,the risk of PTB was increased in tubal factor ART group(OR 1.49,95%CI 1.12-2.00),ovulatory dysfunction ART group(OR 1.87,95%CI 1.29-2.72),and unexplained infertility ART group(OR 1.88,95%CI 1.11-3.17).In addition,compared to the fertile NC group,the risk of LGA was increased in tubal factor ART group(OR 1.28,95%CI 1.11-1.48)and ovulatory dysfunction ART group(OR 1.27,95%CI 1.03-1.57).Conclusion(s):1.ART offspring have an increased risk of PTB and SGA compared to the offspring of NC women.2.ART treatment itself would not deteriorate the neonatal outcomes but could act as a catalyst to amplify the adverse effect of female infertility on PTB.3.Women with tubal factor infertility,ovulatory dysfunction,and unexplained infertility have higher risks of preterm birth after ART treatment.Thus,clinicians should be alert to these kinds of people and provide corresponding prevention strategies before and during pregnancy.