Pregnancy and Neonatal Outcomes Associated with the Use of Assisted Reproductive Technologies

Abstract

Assisted reproductive technologies have become a common method used to treat infertility. These techniques have advanced quickly since the first birth of an in vitro fertilization (IVF) baby in 1978, at the Royal Oldham Hospital in the United Kingdom. Currently, IVF with or without intracytoplasmic sperm injection, is used throughout the world to achieve oocyte retrieval, fertilization, implantation of an embryo, clinical pregnancy, ongoing clinical pregnancy, and a live-born infant. The rationale for selecting one type of fertility treatment over another is multifactorial: the confirmed or unconfirmed cause of infertility, the age of the gamete donor and the recipient, the availability of the type of treatment, and the cost associated with the treatment. The ultimate goal of any fertility treatment is to achieve a successful pregnancy that results in a healthy infant. However, the literature is equivocal on the effects of fertility treatment cycles on the health outcomes of infants and mothers. Presently, there are thirty-six fertility treatment centres across Canada, eighteen of which reside in Ontario. A national, comprehensive database of assisted reproductive technology treatment cycles (Canadian Assisted Reproductive Technologies Register (CARTR) Plus) began collecting data in 2013, and has made the research objectives of this doctoral thesis feasible. Before this data collection system, population-wide studies involving fertility treatments were not possible in Canada. Two understudied issues associated with IVF are the impact of fertility treatments on the maternal serum screening markers used in prenatal screening programs to identify fetal aneuploidies; and the association between fertility treatments and adverse perinatal outcomes, such as preeclampsia and stillbirth. Given the increasing number of women who are using fertility treatments to conceive, it is imperative that studies investigating the association with adverse outcomes are conducted. As the science supporting fertility treatment procedure has advanced, so has prenatal screening. One of the first screening tests that are performed for newly pregnant women, including women who conceived following IVF, is maternal serum screening. The first objective of this doctoral thesis was to systematically review the literature on the association between IVF treatment and maternal serum screening marker levels and nuchal translucency (NT) thickness. After the search and screening of the literature there were 40 studies that were included in this systematic review. A decrease in pregnancy-associated plasma protein A (PAPP-A) and an increase in total human chorionic gonadotropin (hCG) was consistently reported for IVF pregnancies. However, since the levels of the other maternal serum screening markers reported also varied we were unable to generalize about the differences between prenatal screening results in the IVF population. These results led to investigating maternal serum screening marker levels among IVF patients in Ontario, Canada. The second objective of this thesis was three-fold: 1) to investigate the accuracy of IVF identification on the Ontario prenatal screening record, relative to reference standard on the CARTR Plus database; 2) to compare the prenatal screening markers in IVF versus non-IVF pregnancies in the population of Ontario; and 3) to propose updated IVF adjustment factors for prenatal screening in the Ontario population, based on the more accurate coding for IVF status in the CARTR Plus database. Significant differences between IVF and non-IVF groups, based on both the prenatal screening requisition information and CARTR Plus information, were found among the ethnicity adjusted mean multiple of the median (MoM)s for several prenatal screening markers: alpha-fetoprotein (AFP), PAPP-A, unconjugated estriol (µE3), first trimester hCG, total hCG, and dimeric inhibin A (DIA). When we developed the proposed adjustment factors for all CARTR Plus identified pregnancies we found that for PAPP-A, total hCG, and µE3 the mean adjusted marker MoMs were significantly closer to 1.00, as compared to the prenatal screening adjusted or the unadjusted mean marker MoMs. Currently, there is no adjustment made to the other maternal serum screening markers and NT measurement. The third objective was to examine the effect of type of infertility on placental-mediated adverse outcomes (preeclampsia, intrauterine growth restriction, placental abruption, and stillbirth). Type of infertility was classified as male factor (sperm count, poor sperm motility, and abnormal sperm morphology), female factor (ovulation disorders, tubal infertility, and uterine or cervical causes), and unexplained infertility. No significant associations were found between type of conception and the composite outcome, as well as each individual primary outcome. Similarly, the type of infertility was not associated with the composite outcome or any of the individual primary outcomes, except for female factor infertility, which was associated with increased probability of placental abruption. Overall, the results from this doctoral thesis suggest that there are substantial differences seen in maternal serum screening marker MoMs among women who use IVF to conceive, suggesting that appropriate adjustment factors should be employed to ensure accurate results for determining the risk of Down syndrome and trisomy 18. Additionally, although the literature has shown an association between fertility treatment and placental-mediated adverse outcomes no significant associations were found in the population of Ontario. Further studies should be performed to confirm the results of these observational studies.