“Maternal Morbidity and Medically Assisted Reproduction Treatment Types: Evidence from the Utah Population Database”
Authors: Pelikh Alina , Smith Ken R. , Myrskylä Mikko , Debbink Michelle P , Goisis Alice 
Published: August 2024

AbstractStudy questionHow are Medically Assisted Reproduction (MAR) treatments (Fertility enhancing drugs (FED), artificial/intrauterine insemination (AI/IUI)), assisted reproductive technology (ART) with autologous/donor oocytes) associated with maternal morbidity (MM)?Summary answerMore invasive MAR treatments (ART and AI/IUI) are associated with higher risk of MM, whilst less invasive treatments are not; this relationship is partially explained by higher prevalence of multifetal gestation and obstetric comorbidities in women undergoing more invasive treatment, but the persistent association suggests subfertility itself may contribute to maternal morbidity risk.What is known alreadyWomen conceiving through MAR are at higher risk of MM, however, reported risks vary depending on the measurement of MM and data available on confounding.Study design, size, durationBirth certificates were used to study maternal morbidity among all women giving birth in Utah, U.S., between 2009 and 2017 (N=460,976 deliveries); 19,448 conceived through MAR (4.2%). The MM outcome measure included the presence of any of the following: blood transfusion; unplanned operating room procedure; admission to ICU; eclampsia; unplanned hysterectomy; ruptured uterus.Participants/materials, setting, methodsLogistic regressions were estimated for the binary outcome (presence of any of the MM conditions). We assessed MM among women conceiving through MAR (overall and by type of treatment) compared to those conceiving spontaneously in the overall sample before and after adjustment for maternal socio-demographic characteristics (maternal age, family structure, level of education, Hispanic origin, parity), pre-existing maternal comorbidities (i.e., chronic hypertension, heart disease, asthma), multifetal gestation, and obstetric comorbidities (i.e., placenta previa, placental abruption, preterm delivery, cesarean delivery).Main results and the role of chanceWomen conceiving through MAR had higher risk of MM; however, the magnitude of the association differed depending on the type of treatment. In the unadjusted models, more invasive treatments were associated with higher odds of MM: OR 5.71 (95% CI 3.50–9.31) among women conceiving through ART with donor oocytes, OR 3.20 (95% CI 2.69–3.81) among women conceiving through ART with autologous oocytes, and OR 1.85 (95% CI 1.39–2.46) among women conceiving through AI/IUI, whereas women conceiving through FED had similar risks of MM to compared to women conceiving spontaneously (SC), OR 1.09 (95% CI 0.91–1.30). The associations between MAR and MM were largely attenuated once multifetal gestation was accounted for. After controlling for obstetric comorbidities, the associations were further attenuated, yet the coefficients remained higher among women conceiving through ART with either donor oocytes OR 1.70 (95% CI 0.95–3.04) or autologous oocytes OR 1.46 (95% CI 1.20–1.78) compared to women conceiving spontaneously. In analyses limited to singleton pregnancies, the differences in MM between women conceiving through MAR and SC were smaller in the unadjusted models. Nevertheless, women conceiving through more invasive treatments exhibited higher risk of MM. After adjusting for obstetric comorbidities, the coefficients were further attenuated and statistically insignificant for all types of treatments.Limitations, reasons for cautionThe data do not allow us to separate the confounding effects of subfertility on maternal morbidity from those of MAR treatments per se as there is no information on the history of previous infertility treatments or length of trying to become pregnant prior to conception. Our data also do not permit us to distinguish among different ART treatment approaches that could change certain risks (e.g. fresh or frozen embryo transfer, intracytoplasmic sperm injection, or preimplantation genetic screening via blastocyst sampling).Wider implications of the findingsOur findings showing that more invasive MAR treatments are associated with higher MM suggest that subfertility could be an important unobserved factor in MM risk as it could be associated with both higher risk of MM and with undergoing more invasive procedures. Though the odds of MM were generally lower or non-significant after accounting for multifetal gestation, there remain important clinical implications because a high proportion of individuals undergoing MAR in Utah have multiple births. Therefore, the association between MAR, multifetal gestation, and MM may play a role in counselling and patient and clinician choice of MAR therapies.Study funding/competing interest(s)This work was supported by European Research Council agreement n. 803958 (to A.G.). Authors have no conflict of interest to declare. MM was supported by the Strategic Research Council (SRC), FLUX consortium, decision numbers 345130 and 345131; by the National Institute on Aging (R01AG075208); by grants to the Max Planck – University of Helsinki Center from the Max Planck Society (Decision number 5714240218), Jane and Aatos Erkko Foundation, Faculty of Social Sciences at the University of Helsinki, and Cities of Helsinki, Vantaa and Espoo; and the European Union (ERC Synergy, BIOSFER, 101071773). Views and opinions expressed are, however, those of the author only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah’s program in Personalized Health and Utah Clinical and Translational Science Institute. MPD receives salary support from the March of Dimes and the American Board of Obstetrics and Gynecology as part of the Reproductive Scientist Development Program, as well as NICHD 1U54HD113169 and NIMHD 1R21MD019175-01A1.Trial registration numbernot applicable