P-718 Risk of placenta previa in assisted reproduction: population study with sibling analyses from the committee of Nordic ART and safety
Authors: Landsverk E , Westvik-Johari K , Wennerholm U  B , Bergh C , Kyhl F , Spangmose A  L , Vassard D , Pinborg A , Rönö K , Gissler M , Petersen S  H , Opdahl S 
Published: July 2024

Abstract

Study question
Which treatment methods and causes of infertility contribute to the increased risk of placenta previa in assisted reproductive technology (ART)?

Summary answer
Risk was increased across all treatment methods and causes of infertility, but most strongly following fresh blastocyst transfer (fresh-BT) and in women with endometriosis.

What is known already
A higher risk of placenta previa after ART is well established. Recent studies indicate risk differences according to type of embryo transfer, with particularly high risk seen after fresh-BT. Underlying mechanisms are poorly understood, and maternal factors such as cause of infertility might contribute. Within-mother analyses, where each woman serves as her own control (i.e., sibling design), help disentangle treatment contributions from maternal confounders that are constant between pregnancies.

Study design, size, duration
The Committee of Nordic ART and Safety (CoNARTaS) cohort consists of linked nationwide data from health registries in four Nordic countries. Data on ART were from Medical Birth Registries (MBRs) and ART quality registries, and data on placenta previa were from MBRs and hospital discharge/specialist health care registries. We included singleton and multiple births after natural conception (NC, n = 5 614 512) and ART (n = 139 694) in Denmark (1994-2014), Finland (1990-2014), Norway (1988-2015) and Sweden (1988-2015).

Participants/materials, setting, methods
All women who gave their first birth during the study period, at ages 20-45 years, were included, and contributed ≤4 births at 22-44 gestational weeks. We used multilevel logistic regression to compare risk of placenta previa after ART vs NC, both at the population level and within mothers, adjusting for year, maternal age, parity and country. We categorized ART-conception according to embryo cryopreservation, culture duration, and by cause of infertility (any ART method).

Main results and the role of chance
Population level risk of placenta previa was higher for ART (any method) vs NC (adjusted odds ratio [aOR] 4.16, 95% confidence interval [CI] 3.96-4.37). Controlling for constant maternal factors, the association attenuated, but risk remained higher for ART vs NC (within mothers aOR 2.64, 95% CI 2.31-3.02). Compared to NC, pregnancies from fresh embryos had a higher risk increase (population level aOR 4.69, 95% CI 4.41-4.98; within mothers aOR 3.31, 95% CI 2.81-3.91) than from frozen embryos (population level aOR 2.71, 95% CI 2.35-3.13; within mothers aOR 1.59, 95% CI 1.19-2.13). Further categorization by culture duration showed highest risk increase after fresh-BT (population level aOR 11.51, 95% CI 9.75-13.57; within mothers aOR 7.80, 95% CI 4.59-13.27), and lowest risk increase after frozen cleavage stage embryo transfer (population level aOR 2.33, 95% CI 1.93-2.80; within mothers aOR 1.20, 95% CI 0.83-1.75). Similar results were found across sensitivity analyses, including restriction to singletons. Compared to NC, risk was higher across all causes of infertility, where women with endometriosis and ART-conception had the highest risk increase (aOR 9.35, 95% CI 8.50-10.29), and women with polycystic ovary syndrome who conceived by ART had the lowest risk increase (aOR 1.52, 95% CI 1.12-2.09).

Limitations, reasons for caution
Analyses within mothers require that women have several births, hence, results might not apply to women with a single birth. Missing data on ART method or cause of infertility made within-mother analyses by cause of infertility unfeasible. We lacked data on extent of placenta previa (low-lying placenta vs placenta previa).

Wider implications of the findings
Type of embryo transfer and underlying maternal factors, particularly fresh-BT and endometriosis, respectively, both contribute to the increased risk of placenta previa in ART-conceived pregnancies. Identifying the responsible mechanisms might provide opportunities for prevention. Choice of transfer type should incorporate risk of placenta previa as well as other adverse outcomes.

Trial registration number
NA