Preterm birth in assisted reproduction: the mediating role of hypertensive disorders in pregnancy
Authors: Petersen Sindre Hoff , Åsvold Bjørn Olav , Lawlor Deborah A , Pinborg Anja , Spangmose Anne Lærke , Romundstad Liv Bente , Bergh Christina , Wennerholm Ulla-Britt , Gissler Mika , Tiitinen Aila , Elhakeem Ahmed , Opdahl Signe 
Published: December 2024

Abstract

STUDY QUESTION
To what extent can hypertensive disorders in pregnancy (HDP) explain the higher risk of preterm birth following frozen embryo transfer (frozen-ET) and fresh embryo transfer (fresh-ET) in ART compared with naturally conceived pregnancies?

SUMMARY ANSWER
HDP did not contribute to the higher risk of preterm birth in pregnancies after fresh-ET but mediated 20.7% of the association between frozen-ET and preterm birth.

WHAT IS KNOWN ALREADY
Risk of preterm birth is higher after ART compared to natural conception. However, there is also a higher risk of HDP in pregnancies after ART compared to natural conception, in particular after frozen-ET. HDP increases the risk of both spontaneous and medically indicated preterm birth. It is not known to what extent the higher risk of preterm birth in ART-conceived pregnancies is mediated through HDP.

STUDY DESIGN, SIZE, DURATION
This registry-based cohort study included singleton pregnancies from the Committee of Nordic ART and Safety (CoNARTaS) cohort from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015). The analysis included 78 300 singletons born after fresh-ET, 18 037 after frozen-ET, and 4 426 682 after natural conception. The exposure was ART conception with either frozen-ET or fresh-ET versus natural conception. The main mediator of interest was any of the following HDP: gestational hypertension, preeclampsia, eclampsia, or chronic hypertension with superimposed preeclampsia. The main outcome was any preterm birth, defined as delivery &lt;37 weeks of gestation. Secondary outcomes were spontaneous and medically indicated preterm birth, and different severities of preterm birth based on the gestational age threshold.

PARTICIPANTS/MATERIALS, SETTING, METHODS
We linked data from the national Medical Birth Registries, ART registries/databases, and the National Patient Registries in each country using the unique national identity number of the mother. Criteria for inclusion were singleton pregnancies with birth order 1–4 in women aged ≥20 years at delivery. We used logistic regression to estimate odds ratios (ORs) with 95% CIs of preterm birth and decomposed the total effect into direct and mediated (indirect) effects to estimate the proportion mediated by HDP. Main models included adjustment for the year of delivery, maternal age, parity, and country.

MAIN RESULTS AND THE ROLE OF CHANCE
Pregnancies following frozen-ET had a higher risk of any preterm birth compared to natural conception (occurrence 6.6% vs 5.0%, total effect OR 1.29, 95% CI 1.21–1.37) and 20.7% of the association was mediated by HDP (mediated effect OR 1.05, 95% CI 1.04–1.05). The mediation occurred primarily in medically indicated preterm births. Pregnancies following fresh-ET also had a higher risk of any preterm birth compared to naturally conceived pregnancies (occurrence 8.1% vs 5.0%, total effect OR 1.49, 95% CI: 1.45–1.53), but none of this could be mediated by HDP (mediated effect OR 1.00, 95%CI 1.00–1.00, proportion mediated 0.5%). Sensitivity analyses with extra confounder adjustment for body mass index and smoking, and restriction to primiparous women, were consistent with our main findings. Furthermore, the results were not driven by differences in ART procedures (intracytoplasmic sperm injection, culture duration, or the number of embryos transferred).

LIMITATIONS, REASONS FOR CAUTION
Although we could adjust for some important confounders, we cannot exclude residual confounding, particularly from factors associated with infertility.

WIDER IMPLICATIONS OF THE FINDINGS
This population-based mediation analysis suggests that some of the higher risk of preterm birth after ART treatment may be explained by the higher risk of HDP after frozen-ET. If causality is established, investigations into preventive strategies such as prophylactic aspirin in pregnancies after frozen-ET may be warranted.

STUDY FUNDING/COMPETING INTEREST(S)
Funding was provided by NordForsk (project number: 71450), the Nordic Federation of Obstetrics and Gynaecology (project numbers NF13041, NF15058, NF16026, and NF17043), the Norwegian University of Science and Technology (project number 81850092), an ESHRE Grant for research in reproductive medicine (grant number 2022-2), and the Research Council of Norway’s Centres of Excellence funding scheme (project number 262700). D.A.L.’s and A.E.’s contribution to this work was supported by the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreements No 101021566) and the UK Medical Research Council (MC_UU_00032/05). D.A.L. has received support from Roche Diagnostics and Medtronic Ltd for research unrelated to that presented here. Pinborg declares grants from Gedeon Richter, Ferring, Cryos, and Merck, consulting fees from IBSA, Ferring, Gedeon Richter, Cryos, and Merck, payments from Gedeon Richter, Ferring, Merck, and Organon,travel support from Gedeon Richter. All other authors declare no conflicts of interest related to this work.

TRIAL REGISTRATION NUMBER
ISRCTN 35879.