Vascular health after assisted reproduction: A stroke of bad luck?

Since the first published case report of a successful in vitro fertilisation (IVF) pregnancy in 1978,1 the use of assisted reproductive technologies (ART) has markedly increased, accounting for 1% of births in Canada, and rising.2 These procedures have allowed couples struggling with infertility, single-birthing parents and same-sex couples to realise their dreams of procreation. ART often involves ‘preparatory’ steps with high-dose ovarian hyperstimulation, and while this safely enables pregnancy in most individuals, maternal and perinatal risks have been well described. Indeed, the first reported IVF pregnancy was complicated by preterm birth and preeclampsia, which occur more commonly in IVF compared with unassisted pregnancies, in addition to obstetric haemorrhage and other serious conditions.3 Owing to pregnancy at older maternal ages, oestrogen surges related to hyperstimulation and preeclampsia risk, the question of long-term maternal cardiovascular health among those exposed to ART has been raised. This question is part of our evolving scientific understanding of reproductive factors such as polycystic ovarian syndrome, preeclampsia and preterm birth as sex-specific risk factors for cardiovascular disease in women.4 In our 2017 systematic review of 6 studies examining the link between ART and various cardiovascular outcomes, we noted no increased risk of cardiac events but a possible signal for increased risk of stroke warranting further study.4 In addition, recent inquiries concerning maternal mortality rates in the United States have shown that stroke accounts for up to 7% of these largely preventable deaths.5 Two recent large studies have attempted to address whether ART is indeed a risk factor for peripartum stroke. Sachdev and colleagues6 studied more than 30 million individuals with hospital births in the United States and examined 30-day hazards of post-delivery stroke in ART versus non-ART users separately per calendar year from 2010 to 2018, excluding those with a known history of cardiovascular disease, censoring on mortality or loss to follow-up. These authors found a hazards ratio (HR) of 1.66 (95% confidence interval [CI] 1.17, 2.35) for any stroke, which was even higher for haemorrhagic stroke. The event rates were low (ranging from 29 to 37 events per 100,000). The study in the current issue of Paediatric and Perinatal Epidemiology by Magnus and colleagues7 was conducted to address possible bias due to a lack of information on parity and the fragmented time axes in the US study (with the inability to follow individuals across calendar years). The study by Magnus combines data from four Nordic countries, Finland, Norway, Sweden and Denmark, with varying follow-up, examining stroke rates within 1 year post-delivery also using Cox regression. In this study of 3 million first births, there was no increased risk of stroke after ART (HR 1.10, 95% CI 0.77, 1.57). Absolute rates were similarly low to the US study, but consistently higher in ART compared with non-ART groups. Haemorrhagic strokes were also more common in ART pregnancies but the rates were very small (1.7 vs. 1.0 stroke per 10,000 person-years in ART and non-ART pregnancies, respectively). Notably, both studies described but did not adjust for preeclampsia or other hypertensive disorders to avoid collider stratification bias and neither stratified on this variable. Peripartum strokes are thankfully rare events necessitating very large sample sizes to discern an effect due to ART—a relatively rare exposure. With that in mind, available data including these two robust recent studies do point to a modest possible increased risk of stroke in the early postpartum period in ART versus non-ART pregnancies. However, whether there is a signal is not the relevant question. Disentangling these ART-stroke associations from the cause of infertility itself, maternal predisposition or a maternal event such as a hypertensive disorder must be considered before counselling women about any observed risks (or lack thereof). Infertility causes such as ovulatory disorders and endometriosis not captured with these large datasets have been associated with cardiovascular diseases and may partially account for associations that were seen in the US study.8 The fact that haemorrhagic stroke seemed to be consistently more common than ischaemic stroke does raise the possibility that any minimal risk that may exist is mediated by severe peripartum or postpartum hypertension. Preeclampsia-related stroke syndromes are common causes of preeclampsia-related mortality, can occur postpartum and are largely the haemorrhagic stroke type.9 Maternal predisposition for stroke is also challenging to identify using hospital data, as many preexisting risk factors such as non-gestational diabetes mellitus, dyslipidaemia, tobacco use or chronic hypertension are principally captured within ambulatory settings. Mediation analyses preferably in the setting of multi-centre prospective clinical follow-up of ART patients, would help clarify pathways between ART and stroke, in which maternal predisposing risk factors would be accounted for and in which a hypertensive disorder is considered a key intermediate step. Were maternal hypertension the principal mediating factor, the surveillance strategy after childbirth would not differ from the current recommended practice which is close monitoring of maternal blood pressure in women with hypertensive and other cardiometabolic disorders of pregnancy, and screening for cardiovascular risk factors within 3 to 6 months postpartum. For patients contemplating ART, these studies should reassure them—and their providers—that stroke is an exceedingly rare ‘unlucky’ event and only potentially related to the actual infertility treatment, if at all. All ART patients should be monitored for complications during pregnancy, including preeclampsia. Pregnant people with certain pregnancy complications such as preeclampsia or those with preexisting conditions should have blood pressure measured in the early postpartum period and vascular risk factors controlled to reduce the risk of stroke. ND and JU conceptualized the manuscript. ND drafted the manuscript and both revised it for intellectual content. Natalie Dayan is a general internal medicine physician and the Director of Obstetric Medicine at the McGill University Health Centre (MUHC) in Montreal, Canada. She is a scientist at the Research Institute of the MUHC where she studies pregnancy health outcomes after assisted reproduction and postpartum maternal health using epidemiological approaches. Dr. Dayan completed her medical training and earned a master's degree in epidemiology at McGill University and completed a fellowship in obstetric medicine at the University of Toronto. Jacob A. Udell is a cardiologist at Women's College Hospital and Toronto General Hospital and an Associate Professor of Medicine at the University of Toronto in Toronto, Canada. His research focus has been on novel cardiovascular risk factors such as infertility treatment and influenza infection. He completed his medical degree at the University of Toronto, internal medicine at the University of British Columbia and University of Toronto, and cardiology training and a Masters of Public Health at Harvard University. The authors have no conflicts of interest relevant to this work. This manuscript did not utilize any data.

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