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.

自 1978 年首次发表体外受精 (IVF) 成功妊娠病例报告以来，¹辅助生殖技术 (ART) 的使用显着增加，占加拿大新生儿的 1%，并且还在不断上升。²这些手术让患有不孕不育的夫妇、单亲生育的父母和同性伴侣实现了生育梦想。 ART 通常涉及高剂量卵巢过度刺激的“准备”步骤，虽然这可以安全地使大多数人怀孕，但孕产妇和围产期风险已得到充分描述。事实上，第一个报道的体外受精妊娠并发了早产和先兆子痫，除了产科出血和其他严重情况外，与未经辅助妊娠相比，体外受精中更常见这种情况。³

由于高龄孕妇怀孕、与过度刺激和先兆子痫风险相关的雌激素激增，人们提出了接受抗逆转录病毒疗法的孕妇长期心血管健康的问题。这个问题是我们对生殖因素（如多囊卵巢综合征、先兆子痫和早产）不断发展的科学认识的一部分，这些因素是女性心血管疾病的性别特异性危险因素。⁴ 2017 年，我们对 6 项研究进行了系统回顾，研究了 ART 与各种心血管结局之间的联系，我们注意到心脏事件的风险并未增加，但中风风险增加的可能信号值得进一步研究。⁴此外，最近对美国孕产妇死亡率的调查显示，在这些基本上可以预防的死亡中，中风占 7%。⁵

最近的两项大型研究试图探讨 ART 是否确实是围产期卒中的危险因素。 Sachdev 及其同事⁶研究了美国超过 3000 万在医院分娩的患者，并从 2010 年至 2018 年的每个日历年分别检查了 ART 使用者与非 ART 用户的产后中风 30 天风险，不包括那些已知病史的患者心血管疾病，审查死亡率或失访。这些作者发现，任何中风的风险比 (HR) 均为 1.66（95% 置信区间 [CI] 1.17、2.35），出血性中风的风险比更高。事件发生率较低（每 100,000 人中有 29 至 37 起事件）。Magnus 及其同事⁷在本期《儿科和围产期流行病学》中进行了这项研究，旨在解决由于美国研究中缺乏胎次信息和分散的时间轴（无法跨日历年跟踪个人）而可能出现的偏差。 。 Magnus 的研究结合了来自四个北欧国家（芬兰、挪威、瑞典和丹麦）的数据，并采用不同的随访方式，使用 Cox 回归检查产后 1 年内的中风发生率。在这项针对 300 万头胎的研究中，ART 后中风的风险并未增加（HR 1.10，95% CI 0.77，1.57）。绝对比率与美国的研究相似，但与非 ART 组相比，ART 组的绝对比率始终较高。出血性中风在 ART 妊娠中也更常见，但发生率非常小（ART 和非 ART 妊娠中每 10,000 人年分别有 1.7 例和 1.0 例中风）。值得注意的是，这两项研究都描述了先兆子痫或其他高血压疾病，但没有进行调整，以避免碰撞分层偏差，并且都没有对此变量进行分层。

值得庆幸的是，围产期中风是罕见的事件，需要非常大的样本量来辨别 ART（相对罕见的暴露）造成的影响。考虑到这一点，包括最近这两项强有力的研究在内的现有数据确实表明，与非 ART 妊娠相比，ART 妊娠在产后早期中风的风险可能略有增加。然而，是否有信号并不是相关问题。在向女性提供关于任何观察到的风险（或缺乏风险）的咨询之前，必须考虑将这些 ART 与中风的关联与不孕本身的原因、母亲易感性或母亲事件（例如高血压疾病）分开。这些大型数据集中未捕获的排卵障碍和子宫内膜异位等不孕原因与心血管疾病有关，并且可能部分解释了美国研究中发现的关联。⁸出血性中风似乎始终比缺血性中风更常见，这一事实确实提出了一种可能性，即可能存在的任何最小风险都是由严重的围产期或产后高血压介导的。先兆子痫相关的中风综合征是先兆子痫相关死亡的常见原因，可以发生在产后，并且主要是出血性中风类型。⁹使用医院数据来识别母亲的中风倾向也具有挑战性，因为许多先前存在的危险因素，如非妊娠糖尿病、血脂异常、吸烟或慢性高血压主要是在门诊环境中发现的。最好在 ART 患者的多中心前瞻性临床随访的背景下进行中介分析，这将有助于阐明 ART 和中风之间的途径，其中将考虑母亲的易感危险因素，并将高血压疾病视为关键的中间步骤。如果产妇高血压是主要介导因素，则产后监测策略与目前推荐的做法没有什么不同，即密切监测患有妊娠期高血压和其他心脏代谢疾病的妇女的产妇血压，并在 3 至 6 年内筛查心血管危险因素。产后几个月。

对于考虑接受 ART 的患者来说，这些研究应该让他们及其提供者放心，中风是一种极其罕见的“不幸”事件，并且仅可能与实际的不孕症治疗（如果有的话）相关。所有 ART 患者均应监测妊娠期间的并发症，包括先兆子痫。患有某些妊娠并发症（如先兆子痫或已有疾病）的孕妇应在产后早期测量血压并控制血管危险因素，以降低中风风险。