Is receipt of infertility treatment associated with stroke hospitalization?

By Dr. Liji Thomas, MDAug 31 2023Reviewed by Sophia Coveney

While strokes are uncommon during the reproductive period in women, they are responsible for about 7% of deaths in pregnancy. A recent paper on JAMA Network Open sought to capture the association between these events and infertility treatment.

Introduction

With the increasing prevalence of infertility among women, infertility treatment is on the rise. Such treatments are generally thought to be safe, and acute complications are said to be infrequent and non-severe. On the other hand, there is a risk of complications during pregnancy and afterward that is associated with such treatment.

Stroke is the third leading cause of death among Americans, with about 20% of women being at risk for stroke over their lifespans. However, the risk of fatal stroke has declined, especially for ischemic strokes.

When the field is narrowed down to pregnant women, almost 27%, or over a quarter, of pregnancy-related deaths are due to cardiovascular complications. Certain risk factors have been identified,

Many prior studies have focused on the potential link between the chances of a future stroke with infertility treatment, but the results have not been concordant.

There has been speculation that the possible association could be the result of endothelial damage and the prothrombotic condition caused by ovarian hyperstimulation and other treatments for infertility.

The current study was based on data from the population-based Nationwide Readmissions Database that includes patients hospitalized from 28 American states.

What did the study show?

The study included a cohort of over 31 million pregnant women with delivery dates between 2010 and 2018, comparing those who had been treated for infertility with others. All the participants were aged 15-54 years, and all had been hospitalized for some reason during the same calendar year following delivery.

Infertility treatments used in this study population included intrauterine insemination, assisted reproductive technology (ART), fertility preservation, and surrogacy. Only nonfatal strokes were counted towards the outcome.

Less than 1% of the cohort had infertility treatment prior to conception. In this group, there were 105 hospitalizations for stroke, compared to just over 9,000 in the larger group. This corresponds to a rate of 37 vs 29 per 100,000 participants in the infertility and natural conception groups, respectively.

The risk for stroke hospitalization was therefore 66% higher in the first postpartum year after infertility treatment. Most of these strokes were hemorrhagic strokes, for which the risk was doubled, whereas the risk for ischemic stroke went up by about 50%. The strength of association increased for hemorrhagic stroke after adjusting for confounding factors but decreased for ischemic stroke.

Moreover, the risk increased over time, again showing a stronger association for hemorrhagic than for ischemic stroke after adjustment. The increased odds were observable from 30 days postpartum.   

Other studies have concluded that the opposite is true, namely, that infertility treatment is linked to a lower risk of cardiovascular disease.

Some researchers have pointed out that it is possible that ART is used more often as women age. This would mean that the infertility treatment population is already at a higher risk for CVD, which is increased following the use of many hormones and medications during the treatment cycles.

Infertility treatment is associated with a higher risk of ischemic complications involving the placenta, such as abruption, fetal growth restriction, and pre-eclampsia; disorders involving the kidney; and gestational or pre-existing diabetes. These could all increase the risk of cardiovascular disease (CVD).

A second mechanism could involve the prothrombotic or endothelial-damage pathways coupled with the changes in the woman’s circulatory function due to the ART medications. And finally, the women in these situations could be at a pre-existing risk for stroke, due to obesity, smoking, or alcohol use, which is exacerbated by pregnancy changes.

While this has led to the recommendation that older women be screened for CVD before ART, the authors of the current paper posit that all women should receive such screening before infertility treatment.

What are the implications?

The results showed that women treated for infertility had a significantly higher chance of being hospitalized for stroke, especially hemorrhagic stroke, within a year of delivery.

However, the study did not control for diabetes and hypertensive disorders of pregnancy or predating conception or for conditions that could indicate an independent vascular pathology, such as fetal growth restriction or stillbirth.

Future studies will have to incorporate these factors, as well as ethnicity and protocols for the management of the above pregnancy complications, since these could confound the observed associations. 

The  American College of Obstetricians and Gynecologists (ACOG) recommends two follow-up visits, the first at 3 weeks postpartum and then at 12 weeks. Earlier follow-up is indicated in the presence of antepartum complications like hypertensive disorders of pregnancy.

The association of an increased risk of stroke hospitalization within the first year of childbirth in women who have undergone infertility treatment indicates the need for better screening practices to identify those at risk for stroke and properly timed follow-up to reduce the impact of factors that might lead to a stroke both during and after pregnancy.