Suleena Kalra, MD, MSCE¹, Alan Penzias, MD², Eli Adashi, MD, MS³
¹University of Pennsylvania
²Harvard Medical School
³Brown University Warren Alpert Medical School
If the primary mission of any epidemiologic study is to understand the association, magnitude and perhaps causality of an intervention on outcome, the secondary goal is to communicate the findings both to the scientific community and to the public at large.
In a world where print media has largely yielded to digital formats, the competition for a reader’s attention is fierce. The outcomes of fertility treatment were fodder for sensational headlines even before the term “Octomom” became a vernacular code for technology gone awry in 2009. It was no surprise then in February 2022 when the publication of the Journal of the American Heart Association “In-Hospital Complications in Pregnancies Conceived by Assisted Reproductive Technology” (1) sparked headlines such as “Pregnancy and Vascular Risks Surge With Infertility Treatments” (2); and “Do infertility treatments pose a risk to women’s health?”(3)
The study authors utilized a national inpatient sample database over a 9-year period to assess adverse obstetrical and vascular outcomes at delivery in 106,248 pregnancies conceived with ART as compared to 34,167,246 pregnancies conceived without ART. It was notable that women who conceived after ART were older and more likely to be obese. Adjusted analyses controlled for age, zip code income, insurance payer, race and ethnicity, day of admission, year of admission, multifetal pregnancies and comorbidities associated with cardiovascular disease (CVD). The authors reported that ART-conceived pregnancies had a higher risk of vascular complications after adjustment, including a 1.7-fold increase in the odds of arrhythmia and a 2.5-fold increased odds of acute kidney injury. They also corroborated previously reported increases in adverse obstetric outcomes in singleton pregnancies including placental abruption (aOR 1.57; 95% CI 1.41-1.74,) cesarean delivery (aOR 1.38; 95% CI 1.33-1.43,) and preterm birth (aOR: 1.26, 95% CI 1.20-1.32.)
It is noteworthy, though, that although an increased odds of arrythmia and acute kidney injury were reported, that the absolute risk of events was rare. Acute kidney injury was reported in .000026 % (n=9) non-ART pregnancies and 0.0357% (n=38) ART pregnancies. Arrhythmia was also a rare event occurring in 0.000217% (74/34,167,246) of patients with non-ART pregnancies and 0.134% of (143/106,248) of patients with ART pregnancies. The majority of arrythmias were sinus node or supraventricular dysfunction and associated mortality was not reported.
After adjustment, no increased risk of ischemic stroke, cardiomyopathy or venous thromboembolism was found which is reassuring given the size and power of the study. Furthermore, the risk of adverse vascular outcome was highest in women with a history of CVD risk factors (ART pregnancies followed closely by non-ART pregnancies). As the authors stated, it is difficult to ascertain whether the reported increases in arrhythmia and acute kidney injury were due to the ART procedure or maternal characteristics.
Unfortunately, the study design did not allow for the assessment of modifiable factors to decrease the risk. For example, the authors hypothesized that the ovarian hyperstimulation syndrome (OHSS) and its resultant impact on the renin-angiotensin system may be a potential mechanism whereby patients are more vulnerable to vascular complications. Unfortunately, the authors were unable to assess if patients who experienced OHSS), which typically develops within one week of retrieval or within weeks or embryo transfer, were more likely to experience an adverse outcome later on in pregnancy.
The study also did not ascertain whether the risk was more pronounced after fresh embryo transfer as compared to frozen embryo transfer. Previous literature has shown lower chances of placental abruption and low birth weight following frozen embryo transfer. Modifiable strategies at the time of stimulation and transfer are a critical area of investigation to develop risk mitigation protocols and would help inform the underlying biologic mechanisms.
As the authors reference, ART has contributed to the birth of more than 5 million infants to date around the world. The couples who undergo treatment with ART often try for years without success. The journey is arduous and, at times, physically, financially and emotionally depleting. Yet. They persist. Our patients persist through disappointment, through disapproval of friends and family and through isolation. It is important that we frame risks in a way to inform them, to empower them and within a context that they can understand.
It is our responsibility as physicians, scientists, and statisticians to provide patients with risk estimates in an intuitive fashion. For example, to describe the absolute likelihood of an adverse outcome such as acute kidney injury as an increase from 14 cases to 36 cases per 100,000 ART pregnancies as opposed to solely focusing on reporting a 2.5-fold increase in risk. Alternatively, framing risk as a number needed to treat can be helpful for counseling purposes; as a recent study reported that 510 fetal echocardiograms would need to be performed to detect one clinically significant heart defect in IVF conceived pregnancies. (4)
We push back at the authors solemn concluding recommendation in the papers’ abstract “Pregnancies conceived by ART have higher risks of adverse obstetric outcomes and vascular complications compared with spontaneous conception. Clinicians should have detailed discussions on the associated complications of ART in women during prepregnancy counseling”.
Yes, we need to counsel our patients adequately and transparently, but it is our responsibility to assess absolute risk as well as adjusted odds. We must determine too the clinical significance in terms of acute and long-term morbidity before we counsel our patients about a potential lifelong increase in cardiovascular risk. Context and absolute risk matter.
- Wu, P., Sharma, G.V., Mehta, L.S., Chew‐Graham, C.A., Lundberg, G.P., Nerenberg, K.A., Graham, M.M., Chappell, L.C., Kadam, U.T., Jordan, K.P. and Mamas, M.A., 2022. In‐Hospital Complications in Pregnancies Conceived by Assisted Reproductive Technology. Journal of the American Heart Association, 11(5), p.e022658.
- https://www.medindia.net/news/healthinfocus/pregnancy-and-vascular-risks-surge-with-infertility-treatments-205794-1.htm Retrieved 14 June 2022
https://www.healthing.ca/wellness/reproductive-health/do-infertility-treatments-pose-a-risk-to-womens-health Revrieved 14 June 2022
- Bjorkman KR, Bjorkman SH, Ferdman DJ, Sfakianaki AK, Copel JA, Bahtiyar MO. Utility of routine screening fetal echocardiogram in pregnancies conceived by in vitro fertilization. Fertil Steril. 2021 Sep;116(3):801-808. doi: 10.1016/j.fertnstert.2021.04.035. Epub 2021 Jun 29. PMID: 34210397.