Over the past several decades, an increasing amount of pregnancy capable individuals have elected to use assisted reproductive technologies (ART) as a means of conception. In the United States (US) alone, ART constituted nearly 2% of all births and 16% of all multiple births.¹ ART includes in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), followed by fresh embryo transfer; embryos may also be frozen then thawed for future use.

In the US, there have been over 330,000 ART cycles resulting in 77,000 live births; this accounts for 2% of all infants born within this country.² According to the European Society of Human Reproduction and Embryology (ESHRE), pregnancy rates using frozen embryo transfer (FET) have reached as high as 49% in Europe,³ partly due to further refinements in cryopreservation methods.

As the use of FET has had an uptrend within the past decade, growing research efforts have been made to assess its safety. ART poses considerable potential threats to both mother and infant.⁴ Although FET initially was thought to have better obstetric and perinatal outcomes than fresh-embryo transfer,⁵ emerging studies have challenged this concept.

Maheshwari et al. found that when compared to fresh embryo transfer, FET is associated with a significant risk of high birth weight, large for gestational age babies, and hypertensive disorders in pregnancy (HDP).⁵ This is consistent with similar studies which have found higher rates of HDP, including gestational hypertension and preeclampsia, in mothers using FET when compared to fresh embryo transfer.⁶ Given these emerging findings, future studies are imperative to further define cardiovascular risk factors of at risk mothers to mitigate morbidity during pregnancy.

Methods
A population-based study was completed to compare women who had both an IVF and naturally conceived pregnancy, named the sibling comparison, which included nearly 33,000 pregnancies. Recent national data from medical birth registries from Denmark, Norway, and Sweden of nearly 2.4 million women between the ages of 20 to 44 years of age who had single deliveries during the years 1984-2015 were studied.

The cohort included a total of over 4.5 million pregnancies, 4.4 million that were naturally conceived and nearly 78,000 and 18,000 pregnancies that were fresh embryo transfers and FET, respectively. The study was conducted to determine if parental factors or IVF treatment was the primary cause for hypertensive disorders. Lastly, the odds of developing HDP after fresh versus FET compared to natural conception were adjusted for confounding variables such as birth year, maternal age, and parity.

Results
Pregnancies resulting from FET had a significantly higher risk of HDP when compared with naturally conceived pregnancies at the population level (7.4% vs. 4.3%, adjusted odds ratio 1.74, 95% confidence interval [CI] 1.61-1.89). There was minimal difference in the adjusted odds of HDP between FET and naturally conceived pregnancies (adjusted odds radio 1.02, 95% CI 0.98-1.07). In women who had a natural conception and FET, the risk of HDP after embryo transfer was nearly twice as high compared to pregnancies from natural conception.

In the same group, FET had similar odds of HDP as compared to their siblings conceived naturally (adjusted odds radio 0.99, 95% CI 0.89-1.09). For all means of conception, women with HDP in their first pregnancy were less likely to have a second pregnancy when compared to women without HDP.

Conclusions
In this population-based cohort study examining deliveries in nearly 2.3 million women over almost three decades, the risk of HDP after FET was significantly higher than after natural conception. Women undergoing ART with FET or fresh embryo transfer were older when compared to those that conceived naturally. Moreover, pregnancies or infants conceived from both frozen and fresh embryo transfer were born preterm, nearly 7% and 8% respectively, when compared to babies after natural conception (5%).

Key Take Home Point
The risk of HDP was found in FET and not fresh embryo transfer. The explanation to this difference is not fully understood. It may be due to epigenetic changes driven by the freezing and thawing of the embryo and improper trophoblastic invasion, as seen in preeclampsia. This process is not driven by growth hormone and is known to increase the risk of HDP.

Even after recent advances in cryopreservation and improvement in ART by single embryo transfer, women utilizing FET may be a high-risk subgroup that would benefit from additional counseling. This study helps highlight a subgroup that may benefit from mitigating cardiovascular risk factors to be addressed prior to ART. It is imperative to optimize preconception cardiovascular health to attenuate the burden of HDP during pregnancy, especially in women utilizing FET as a means of conception.

References

1. Sunderam S, Kissin DM, Zhang Y, et al Assisted reproductive technology surveillance - United States, 2016. MMWR Surveill Summ 2019;68:1-23.
2. Assisted Reproductive Technology (ART) (cdc.gov). 2017. Available at: https://www.cdc.gov/art/artdata/index.html. Accessed 10/01/2022.
3. Wyns C, De Geyter C, Calhaz-Jorge C, et al. ART in Europe, 2017: results generated from European registries by ESHRE. Hum Reprod Open 2021;Aug 5:[Epub ahead of print].
4. Luke B, Gopal D, Cabral H, Stern JE, Diop H. Pregnancy, birth, and infant outcomes by maternal fertility status: the Massachusetts Outcomes Study of Assisted Reproductive Technology. Am J Obstet Gynecol 2017;217:327.e1-327.e14.
5. Maheshwari A, Pandey S, Raja EA, Shetty A, Hamilton M, Bhattacharya S. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update 2018;24:35–58.
6. Luke B, Brown MB, Eisenberg ML, et al. In vitro fertilization and risk for hypertensive disorders of pregnancy: associations with treatment parameters. Am J Obstet Gynecol 2020;222:350.e1-350.e13.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Prevention, Vascular Medicine, Hypertension, Dyslipidemia

Keywords: Live Birth, Gestational Age, Eclampsia, Sperm Injections, Intracytoplasmic, Pre-Eclampsia, Growth Hormone, Confounding Factors, Epidemiologic, Cohort Studies, Cardiovascular Diseases, Confidence Intervals, Risk Factors, Fertilization in Vitro, Semen, Cryopreservation, Multiple Birth Offspring, Registries, Morbidity, Heart Disease Risk Factors, Counseling, Epigenesis, Genetic, Hypertension, Hypertension, Pregnancy-Induced, Pregnancy, Embryo Transfer

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