The fetus and placenta have been considered “asexual” in terms of research, yet numerous studies indicate that sex differences can originate early in fetal organogenesis [1]. Sex-specific regulatory pathways control the sexually dimorphic characteristics in organs such as the placenta which could influence variation in toxicant transport and accumulation, hormone levels, and immune response experienced by the fetus [2]. Patient comorbidities can impact the intrauterine environment and subsequently fetal adaptation may differ by sex [1]. Specifically, fetal sexual dimorphism has been an area of interest in the field of preeclampsia (PE). PE affects about 5-7% of pregnant patients worldwide and is a leading cause of maternal and neonatal morbidity and mortality [3]. While the pathophysiology of PE is not yet fully understood, an association between angiogenic biomarkers and the development of the disease has been well-established [4], [5], [6].

In patients with PE, levels of anti-angiogenic proteins, such as soluble fms-like tyrosine kinase (sFlt1), are elevated while levels of pro-angiogenic proteins like placental growth factor (PlGF) are lower in comparison to patients without PE [7], [8], [9]. Previously published data in patients with suspected PE has identified an sFlt1/PlGF cut-off ratio of 38 in predicting the absence of PE when sFlt1/PlGF ≤38 with a high negative predictive value [7]. However, data on angiogenic profiles with respect to fetal sex has been conflicting. Brown et al. [10] showed that female fetuses had significantly higher levels of sFlt1 and PlGF than male fetuses in uncomplicated pregnancies while no difference was found in these markers between fetal sex in pregnancies complicated by PE, preterm birth, and small for gestational age neonates. Andersen et al. [11] demonstrated that female fetal sex was associated with a higher sFlt1 level and sFlt1/PlGF ratio in healthy pregnancies, and this difference was greater in pregnancies subsequently complicated by PE. Conversely, male fetuses were associated with a significantly lower angiogenic ratio. Similarly in 2018, sFlt1 was found to be significantly lower in patients with PE and male fetuses [12].

In contrast, a 2017 meta-analysis including 3,163,735 patients found no association between male fetal sex and maternal risk of PE. Further subgroup analysis of these studies evaluating non-Asian populations showed that male sex was associated with an increased risk of PE and eclampsia [13]. In a separate study, Black pregnant patients carrying a male fetus were found to have higher odds of PE compared to Black patients carrying a female fetus and White pregnant patients, suggesting a possible link between fetal sex and high risk racial populations such as Black patients [14].

Due to mixed results obtained from prior studies, the objective of our study was to analyze the difference in our patient population carrying male and female fetuses as it pertains to the angiogenic profile in normal and hypertensive pregnancies. Our goal was to characterize angiogenic biomarkers profiles in relation to fetal sex in these patients.