Placentation, Hypertensive Disorders, and Neonatal Outcomes

Hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, are associated with a range of downstream adverse neonatal and paediatric outcomes. These outcomes may occur directly from exposures to disease processes related to abnormal placentation, as a result of iatrogenic preterm birth or both. Placental dysfunction in preeclampsia is believed to occur secondarily to abnormally narrowed spiral arteries that retain muscle in the media of the vessel wall, resulting in susceptibility to vasoconstrictive agents and other factors that further narrow the vessel lumen, compromising placental perfusion [1]. Preeclampsia can manifest primarily as maternal organ injury resulting in characteristic symptomatology, physical exam findings and laboratory abnormalities that may be severe enough to require delivery to preserve the safety of the mother. Alternately, placental abnormalities leading to preeclampsia may present with only mild blood pressure elevations and proteinuria without evidence of maternal organ injury but with more severe consequences for the fetus, including restricted growth, Doppler abnormalities of fetal vessels, oligohydramnios and increased risk for stillbirth. Given that preeclampsia is characterised by compromised placental perfusion and ischaemia, foetuses exposed to preeclampsia may undergo significant in utero physiological and metabolic adaptations that are consequential after birth and into childhood. In ‘Maternal hypertensive disorders of pregnancy and electrocardiographic findings among newborns—a Copenhagen Baby Heart Study,’ Nørskov and colleagues [2] analysed data from the Copenhagen Baby Heart Study, a prospective, population-based cohort study of more than 27,000 children that included pregnancy and delivery information. The Copenhagen Baby Heart Study is designed to characterise the prevalence of neonatal cardiac abnormalities and associated outcomes and establish reference norms for cardiac parameters and biomarkers. Enrolled infants underwent electrocardiographic (ECG) examination and transthoracic echocardiography within 60 days of birth [2]. The investigators found that infants exposed to preeclampsia had prolonged QRS durations and lower maximum amplitudes of the R-wave in V1. These findings add to prior cardiovascular research on neonates exposed to preeclampsia, including another study from the Copenhagen Baby Heart Study that found infants exposed to preeclampsia showed signs of myocardial remodelling and altered systolic and diastolic function on echocardiography [3]. The long-term clinical significance of these findings is unclear, although there is evidence that exposure to preeclampsia results in cardiac changes that persist through adolescence [4]. In the future, research findings such as these may represent an opportunity to analyse the effects of both interventions during pregnancy designed to reduce preeclampsia risk and determine to what degree maternal risk prediction is associated with neonatal outcomes. In terms of the former, an essential change in obstetric practice within the past decade has been the recommendation to administer aspirin to reduce the risk of developing preeclampsia [5]. Preeclampsia is known to be associated with increased platelet thromboxane and low doses of aspirin were found to decrease maternal platelet thromboxane selectively [6]. Randomised trials have shown that patients who received aspirin were at lower risk of developing preeclampsia [7]. A Cochrane meta-analysis found that antiplatelet agents reduced the risk of proteinuric pre-eclampsia by 18%, preterm birth by 9%, small-for-gestational-age neonates by 16%, and a composite of adverse maternal and neonatal outcomes by 10% [8]. While it is unknown how aspirin reduces the risk of preeclampsia, multiple mechanisms have been proposed, including improved placentation, decreased placental arterial vasoconstriction and increased vasodilation, inhibition of platelet aggregation leading to decreased placental infarction, and anti-inflammation [9]. If aspirin administration improves placental function, it is possible that aspirin could similarly decrease the likelihood of cardiovascular and other physiological abnormalities among neonates of at-risk women, both by reducing preeclampsia likelihood and, when present, disease severity. In terms of risk prediction, the past decade has also seen advancements in the prediction of preeclampsia, using both ultrasound and serum markers to improve the identification of women who are at high risk for this condition. Currently, the US Preventive Services Task Force recommends aspirin prophylaxis based on the presence of at least one major clinical risk factor, including multifetal gestation, chronic hypertension, pregestational type 1 or 2 diabetes, renal disease, autoimmune disease including systemic lupus erythematosus and antiphospholipid syndrome, or a history of preeclampsia [5]. Clinical risk factor screening may have limited sensitivity. However, a recent meta-analysis found that the Fetal Medicine Foundation's first-trimester prediction model for preeclampsia, which includes maternal mean arterial pressure, uterine artery pulsatility index (a measure of placental function and perfusion), serum placental growth factor, and clinical maternal factors, performed exceptionally well, with a pooled area under the receiver-operating-characteristics curve of 0.90 (95% prediction interval 0.76–0.96) for predicting preterm preeclampsia. This improved screening capability enables early identification of pregnant patients well before clinical presentation and neonatal outcomes develop. Given improved preeclampsia risk prediction, the demonstration of aspirin as a modestly effective therapeutic, and more granular outcomes data on neonates and children exposed to preeclampsia, there are new possibilities to expand our understanding of the relationship between exposures, interventions, and outcomes in patients at risk for preeclampsia and their offspring. If at-risk patients for preeclampsia can be reliably identified, including patients who are most likely to have severe disease resulting in preterm preeclampsia, fetal growth restriction, and iatrogenic preterm delivery, a more appropriate starting point in subsequent research may be the first trimester of pregnancy. Likewise, clinical outcomes and risk estimates will be most meaningful if they consider the preventive effect of aspirin therapy. Finally, maternal linkages in electronic health records to neonatal and paediatric outcomes (and to payer data in the United States) may facilitate the analysis of meaningful long-term outcomes that complement large-scale coordinated research efforts such as the Copenhagen Baby Heart Study. It may be some time before research catches up with emerging diagnostics and current clinical practices, but a comprehensive view of preeclampsia disease processes and outcomes will ultimately require granular, up-to-date models of pregnancy findings and management alongside detailed neonatal and paediatric outcomes such as those presented by Nørskov et al. Alexander M. Friedman conceived of and drafted this manuscript. Dr. Friedman is supported by funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R01HD104943); however, this funding was not used to support this research. Dr. Friedman has also served on an advisory board for Biogen and Sage. The author has nothing to report.