Preeclampsia: Short-term and Long-term Implications

The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring's life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes presented increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in females. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.

Hypertension complicates 2% to 8% of all pregnancies and is a leading cause of maternal and perinatal morbidity and mortality globally. Given the prognostic role that angiogenic markers play in evaluation of patients with “suspected preeclampsia,” the International Society for the Study of Hypertension in Pregnancy incorporated angiogenic imbalance into the 2021 definition of preeclampsia. As women with “suspected preeclampsia” are a heterogeneous group, with some already meeting the diagnostic criteria for preeclampsia, we evaluated whether the soluble fms-like tyrosine kinase-1/placental growth factor ratio adds prognostic value among these women.

This study aimed to assess the additive value of soluble fms-like tyrosine kinase-1/placental growth factor ratio when the diagnostic criteria for preeclampsia have already been met.

This was a secondary analysis of a prospective cohort study of patients presenting to obstetrical triage with suspected preeclampsia at ≥20⁺⁰ weeks’ gestation from July 2009 to June 2012 in Boston, United States. Clinicians were masked to soluble fms-like tyrosine kinase-1/placental growth factor ratio results. Clinical records were reviewed for maternal and neonatal care and outcomes. The value of the soluble fms-like tyrosine kinase-1/placental growth factor ratio (≤38, >38, or >85) was assessed for identifying women at low or high risk of evolving into preeclampsia with severe features within 2 weeks of the triage visit, with preeclampsia with severe features being defined by the American College of Obstetricians and Gynecologists (2013 definition). Based on information in obstetrical triage, preeclampsia among triage patients was defined either by: (1) The International Society for the Study of Hypertension in Pregnancy “restrictive” criteria (ie, new-onset hypertension and proteinuria at ≥20 weeks), or (2) The International Society for the Study of Hypertension in Pregnancy “broad” maternal criteria (ie, new-onset hypertension with proteinuria or one/more relevant maternal end-organ complications).

Of 1043 patients included, 459 presented at 20⁺⁰ to 34⁺⁶ weeks and 584 at ≥35⁺⁰ weeks. In triage, 25.8% of women with “suspected preeclampsia” already met the preeclampsia criteria based on the International Society for the Study of Hypertension in Pregnancy broad criteria and 22.0% based on the restrictive criteria. In separate multivariable analyses adjusted for gestational age, a soluble fms-like tyrosine kinase-1/placental growth factor ratio >38 was independently associated with preeclampsia with severe features within 2 weeks even after adjusting for preeclampsia diagnosis in obstetrical triage, whether that preeclampsia were defined restrictively (odds ratio, 15.62; 95% confidence interval, 8.91–27.40) or broadly (odds ratio, 14.56; 95% confidence interval, 8.30–25.56). A soluble fms-like tyrosine kinase-1/placental growth factor ratio ≤38 was good at ruling out development of preeclampsia with severe features within 2 weeks among all patients and among those meeting the restrictive or broad definitions of preeclampsia (negative likelihood ratios, ≤0.16), driven by performance of the ratio before 35 weeks (ie, negative likelihood ratio ≤0.12). A soluble fms-like tyrosine kinase-1/placental growth factor ratio >85 was good at ruling-in preeclampsia with severe features within 2 weeks among women with suspected preeclampsia, either before (positive likelihood ratio, 8.20) or after 35 weeks (positive likelihood ratio, 6.00) and fair at ruling-in preeclampsia with severe features within 2 weeks when preeclampsia had already been confirmed in patients at <35 weeks (restrictively positive likelihood ratio, 3.48, or broadly positive likelihood ratio, 3.40).

Our findings support the prognostic value of the soluble fms-like tyrosine kinase-1/placental growth factor ratio among patients with confirmed preeclampsia, particularly to identify those both likely and unlikely to progress toward the development of severe features in the next 2 weeks and those who may be most appropriate for expectant and potentially outpatient care. Our findings support the incorporation of angiogenic imbalance into the definition of preeclampsia, particularly at 20–34⁺⁰ weeks.

It is not fully elucidated whether preeclampsia (PE) is a marker or a cause of chronic kidney disease (CKD). To test the hypothesis of a biphasic relationship between PE and CKD, we assessed PE prevalence in women who underwent a kidney biopsy.

This retrospective, observational study recruited patients who underwent a kidney biopsy after delivery in 2014 to 2019 in 3 Italian Centers (Cagliari, Bari, Messina); low-risk pregnancies observed in Cagliari served as controls. A history of PE was assessed on the clinical charts and by phone interview.

In the biopsy cohort (379 pregnancies, 205 patients; 38 PE in 32 patients), kidney biopsy shows clustering in the first 5 years after PE (11 of 32). Pre-existing CKD was detected in 8 of 11 of these cases. Focal-segmental glomerulosclerosis (FSGS) and complex lesions were found in 12 of 32 biopsies. The odds ratio (OR) of having had a PE episode, compared with 561 low-risk pregnancies, was 10.071 (95% CI: 4.859–20.875; P < 0.001); multiparity maintained a protective effect (OR: 0.208). The delivery-to-biopsy time was significantly shorter in women with PE, both considering the first or the last PE versus the first or last delivery in patients with or without PE episodes. The characteristics of PE did not differ as compared with low-risk controls.

Within the limitation of the retrospective design, our study, quantifying the association between needing a kidney biopsy and history of PE, suggests a biphasic pattern, with a peak in the first 5 years after delivery (probably due to pre-existing diseases) and a later increase, suggesting that PE may have later played as one hit in a multiple-hit pathogenesis.

Pre-eclampsia is associated with an increased risk of future cardiovascular disease. Maladaptive placentation or malperfusion, as well as predisposing cardiovascular or metabolic risk for endothelial dysfunction, contribute to the systemic inflammatory response that establishes the origins of the disease. The purpose of this study was to investigate the relationship between placental size and cardiovascular risk when assessed at six months postpartum in women who experienced pre-eclampsia.

Maternal clinical and biochemical cardiovascular risk factors were used to categorize preeclamptic women into high vs. low lifetime cardiovascular disease risk profiles at six months postpartum. A multivariable logistic regression model was then used to identify the association between placental weight to birth weight ratio and high lifetime cardiovascular disease risk, adjusting for maternal age, pre-pregnancy BMI, and severity of pre-eclampsia. A p-value of < 0.05 was deemed statistically significant.

186/216 women with pre-eclampsia who attended the Maternal Health Clinic met inclusion criteria. No significant differences were observed for placental morphometric measurements between women who screened as having a high vs. low lifetime risk profile for cardiovascular disease at six months postpartum. However, using multivariable modelling that controlled for maternal age, pre-pregnancy body mass index, gestational age at delivery, and severity of pre-eclampsia, a low placenta to birth weight ratio (<15%) was associated with an increased odds of high lifetime cardiovascular disease risk (p < 0.009).

The findings of the current study identify clinical measurements that can be collected at the time of delivery which may help identify specific women who may benefit most from postpartum cardiovascular risk screening and intervention.

Aortic intima-media thickness (aIMT) and its ratio to aortic diameter (aIMT/AoD) were measured on the second and fifth postnatal day in 39 neonates exposed to early-onset preeclampsia and 39 controls. Both aIMT and aIMT/AoD were higher in neonates exposed to preeclampsia (P < 0.001 for all comparisons).

To compare outcomes, specifically development of preeclampsia with severe features (sPE), between angiogenic biomarker-based admission and admission based on routine clinical care.

This secondary analysis of a prospective study evaluated soluble fms-like tyrosine kinase-1 (sFlt1)/placental growth factor (PlGF) ratio in women presenting to triage for preeclampsia evaluation. Biomarkers levels were measured in samples collected from triage and analyzed retrospectively after outcomes were achieved. For this analysis patients would be hypothetically assigned to ‘discharged’ with a sFlt1/PlGF ratio ≤ 38 and ‘admitted’ with a sFlt1/PlGF ratio > 85. Development of sPE and other outcomes were then compared using the biomarker and clinical criteria for admission.

459 patients were included in this analysis. Using biomarker criteria, a larger proportion of patients were hypothetically discharged (67.8% vs 51.0%, p < 0.0001). A larger proportion of patients ’admitted’ with a high biomarker level developed sPE (69.5% vs 40.9%, p < 0.0001). A sFlt1/PlGF ratio ≤ 38 had a negative predictive value of 96.8% for development of sPE within two weeks.

Assessment of angiogenic biomarkes that ’discharges‘ patients with a low sFlt1/PlGF ratio and ’admits’ patients with high ratio could result in reduced admissions and increased admission of patients at risk for developing sPE. Randomized trials are needed to determine the effectiveness of angiogenic biomarker use in decision making in a triage setting among women with suspected preeclampsia.