Volume 03 · Issue 02 · 2021

Preeclampsia (PE), a multisystem disorder in pregnancy, is a main cause of perinatal mortality and is associated with long-term maternal complications. For a long time, PE was defined as the new onset hypertension and proteinuria after 20 weeks’ gestation. It had been shown that this "gold standard definition" is not able to provide a sufficient prediction of PE-related fetal and/or maternal complications. In 2018 the International Society for the Study of Hypertension in Pregnancy recommended a broader definition of the disease. The new definition of the International Society for the Study of Hypertension in Pregnancy ruled out proteinuria as mandatory for the diagnosis of PE. This new definition increases the number of patients diagnosed as preeclamptic by nearly 21%, which is not accompanied by an increased severity of maternal outcomes. Including angiogenic biomarkers, however, has been shown to increase detection of adverse outcomes.

The pathophysiology of PE is complex and not yet completely explained. Advances in prediction and diagnosis have been achieved by discovery and clinical evaluation of biomarkers, especially of placental origin. A broad spectrum of biomarkers has been tested, a few of them have been introduced into the clinical practice as of today. Especially angiogenic biomarkers that are rooted in the pathophysiology of PE have been demonstrated to be important in the prediction and diagnosis of adverse outcomes. At a cut-off value of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF)-ratio of 85, early-onset PE <34⁺⁰ weeks of gestation can accurately be diagnosed with a sensitivity of 89% and a specificity of 97%. The Prediction of short-term outcome in pregnant women with suspected preeclampsia (PROGNOSIS) study has shown that the high negative predictive value (99.3%) of the sFlt-1/PlGF-ratio below 38 in patients with suspected PE rules out the onset of the disease within one week. PROGNOSIS Asia, evaluating the sFlt-1/PlGF-ratio cut-off of 38 in an Asian population, confirmed the excellent accuracy in prediction.

Recently, the angiogenic biomarkers have been integrated in multi-marker prediction models. Digital approaches, integrating algorithm-based decision support tools paired with home monitoring devices may be the next step in enhancing predictive accuracy and thus bear the potential to reduce maternal and/or fetal morbidity and mortality and save costs for the payer in parallel. The objective of this review is to provide an overview of current methods for predicting and diagnosing PE.

Preeclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality worldwide. This disorder has profound short-term and long-term impacts on both the affected woman’s and her child’s health. Early-onset PE requiring preterm delivery (preterm PE) is of particular importance because it is associated with a higher risk of adverse pregnancy outcomes than term PE. First trimester screening model developed by the Fetal Medicine Foundation (FMF), which uses Bayes-theorem to combine maternal characteristics and medical history together with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, has been proven to be effective and have superior screening performance to that of traditional risk factor-based approach for the prediction of PE. Identification of high risk pregnant women for preterm PE and giving aspirin prophylaxis before 16^th week of gestation would reduce the incidence of preterm PE. In Asia, although the prevalence of PE is slightly lower than the global estimation, early screening and prevention of this life-threatening condition is still crucial. The FMF Bayestheorem based screening method has been validated in a large-scale prospective Asia-wide study and revealed that the first trimester triple test achieves the highest detection rate, compared with the traditional risk factor-based approaches, and that the screening performance is comparable to the published data from the FMF in East Asian women. However, in order to achieve optimal screening performance, the key is to establish standardized methods for biomarker measurements and regular biomarker quality assessment, as each biomarker is susceptible to inaccurate measurement, thus affecting performance of screening. Furthermore, it is of great importance to emphasize that the optimal preventive effect of aspirin on preterm PE is clearly associated with good compliance to treatment. In conclusion, global implementation of an effective first trimester "screen and prevent" program for preterm PE would provide the opportunity to reduce the risk of both short-term maternal and perinatal morbidity and mortality, with the possibility of intergenerational prevention of future chronic diseases for both the mother and her offspring.

Hypertension in pregnancy is currently defined as a systolic blood pressure (BP) of 140 mmHg or more, or a diastolic BP of 90 mmHg or more. This level of BP warrants antihypertensive therapy. Treating to a target BP of 135/85 mmHg halves the risk of severe hypertension that is itself associated with adverse maternal and perinatal outcomes, similar in magnitude to preeclampsia. While based on the results of the Control of Hypertension in Pregnancy Study (CHIPS) trial, this finding is consistent with all antihypertensive trials to date. Also, in the CHIPS trial, "tight" BP control also halved the risk of progression to thrombocytopenia and elevated liver enzymes for the mother, without adverse effects for the fetus or newborn. This was true regardless of the gestational age at which BP control was instituted. While methyldopa, labetalol, and nifedipine are the most commonly-recommended oral antihypertensives, it is not clear that one antihypertensive agent has advantages over the others for treatment of non-severe hypertension in pregnancy. No antihypertensives, including renin-angiotensin-aldosterone system (RAAS) inhibitors, have been shown to be teratogenic, although there may be an increase in malformations associated with the underlying condition of chronic hypertension. Atenolol and RAAS inhibitors should not be used once pregnancy is diagnosed, based on fetotoxicity. At present, BP treatment targets used in clinic are the same as those used at home as the differences are quite variable among hypertensive women. For treatment of acute severe hypertension, the most commonly-recommended antihypertensives are oral nifedipine, IV labetalol, and IV hydralazine, although oral agents have also been shown to be effective in the majority of women; while concerns raised about IV hydralazine-induced maternal hypotension and its consequences have not been confirmed, this medication may be an inferior antihypertensive to oral nifedipine. While treatment recommendations are based on evidence, women should be engaged in decision-making, as their values may alter target BP and antihypertensive choice. Future work will clarify the optimal target BP based on home BP measurements; whether BP targets should be lowered further if the definition of hypertension is based on a lower BP; which, if any, antihypertensive medication for non-severe hypertension is better with regards to maternal and perinatal outcomes; and whether factors beyond BP level (such as variability, race, and other physiological variables) should inform antihypertensive therapy in pregnancy.

Preeclampsia remains associated with an increased risk of maternal and perinatal morbidity and mortality, and the burden of that excess risk is largely borne by pregnant women and their families in low- and middle-income countries (LMICs). Therefore, the Bill & Melinda Gates Foundation funded the PREeclampsia - Eclampsia Monitoring, Prevention, and Treatment (PRE-EMPT) initiative to accelerate progress. From PRE-EMPT, and related activity, have come a number of impactful findings. First, there is increasing global support for broadening the definition of preeclampsia to include women with hypertension and either significant proteinuria or evidence of target organ damage or fetoplacental compromise (including evidence angiogenic imbalance). Second, using blood pressure (BP) data from the Community-Level Interventions for Preeclampsia trials in India, Mozambique, and Pakistan, acquired on validated-for-pregnancy, semi-automated, low-cost BP devices, there are now population-level, rather than facility-based, estimates for the burden of pregnancy hypertension (sub-categorized into preeclampsia (4%-6%), gestational hypertension (7%-12%), and chronic hypertension (0.3%-0.6%)). Third, there is an identified need to understand biological pathways that underlie the causation of preeclampsia in LMICs. Fourth, the Community-Level Interventions for Preeclampsia trials have shown that providing at least eight antenatal contacts, in this case using digital health-supported community health workers, cost-effectively reduces the burden of maternal (by 60%), fetal (60%), and neonatal (40%) mortality. Fifth, what is the utility and cost-effectiveness of routine proteinuria screening of normotensive pregnant women? Sixth, clinical risk factor-based prediction of preeclampsia remains most relevant for most women in LMICs; calcium replacement (≥1 g/day) and low-dose aspirin (100-175 mg/day) are the most useful directly preventative interventions. However, achieving sustainable development goals (SDGs) not directly related to health are more likely to reduce the global burden of preeclampsia and its consequences. Seventh, should a woman develop preeclampsia, personalized maternal time-of-disease risk estimates are available through the PIERS (Preeclampsia Integrated Estimate of RiSk) models, either with (fullPIERS) or without (miniPIERS) access to laboratory testing. Assessment of perinatal risks in LMICs is largely driven by gestational age; however, evidence of significant angiogenic imbalance may identify risk of intrauterine fetal death. Eighth, Control of Hypertension in Pregnancy Study trial data show that women with non-severe pregnancy hypertension (systolic BP 140-159 mmHg or diastolic BP (dBP) 90-109 mmHg) should receive an antihypertensive medication for a target dBP of 85 mmHg. Ninth, for women with severe pregnancy hypertension (systolic BP ≥160 mmHg or dBP ≥110 mmHg), oral antihypertensive management with either nifedipine, labetalol, or, less so, methyldopa will lower BP into the non-severe hypertension range. Tenth, magnesium sulfate remains the sole agent of choice for preventing and treating eclamptic seizures. Eleventh, corticosteroids should be administered to women at risk of delivery <35⁺⁰ weeks’ gestation. Twelfth, although delivery of the placenta initiates resolution of the maternal syndrome of preeclampsia, decisions to initiate delivery should be guided by gestational age and maternal and fetal status. Many women will experience significant postpartum deterioration; delivery should not be equated with "cure" . Thirteenth, whether the development of preeclampsia identifies women at increased risk for early-onset cardiovascular disease in LMICs must be determined.

The syncytiotrophoblast, a fused single-cell layer between mother and fetus, constitutively releases extracellular vesicles (STBEV) directly into the maternal circulation. STBEV contain a variety of proteins and RNA which can be targeted to specific cells. In preeclampsia, asymptomatic placental oxidative stress is a precursor to later multi-organ dysfunction in the mother. Increased STBEV release in preeclampsia is considered a manifestation of syncytiotrophoblast stress, which may play a key role in signaling between fetus and mother. STBEV release in preeclampsia changes, both in terms of volume and content. In this review, we outline the latest advances in STBEV isolation and detection. We consider evidence for differential STBEV release, protein cargo and RNA content in preeclampsia, highlighting common pitfalls in study design. We summarise studies to date demonstrating STBEV actions on target cells. Ultimately, we consider how STBEV fit into the pathophysiology of the heterogeneous syndrome of preeclampsia. The key unifying concept in early- and late-onset preeclampsia is syncytiotrophoblast stress. We submit that STBEV are the key stress signal in preeclampsia. We believe that further investigation of STBEV release, content, and actions may offer valuable insights into preeclampsia pathophysiology and potential new clinical diagnostics and therapeutic targets.