Hypertension in Pregnancy
Zwertbroek, Eva
DOI:
10.33612/diss.127418195
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Publication date:
2020
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Citation for published version (APA):
Zwertbroek, E. (2020). Hypertension in Pregnancy: Timing of delivery and early screening.
https://doi.org/10.33612/diss.127418195
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General introduction
GENERAL INTRODUCTION
Hypertensive disorders of pregnancy
‘Hypertensive disorders of pregnancy’ cover a broad spectrum of diseases characterized by elevated blood pressure during pregnancy. Subgroups within this group of disorders are mainly identified by the gestational age at onset of hypertension and the coexistence of proteinuria or other symptoms, as shown in table 1.1,2 Whereas HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets) was regarded as an independent hypertensive disorder in the past, it is currently seen as a specific combination of systemic symptoms and therefore a subtype of pre-eclampsia or superimposed pre-eclampsia.
Table 1. Hypertensive disorders of pregnancy: classification
Subgroup designation Hypertensiona Proteinuriab /
Other systemic symptomsc
Gestational hypertension ≥ 20weeks of gestation None
Preeclampsia ≥ 20 weeks of gestation Present
Chronic hypertension Before pregnancy OR
< 20 weeks of gestation
None OR stable pre-existing symptoms
Superimposed preeclampsia < 20weeks of gestation New OR worsening
pre-existing symptoms
a.Defined as systolic BP ≥140 and/or diastolic BP ≥90 mm Hg.
b.Usually ≥1+ on dipstick, protein/creatinin ratio ≥ 30mg/mmol or 24 hour protein ≥300mg/L c.Maternal organ dysfuncion: abnormal renal, liver, hematologic laboratory findings or neurologic complications; or fetoplacental abnormalities.
Preeclampsia affects up to 3% of all pregnancies, whereas all hypertensive disorders complicate 5-10% of all pregnancies depending on the population and the disorder.3 Hypertensive disorders can lead to renal failure, pulmonary edema, eclampsia and eventually death.4 It is the leading cause of maternal deaths in industrialized countries, accounting for 16% of maternal deaths.5 Women who survived a hypertensive disorder of pregnancy are at increased risk of recurrence in their subsequent pregnancy. In addition, long-term effects include increased risk of hypertension, cardiovascular diseases, diabetes mellitus, cognitive dysfunctions and renal dysfunction.6-8 Moreover, hypertensive disorders are also associated with risks for the neonate, such as fetal growth restriction, preterm birth, increased rate of intensive care admission and stillbirth.9 In total 4-9% of stillbirths are associated with a hypertensive disorder and up to 25% of
all preterm births are directly related to hypertensive disease.10,11 Furthermore, children born from a pregnancy complicated by a hypertensive disorder are at increased risk of long term health problems such as impaired cognitive function, high blood pressure, stroke, coronary heart disease and epilepsy.12
Etiology of hypertensive disorders of pregnancy
Even though it is generally agreed that preeclampsia originates from the presence of a placenta, the etiology remains not fully understood.13 Two theories are broadly distinguished: the disease could either be a result of abnormal placentation, or resulting from cardiovascular maladaptation.14
The most commonly accepted theory over the past decades is the placental pathway. 15 The maternal immune system is considered to adapt insufficiently to the trophoblast cells.16 This is thought to result in abnormal invasion of the trophoblast cells in the myometrium. Poor placentation, as demonstrated by insufficient spiral artery remodeling, could lead to a placenta under hypoxic conditions with oxidative stress. Hypo-perfusion as a result of abnormal placentation in preeclampsia could lead to impaired fetal growth, histological changes of the placenta and the release of e.g. vaso-active factors possibly influencing maternal physiological adaptation.
An alternative explanation for preeclampsia is that placental dysfunction is secondary to maternal cardiovascular maladaptation in pregnancy.17 Pregnancy presents a substantial cardiovascular load on the maternal heart.18 Recent studies have shown that cardiovascular dysfunction precedes the onset of the hypertensive disorder in pregnancy. In addition, cardiovascular dysfunction predominates the clinical syndrome with an increased vascular resistance, impaired myocardial relaxation and increased B-type natriuretic peptide (BNP) levels.19-21 Placental hypo-perfusion and oxidative stress may be the consequence of a suboptimal hemodynamic adaptation to the pregnancy, instead of only impaired trophoblast invasion.22,23,24,25 In addition, established risk factors for preeclampsia include advanced maternal age, obesity, ethnicity and pre-pregnancy co-morbidities such as diabetes and chronic hypertension. These factors have always been considered to predispose to poor placentation, despite all also being well-recognized risk factors for cardiovascular disease. Perhaps the strongest risk factor for developing preeclampsia is a history of preeclampsia in a previous pregnancy (Risk ratio = 8.4, 95% CI = 7.1 – 9.9).26,27 Recurrence risk
of preeclampsia could be explained by either pathways. The dispute between these two etiologies remains currently unresolved.
Managing hypertensive disorders of pregnancy
Regardless of the causal mechanisms, the occurrence of hypertension is provoked by pregnancy. Although the use of anti-hypertensive drugs and magnesium sulfate is critical for the reduction of morbidity and mortality, delivery of the baby and the placenta is the only curative treatment.28 In most patients this halts the progression of the disorder and has the potential to prevent maternal and neonatal morbidity and mortality. However, if the pregnancy is not yet advanced early delivery may result in preterm birth, which is associated with both short-term morbidity such as respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, necrotizing enterocolitis and intraventricular hemorrhage as well as long-term morbidity such as developmental problems, cognitive dysfunction and atypical psychosocial patterns.29-32 As a result, timing of delivery is a balance of maternal benefits of earlier delivery to stop disease progression versus the disadvantages of early iatrogenic delivery for the neonate.
Timing of delivery
Optimal timing of delivery depends on the severity of the disease and gestational age. In the period in which substantial neonatal morbidity is expected, between 24 and 34 weeks of gestation, the aim should be to prolong pregnancy, even in
severe hypertensive disorders.33,34 A recent meta-analysis showed that maternal outcomes are similar between inducing labor and expectant management, whereas for the neonate expectant management improves most neonatal outcomes (except for fetal growth restriction).35 On the other hand, beyond 34 weeks, women with severe hypertensive disorders should be delivered, in view
of the relatively mild neonatal morbidity.30
When a non-severe hypertensive disorder is diagnosed at term, immediate delivery should be the preferred management strategy. The HYPITAT I RCT showed that immediate delivery decreases maternal risk of progression of disease and adverse outcomes without affecting neonatal outcomes.36
In women with a non-severe hypertensive disorder diagnosed before term, benefits of delivery for the mother need to be weighed against the adverse consequences of iatrogenic preterm birth for the neonate. This issue was addressed in the HYPITAT-II (Hypertension and Preeclampsia Intervention Trial at
near Term), in which immediate delivery was compared to expectant monitoring in women with gestational hypertension or mild pre-eclampsia. The composite adverse maternal outcome occurred in 1.1% of the 352 women allocated to immediate delivery versus 3.1% of the 351 women allocated to expectant monitoring (RR 0.36, 95% CI 0.12–1.11). In the immediate delivery group 5.7% of the neonates were diagnosed with respiratory distress syndrome compared to 1.7% in the expectant monitoring group (RR 3.3, 95% CI 1.4–8.2)37. It was concluded that in women with a mild hypertensive disorder diagnosed preterm, immediate delivery is not justified as it significantly increases the short-term risk of RDS, even though it may reduce an already small risk of adverse maternal outcome. As a consequence, expectant monitoring was considered to be the preferred strategy, until the clinical situation of the women required delivery.
The advice towards timing of delivery in this group of late preterm hypertensive disorders is generally based on short term maternal and neonatal outcomes. However, long-term consequences for the neonate are important to consider. Preterm delivery, be it with or without short-term neonatal morbidity, is associated with long-term neurodevelopmental problems in the offspring.30 More precisely, below 36 weeks, risk of developmental delay increases with decreasing gestational age at birth.38 Nonetheless, very few studies have investigated long-term consequences of hypertension in pregnancy for the neonate. Pregnancies complicated by severe preeclampsia had more often impaired neurodevelopment as compared to healthy controls. In these severe preeclampsia cases, children born preterm were at increased risk of developmental problems compared to the children born at term.39 In late preterm hypertensive disorders, the long-term effects of immediate versus deferred delivery on the offspring are unknown. In the attempt to define an optimal timing of delivery in late preterm hypertensive disorders, both short-, and long-term effects on the offspring should be investigated.
Timing of delivery – best available evidence
Various randomized controlled trials have evaluated immediate delivery versus expectant monitoring at several gestational ages. These trials evaluated different hypertensive disorders and outcomes and use different criteria. Studies mostly used a composite of adverse outcomes due to the rarity of severe outcomes. All of the above makes it difficult to draw general conclusions regarding optimal timing of delivery. Combining individual participant data (IPD) from randomized
controlled trials has the potential to overcome these drawbacks and provide stronger evidence to guide clinical practice and future research.
Prediction of progression to severe disease
Although routine immediate delivery in the late preterm period (34-37 weeks) is not justified for all, some women might benefit from earlier delivery. Examples are women with an a priori higher risk of progression to HELLP or eclampsia, such as women with preeclampsia or women with a prolonged exposure to deteriorating clinical conditions i.e. nulliparous women and women with a higher cervical length. If women at high risk of progression to a more severe stage of disease could be identified and targeted for delivery, maternal complications may be reduced. At the same time, prediction may prevent unnecessary preterm births in women at low risk.40
Various predictors of maternal complications in women with hypertensive disorders have been studied in the past.41-43 Besides maternal characteristics, clinical symptoms and laboratory findings biomarkers are an upcoming field of interest. Evidence is increasing on the role of angiogenic factors: circulating maternal serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1) are increased in preeclampsia, and placental growth factor (PlGF) is decreased. Since these biomarker-tests are not yet incorporated in routine clinical practice there is need for a prediction model that includes clinically relevant parameters (preferentially parameters clinicians use when deciding on the management policy). Prevention of progression to severe disease that imposes iatrogenic (emergency) delivery is relevant. A prognostic model with clinical parameters could support clinicians in the management of late preterm hypertensive disorders by either preventing unnecessary interventions or identifying women at risk of progression to a more severe stage of the disease.
Prediction & prevention
Early prediction of preeclampsia
Early prediction of preeclampsia could allow for early intervention. A massive amount of studies have identified first trimester biophysical and biochemical markers to predict preeclampsia.44 Most studies included various variables alone or in combination: maternal risk characteristics (gestational age at
the time of assessment, age, height, weight, ethnicity, smoking status), the
general and obstetric medical history (parity, method of conception, presence
anti-phospholipid syndrome, presence of hypertensive disorders in the family),
mean arterial blood pressure, pregnancy associated plasma protein A (PAPP-A), placenta growth factor (PlGF), beta-human chorionic gonadotrophin (b-hCG), alphafetoprotein (AFP) and uterine artery Doppler. Very few models have been externally validated, which precludes their implementation in clinical practice.45 The Fetal Medicine Foundation first trimester screening algorithm includes maternal characteristics, obstetric and medical history, mean arterial blood pressure, uterine artery Doppler, and maternal serum markers (PAPP-A and PlGF). This screening algorithm has been extensively studied, updated and externally validated in different populations. The FMF screening algorithm predicts 90% of early preeclampsia, before 32 weeks. For preeclampsia occurring up to 37 weeks, the FMF algorithm predicts 85% of cases. This is achieved at a screen positive rate of 10%.46 Nonetheless, based on the study of Allen et al, the algorithm is not yet optimal to differentiate between the highest and lowest risk groups and it should be validated before applying it to a specific population.45 An accurate prediction model is needed to identify who is at high risk and may need preventive treatment.
Prevention
Over the last decades, extensive research focused on prevention of preeclampsia via supplementation with calcium, folic acid, vitamins E and C and aspirin.47-49 Aspirin is well-known for its safety outside pregnancy and is now part of standard antenatal care.50 When administered before 16 weeks it reduces the risk of preeclampsia, fetal growth restriction, preterm birth and perinatal death. The benefits, however, seem dose related: a dose of >80mg seems to be optimal.51 In 2018, the ASPRE trial, randomized women to 150 mg of aspirin or placebo from 11 to 36 weeks of gestation. Aspirin use reduced early preeclampsia by 60% but did not reduce term preeclampsia.52 The hypothesis is that aspirin shifts the onset of preeclampsia towards a more advanced gestational age or even to the end of pregnancy.53 Early preeclampsia has the strongest association with neonatal complications (due to preterm birth or growth restriction), and maternal complications (because of the prolonged time to term). The ASPRE trial included women at high risk of preeclampsia as identified by the FMF preeclampsia screening algorithm. Prior to implementation of the findings of the ASPRE trial (administration of 150mg aspirin to ‘high risk’ patients) the ‘high risk’ population should be properly defined. Currently, administration of aspirin is prescribed for women with strong risk factors of preeclampsia.54,55 Screening by risk factors as recommended by the National Institute for Health and Care Excellence (NICE)
only detects 46% of early preeclampsia and 42% of preterm preeclampsia, at a screen positive rate of 12%.56 The American Congress of Obstetricians and Gynecologists (ACOG) only recommends aspirin for women with a history of preeclampsia in at least two pregnancies or preeclampsia requiring delivery < 34weeks57. This results in a detection rate of 6% of early preeclampsia and 5% for preterm at a false positive rate of 0.2%.56 The majority of high risk women are not correctly identified in current standard practice. The FMF algorithm is superior in terms of detection and false positive rates to screening by only a ‘checklist’ as the national guidelines recommend. Even though this algorithm has been extensively evaluated and improved in the UK, a validated screening algorithm for the specific population is needed before implementing the ASPRE recommendations worldwide. This is also recommended by the International Society for the Study of Hypertension in Pregnancy (ISSHP).1.
AIM AND OUTLINE OF THIS THESIS
The aim of this thesis is to investigate strategies to prevent health problems - both in the mother and the child - related to hypertensive disorders of pregnancy. This is achieved on the one hand by providing insight on short and long-term consequences of immediate delivery and expectant monitoring in non-severe late preterm hypertensive disorders. Furthermore we aim to evaluate the performance of first trimester prediction of hypertensive disorders to allow for early intervention to prevent preeclampsia.
Part 1. Timing of delivery for optimal management in late preterm hypertensive disorders.
The HYPITAT-II trial compared immediate delivery with expectant monitoring for women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation. Chapter 2 contains the 2 year follow up of the children after the HYPITAT II trail and chapter 3 contains the 5 year follow up of this RCT. Chapter 4 describes the risk assessment of progression to severe disease, based on the expectant monitoring arm. The results of the Individual participant data meta-analysis (IPDMA) of immediate delivery versus expectant monitoring in women with hypertensive disorders beyond 34 weeks of gestation are described in chapter 5.
Part 2. Future perspectives: early prediction and prevention of preeclampsia.
Chapter 6 describes a prospective cohort study, which evaluates the performance of the Fetal Medicine Foundation first trimester preeclampsia screening algorithm in the Netherlands. The reproducibility and repeatability of one of the predictors in the algorithm, the uterine artery pulsatility index, is evaluated in chapter 7.
Part 3. Summary, general discussion and conclusion.
Chapter 8 contains a summary of the thesis, a general discussion, future perspectives and conclusion. This chapter puts the work described in this thesis in the context of current clinical practice.
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57. Committee opinion summary no. 638: First-trimester risk assessment for early-onset preeclampsia.
