Center for Advanced Research in Hypertensive Disorders of Pregnancy

Rationale/gaps

HDP affect nearly 10% of pregnancies, and preeclampsia increases maternal/ perinatal morbidity/mortality risks.  Hypertension is a protective adaptive response to ensure perfusion to the fetus. So, maternal/fetal outcomes can be optimised by (1) maintaining BP to ensure placental perfusion without increasing maternal risk and (2) timing delivery to reverse the changes without compromising neonatal outcomes. Long-term complications of pre-eclampsia include cardiovascular disease, obesity and cognitive dysfunction. Recent reviews suggest a six-fold higher risk of hypertension within 2 years of birth in women who experienced pre-eclampsia and persistence of cardiac changes. In the CHIPS trial, tight control (diastolic BP <85mmHg, as opposed to 100-105mmHg) resulted in a reduction in severe hypertension without a reduction in maternal adverse events. A non-significant increase in pregnancy loss or NICU care was noted, with subgroup analysis showing higher adverse perinatal outcomes (OR 1.8,95%CI 1.0-3.4) among gestational hypertension with tight BP control.Lower adverse events are observed with (i) a reduction in central BP rather than peripheral BP(pBP) and (ii) a reduction in PP amplification, leading to beneficial effects on microvasculature.  Both these benefits are noted with calcium channel blockers and ACEI; compared to beta-blockers such as labetalol, which primarily reduces pBP, In a meta-analysis, amlodipine with no reflex tachycardia and lower BP variability achieved better BP control than intermediate-release nifedipine. ACEIs reverse cardiac remodelling, but this effect in postpartum is uncertain. After HYPITAT trials, most guidelines recommended delivery by 37 weeks. However, in the HYPITAT-1 trial, maximum reduction of composite adverse events was shown with delivery at 38-39 weeks (RR 0.63;0.43-0.94) than those delivering earlier (RR 0.75;0.52-1.08).

Novelty

Guidelines for the management of the HDP highlight the lack of information regarding the ideal threshold for initiating antihypertensive medication and inconclusive evidence on the choice of first-line antihypertensives. The current choices are extrapolated from information from the CHIPS trial, which mainly included chronic hypertensives. This study proposes to identify the ideal threshold to initiate and titrate treatment, comparing tight control of BP (initiate at 90mm Hg and maintain below that level) to a higher cut-off (initiate at 150/ 100 mmHg and maintain between 140-150/90-100 mm Hg). With better central hemodynamic effects, amlodipine may be superior to labetalol or nifedipine (the current antenatal first-line antihypertensive). The ACE inhibitors, which are safe in lactation and can reverse cardiac remodelling, or Amlodipine with better central effects, may be better antihypertensive medications in the postpartum period.  With the least perinatal adverse outcome and loss reported at 39weeks, the study will also assess the timing of delivery in women with preeclampsia or gestational hypertension, comparing delivery at 37 weeks or prolonging up to 39weeks, unlike earlier trials where expectant management was continued till 41weeks, probably leading to more adverse events. An economic analysis is planned alongside the clinical trial.

Objectives

1. To determine if short-term maternal/fetal and long-term outcomes differ with different thresholds (140/90mmHg vs. 150/100mmHg) of antihypertensive initiation and choices of medications (Labetalol, Nifedipine, Amlodipine) for hypertension during pregnancy.

2. To assess whether the incidence of short-term maternal/fetal and long-term outcomes differs between delivery at 37 weeks and 39 weeks.

3. To evaluate the impact of treatment thresholds (140/90mmHg vs. 150/100mmHg) and antihypertensive choices (Labetalol, Enalapril, Amlodipine) on composite adverse and long-term maternal outcomes for postpartum hypertension.

4. To assess the cost-effectiveness of the above antihypertensive management strategies and delivery timing for HDP from healthcare system and societal perspectives, focusing on maternal and neonatal health outcomes.

Methods

Three pragmatic randomised controlled trials, two of which are SMART trials, will be conducted among those with HDP, excluding those requiring delivery within 48 hours and chronic hypertension in seven tertiary centres.For assessing BP threshold and choice of anti-hypertensive, women will enrol at 30 weeks or later. Stratified randomisation(site and type of HDP) will be followed, with block randomisation sequence concealed in a sequential number of opaque envelopes. Monitoring with BP(three times daily), investigations evaluating target-organ involvement and weekly monitoring with ambulatory BP (peripheral and central BP) will be done. FOCUS for hemodynamic evaluation will be done at enrolment, before planning delivery, and hospital discharge. Women developing any complications between 30-36 weeks will be managed following institute protocols, and the details of the outcomes and mode of delivery will be collected.  Those not delivered by 36 weeks gestation or admitted between 36- 39 weeks will be randomised for the timing-of-delivery arm, and delivery will be completed by 39 weeks. BP monitoring is continued in postpartum, and laboratory investigation will be performed when indicated in postpartum. Those with BP > 140/90mmHg will be randomised in the postpartum arm.

Follow-up will be done on the 2nd & 6 weeks, and at 3, 6,12, and 18 months with the evaluation of BP (central and peripheral), hemodynamic profile, renal function and mental health screening with PHQ9 questionnaire.

Short-term outcomes: Need for additional antihypertensive and severe hypertension episodes, composite adverse (a) maternal or (b) perinatal outcome

Long-term outcomes: Adverse Maternal cardiovascular or mental health problems or adverse infant outcomes.

Expected Outcomes

This study aimed at identifying the threshold as well as the choice of antihypertensive in women with preeclampsia and gestational hypertension without severe disease, both in the antenatal and the postpartum period. It might also suggest reducing the risk of adverse perinatal events, without the increase in adverse maternal outcomes, by aiming to deliver all by 39 weeks compared to delivering at 37 weeks. This is unlike the other trials where the expectant management is continued till 41 weeks, which might have increased the risk of complications for the mother. The choice of the antihypertensive, as well as the effect of other interventions, the i.e. threshold of starting antihypertensive and the timing of delivery on the short and long-term adverse outcomes or events to the mother and baby, will also be assessed. This will also result in the identification of those women at increased risk of discharge in the postpartum, which can aid in implementing a targeted approach of follow-up and intervention in the future for women identified as high-risk. An economic analysis planned alongside the clinical trial will aid in assessing the implication of these initiatives in our setting for adaptation into guidelines.