Pre-eclampsia, and in particular severe pre-eclampsia, represents a significant risk to maternal health. Treatment of elevated blood pressure – one of the primary signs of pre-eclampsia – reduces the risk for maternal complications such as cerebral haemorrhage and cerebral oedema. Regimens for the acute treatment of very high blood pressure (sBP ≥160mmHg and/or dBP ≥110mmHg) that have been subjected to clinical trials have generally used medications administered intravenously (e.g., hydralazine and labetalol).
While these regimens are effective, they present certain challenges in low-resource settings. They require intravenous access and careful monitoring as they may reduce blood pressure overly rapidly, potentially destabilising maternal haemodynamics at the expense of the fetal condition. A number of oral strategies have been suggested, and a few have been described in clinical practice. However, we are unaware of any trials comparing oral regimens alone. Evidence of the relative risks and benefits of different oral regimens will help to develop the data to provide guidance for antihypertensive use in pregnancy, especially where multiple drugs are available.
In collaboration with colleagues at the University of British Columbia, the University of Washington, Government Medical College (GMC) and Daga Memorial Women’s in Nagpur, India, Gynuity Health Projects is conducting a study testing three oral regimens for women with severe hypertension in pregnancy.
To compare the efficacy of oral labetalol, oral nifedipine, and oral methyldopa for management of severe hypertension in pregnant women.
- To assess adverse outcomes and necessity for additional hypertensive treatment among women in the three study arms.
- To assess maternal and fetal outcomes among women in the three study arms
Phase 1. A pilot study of three oral antihypertensive regimens for management of acute hypertension in pregnancy
Given the uncertainty of the effect of each of these drugs on this population, first we will conduct an open-label pilot study of the three proposed drug regimens prior to start of the randomized trial. The pilot will enroll 10 women in each study group (group A, then B, then C [below]), in succession. The pilot study will allow us to confirm the accuracy of our efficacy estimates and evaluate the proposed dosing regimens and any potential logistical problems prior to the start of the larger trial.
Group A: Women will receive 10mg oral nifedipine (intermediate acting). If either sBP exceeds 155mmHg or dBP 105mmHg after 1h, an additional 10mg dose can be provided each hour for two additional doses (30mg total).
Group B: Women will receive oral labetalol 200mg. If either sBP exceeds155mmHg or dBP 110mmHg after 1h, an additional 200mg dose can be provided each hour for two additional doses (200mg).
Group C: Women will receive a single dose of methyldopa 1000mg.
Three arm RCT
Women will be allocated by chance to one of three oral antihypertensive regimens: labetalol, nifedipine, or methyldopa. Rates of efficacy, side effects, and maternal and fetal outcomes will be assessed and compared. Enrolled women will be randomised to one of three treatment groups (the final dosing regimens will be determined from the dose finding phase 1).
Group A: Women randomised to Group A will receive 10mg oral nifedipine (intermediate acting); dose escalation determined by the pilot phase.
Group B: Women randomised to Group B will receive oral labetalol 200mg; dose escalation determined by the pilot phase.
Group C: Women randomised to Group C will receive a single dose of methyldopa 1000mg; dose escalation determined by pilot phase.
In all groups, if the treatment goal (defined as sBP 130-150mmHg and dBP 80-100mmHg) is achieved within 6h treatment will be continued up to 24 hours postpartum unless deemed clinically unnecessary after delivery. If the treatment goal is not achieved within 6h, women will receive the standard of care treatment for this indication. After the administration of the drugs, BP and pulse will be recorded every 20min.
The primary outcome will be a BP within the target range at 6h without an adverse outcome. Adverse outcomes include hypotension (sBP <120 mmHg and/or dBP <70 mmHg and foetal compromise), Caesarean section for fetal distress, severe headache or eclampsia.
As of 1 March 2017, 694 women were enroled. We anticipate trial enrolment will be completed in September 2017.