Antihypertensive therapy for pregnancy hypertension and implications for fetal and neonatal heart rate monitoring: A systematic review of randomized trials and observational studies

Abstract

Introduction: Our objective was to evaluate whether antihypertensives affect fetal (FHR) or neonatal (neoHR) heart rate.

Material and methods: Electronic databases and clinical trial registers were searched to August 31, 2024. Eligibility included randomized (RCTs) or observational studies evaluating antihypertensives for pregnancy hypertension. Two reviewers independently assessed studies for inclusion and extracted data. Random effects meta-analysis was used to determine risk ratios (RRs) and 95% confidence intervals (CIs). Network meta-analysis was undertaken in a sensitivity analysis.

Results: Fifty-four RCTs (n = 5736 pregnancies) and 28 observational studies (n = 2 283 855) reported FHR (usually visually-interpreted) or neoHR (usually clinically-assessed). FHR: NON-SEVERE HYPERTENSION: Antihypertensives did not increase adverse FHR effects in RCTs of antihypertensives versus placebo/no therapy (RR = 1.08, 95% CI [0.62-1.89]; I² = 43%; N = 10, n = 1567 pregnancies), antihypertensives versus methyldopa (RR = 1.40 [0.97-2.04]; I² = 0%; N = 6, n = 515), or labetalol or pure beta-blockers versus other antihypertensives (RR = 1.70 [0.96-2.99]; I² = 30%; N = 5, n = 501). In observational studies, adverse FHR effects were more common with: labetalol versus methyldopa, nifedipine or Chinese herbal medication (RR = 2.17 [1.15-4.08]; I² = 47%; N = 4, n = 664), and bendroflumethiazide versus metoprolol (but not hydralazine), but 95% CIs were wide. FHR: SEVERE HYPERTENSION: Antihypertensives had no FHR effects in RCTs of antihypertensives versus either: placebo/no therapy (RR = 0.43 [0.16-1.20]; I² = 0%; N = 3, n = 242), hydralazine (RR = 0.71 [0.29-1.72]; I² = 13%; N = 11, n = 727), or CCBs (RR = 0.52 [0.12-2.16]; I² = 0%, N = 9, n = 1675). In observational studies, there was no difference for labetalol versus other antihypertensives (RR = 0.34 [0.10-1.14], I² = 87%; N = 4, n = 590), with heterogeneity due to a lower-quality labetalol versus hydralazine study. There were fewer adverse FHR effects for nifedipine versus hydralazine study (RR = 0.09 [0.01-0.68]; n = 49).

Neohr: SEVERE HYPERTENSION: RCTs of antihypertensives versus placebo/no therapy were not associated with adverse neoHR effects (RR = 1.26 [0.31-5.19]; I² = 66%; N = 4, n = 406), with heterogeneity attributed to more neoHR effects with continuously monitored neoHR. Observational studies revealed no effect on neoHR of antihypertensives versus no therapy (RR = 1.06 [0.67-1.67]; I² = 54%; N = 4, n = 37 359), but labetalol was associated with more adverse effects and metoprolol with fewer. In RCTs of antihypertensives versus other antihypertensives, there was no difference in adverse neoHR (RR = 3.0 [0.13-71.74]; N = 3, n = 162). Observational studies showed adverse neoHR effects in labetalol versus pure beta-blockers (RR = 1.99 [1.36-2.91]; I² = 0%; N = 3, n = 16 204). No severe hypertension RCTs reported neoHR. Observational studies were limited. Network meta-analysis showed no significant relationships between antihypertensives and FHR or neoHR; 95% CIs were very wide.

Conclusions: Evidence is inadequate to draw reliable conclusions about the impact of antihypertensives on FHR or neoHR. At present, adverse FHR or neoHR effects should be attributed to evolving placental dysfunction.

Keywords: antihypertensive; fetal heart rate; neonatal heart rate; observational study; pregnancy; randomized trial.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 flow diagram for updated systematic reviews which included searches of databases, registers, and other sources. N, number; OBS, observational; RCT, randomized controlled trial. *From studies in the Waterman et al. review, one RCT was excluded due to overlap, an two OBS studies were excluded due to wrong outcome and study design. †For a list of trials excluded, please see Table S2.

FIGURE 2

(A) Forest plots of RCTs assessing the impact of antihypertensives (vs. placebo/no therapy) on adverse FHR effects, among women treated for non‐severe hypertension. (B) Forest plots of RCTs assessing the impact of antihypertensives (vs. methyldopa) on adverse FHR effects among women treated for non‐severe hypertension. (C) Forest plots of RCTs assessing the impact of labetalol or other beta‐blockers (vs. other antihypertensives) on adverse FHR effects among women treated for non‐severe hypertension. (D) Forest plots of OBSERVATIONAL studies showing the effects of antihypertensives (vs. other antihypertensives) on adverse FHR effects among women with non‐severe hypertension. B‐blocker, beta‐blocker; CCB, calcium channel blocker; FHR, fetal heart rate; RCTs, randomized controlled trials.

FIGURE 3

(A) Forest plots of RCTs evaluating the impact of antihypertensive therapy (vs. placebo/no treatment) on adverse FHR effects, among women with severe hypertension. (B) Forest plots of RCTs evaluating the impact of antihypertensive therapy (vs. hydralazine) on adverse FHR effects, among women with severe hypertension. (C) Forest plots of RCTs evaluating the impact of antihypertensive therapy (vs. CCBs) on adverse FHR effects, among women with severe hypertension. (D) Forest plots of OBSERVATIONAL studies showing the effects of antihypertensives on adverse FHR effects, among women with severe hypertension. CCB, calcium channel blocker; FHR, fetal heart rate; RCTs, randomized controlled trials.

FIGURE 4

(A) Forest plots of RCTs evaluating the impact of antihypertensives (vs. no therapy) on neonatal HR, among women treated for non‐severe hypertension. (B) Forest plots of OBSERVATIONAL studies showing the effects of antihypertensives (vs. no therapy) on neonatal HR among women with non‐severe hypertension. (C) Forest plots of RCTs showing the effects of antihypertensives (vs. other antihypertensives) on neonatal HR among women with non‐severe hypertension. (D) Forest plots of OBSERVATIONAL studies showing the effects of antihypertensives (vs. other antihypertensives) on neonatal HR among women with nonsevere hypertension. HR, heart rate; RCTs, randomized controlled trials.