Interpretation, in Light of Other Evidence
Most prior studies were small, yielding inconclusive results, and many observational studies compared treated women to healthy pregnant women, making confounding likely. Our finding of lower SGA risk with methyldopa compared to labetalol (aOR 0.77, 95% CI 0.63 to 0.92) is consistent with one recent RCT, which found the prevalence of SGA to be 21% with methyldopa vs. 41% with labetalol (OR 0.37, 95% CI 0.23-0.61).10 Similar results were found by Magee et al. in a secondary analysis of RCT data.12 The Cochrane meta-analysis of RCTs compared methyldopa to all β-blockers grouped together and reported a combined RR of 1.19 (0.76, 1.84). Grouping labetalol together with other β-blockers is problematic because it has different receptor specificity and thus may have different effects on outcomes. Another limitation is that the Cochrane analysis combined results from studies with heterogeneous methods.
We found a slightly higher risk of preterm delivery with nifedipine compared to labetalol in an analysis including over 4000 women. The Cochrane review found only one relevant RCT, a study of 112 women yielding an RR of 1.61 that was not statistically significant.37 Our point estimate is compatible with theirs, with greater precision. For NICU admission, we observed slightly higher risk with nifedipine than labetalol (aOR 1.21, 95% CI 1.02 to 1.43). Similarly, in a recent RCT of women with severe hypertension in pregnancy, NICU admission was more frequent with nifedipine (18%) than labetalol (10%), yielding a risk difference of 7.8 (95% CI 2.2 to 13.4).38 The Cochrane meta-analysis reported a summary RR of 1.14 and 95% CI of 0.63 to 2.05, wide enough to be consistent with our finding. Still, since our study was not randomized, our findings could reflect confounding, including by indication for use, since nifedipine is also used for tocolysis. Many women who took nifedipine did so fairly early in pregnancy; the median gestational age at index fill for nifedipine was 20.8 weeks (compared to 18.8 weeks for labetalol), which provides evidence that much of the use we observed was in fact for hypertension.
Current US guidelines recommend labetalol and nifedipine above other medications and state that methyldopa is less preferred because of possible lower effectiveness and adverse effects.39 UK guidelines recommend labetalol, followed by nifedipine and then methyldopa.7 There is little evidence to support these recommendations, and several older RCTs suggested that labetalol and methyldopa are equally effective in lowering BP.40-42If methyldopa were less effective in controlling maternal BP, this might increase the risk of other harmful outcomes such as preeclampsia or indicated preterm birth, a pattern that we did not observe. While recognizing the potential for unmeasured confounding, our large observational study suggests that outcomes are very similar between methyldopa and labetalol, except for SGA. We suggest that for hypertensive pregnancies where there is substantial concern for SGA, it may be reasonable to give more consideration to methyldopa.
While it is concerning that labetalol appeared to convey higher risk of SGA, infants born SGA have variable trajectories: they may remain small, return to a normal growth curve or experience compensatory weight gain leading to childhood obesity. Future studies should examine child growth and development.