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.