In a large prospective cohort of women with hypertension during pregnancy, maternal use of antihypertensive medications other than βbs was associated with both major perinatal morbidity and mortality, while βb use was not. The greatest risks for adverse perinatal outcomes were related to the combined use of βb and non-βb medications. All forms of antihypertensive therapy were associated with a higher risk for SGA, preterm birth and admission to the NICU, and multiple therapy had the strongest association with these events. Similar relationships were evident in the sub-group of women with chronic hypertension during pregnancy, except that use of a non-βb drug was not associated with SGA or preterm birth before 32 weeks.
Several study limitations should caution the reader from drawing definitive conclusions about the impact of antihypertensive therapy on perinatal outcome. First, we did not obtain information on drug dose, duration of use or route of administration. Thus, this study provides no information about the existence of a dose-response relationship between drug use and adverse perinatal events. Because this was not a randomized clinical trial, bias due to confounding by indication was likely present, in that women with milder forms of hypertension may have received lower doses of oral therapy (e.g., atenolol), while those with more severe hypertension were probably prescribed a higher dose of an intravenous medication (e.g., hydralazine). However, we do know that because the most commonly used agents in this study – atenolol, nifedipine and methyldopa – were not available intravenously, their use probably extended beyond the acute management of severe maternal hypertension with impending delivery. Similarly, although we did not discriminate between the types of βb prescribed in our study sample, or between the various types of non-βb drugs, we may assume that most of these relationships are reflective of the use of atenolol, nifedipine and methyldopa.
βb medications are contraindicated in individuals with specific diseases like asthma, a common condition whose presence in pregnancy has been associated with an increased risk for preeclampsia, preterm delivery and SGA . Accordingly, absence of βb use may have been confounded by the presence of other diseases like asthma, which could explain the relatively lower degree of perinatal morbidity with βb therapy compared to non-βb treatments. Similarly, there may have been a lower threshold for induction of labor or Cesarean delivery among women who were referred to our center for the management of more complex or severe maternal hypertension or fetal disease. Thus, because these data may be biased, and their internal and external validity questioned, they may not be applicable to some women with stable, mild and asymptomatic hypertension.
Two Cochrane Collaboration systematic reviews have examined the use of βbs  as well as all types of medication  for the treatment of pregnant women with mild to moderate hypertension. In the first review, comprising 14 randomized trials of oral βbs versus placebo or no therapy , βbs decreased the risk of progression to severe hypertension (relative risk [RR] 0.37, 95% CI 0.26–0.53) and the need for additional antihypertensive drugs (RR 0.44, 95% CI 0.31–0.62) . However, there was insufficient data to draw conclusions about the effect on perinatal mortality or preterm delivery, but βbs were minimally associated with SGA (RR 1.34, 95% CI 1.01–1.79). Among 11 trials, βbs appeared to be both equally effective and as safe as methyldopa . In the second review, comparing antihypertensive drugs with placebo or no treatment, active therapy reduced the risk of severe hypertension (24 trials; RR 0.52, 95% CI 0.41–0.64), but not preeclampsia (19 trials; RR 0.99, 95% CI 0.84–1.18), perinatal death (23 trials; RR 0.71, 0.46–1.09), preterm birth (12 trials; RR 0.98, 95% CI 0.85–1.13), or SGA (17 trials; RR 1.13, 0.91–1.42) . Thus, within a heterogeneous group of randomized trials , treatment of mild to moderate hypertension, whether in the form of βbs or other drugs, remains controversial.
The advantage of a large, prospective study like MOS HIP 2 is its ability to examine several important "hard" perinatal outcomes, and to generate estimates of effect size with statistical certainty. MOS HIP 2 provided information on perinatal outcomes within the realm of clinical practice, and included a broad array of women with different mechanisms and degrees of hypertension. By adjusting for multiple potential confounders, such as the gestational age at which the BP rose, we may have reduced the likelihood that antihypertensive drug use was merely a marker of both the acuity and degree of hypertension and, accordingly, the associated risk of preterm delivery and neonatal prematurity. Similarly, by limiting our sub-group analysis to women with chronic hypertension, we increased the likelihood that maternal exposure to antihypertensive therapy would be of longer duration. In doing so, there remained no relationship between βb use and the primary endpoint of major perinatal disease or death, an association that was observed for both non-βb and combination drug therapy.
The debate about whether βb drugs [3, 5] or antihypertensive treatment in general [2, 18] may cause IUGR neither begins nor ends with the current study. Even randomized clinical trials [2, 3, 5] of active therapy are biased by the presence of co-intervention, cross-over, contamination and drop-outs. For example, in a well-publicized clinical trial by Butters et al., 33 women with mild primary hypertension were randomized to atenolol or placebo at approximately 16 weeks gestation . Infants of mothers assigned atenolol weighed an average of 910 g less than those in the placebo group, but four women in the placebo group withdrew from the study. A second trial compared atenolol with placebo for the treatment of mild gestational hypertension during the third trimester, with no difference in birthweight between groups; however, data were reported on only 85 of 120 women (70.8%) randomized . A recent clinical trial randomized 56 asymptomatic women with an increased cardiac output before 24 weeks gestation to either atenolol or placebo . For the primary outcome of preeclampsia, the relative risk was 0.3 (95% CI 0.07–1.4) in favor of atenolol, and only in the small sub-group of nulliparous women was treatment with atenolol significantly associated with a 440 g mean lower mean birthweight (p = 0.02). Thus, although it is possible that atenolol may cause some degree of growth restriction, this has not been demonstrated when the drug is compared to another form of active treatment , or in the presence of more severe hypertension, when maternal benefit may be greater. Finally, no class effect has been demonstrated for βbs in general .
It may not be surprising that the risk of preterm delivery in our study was significantly associated with the use of antihypertensive therapy, since the initiation of therapy might simply reflect the onset of either new or worsening hypertension and the need for delivery. However, it is possible that βbs possess tocophilic properties that could predispose a woman to preterm labor. At least two placebo-controlled clinical trials have used intravenous βbs in the management of dysfunctional labor, reporting lower rates of Caesarian delivery with active treatment [21, 22]. The relative degree of association observed in this study was substantially lower with βb than non-βb antihypertensive drugs, for delivery before 32 (OR 7.6 versus OR 13.4 among all women, respectively) or 37 weeks (OR 5.1 versus OR 10.3, respectively).
Combined antihypertensive therapy was a strong marker for preterm birth and a moderate indicator of SGA. Interestingly, however, the associated risk for other serious perinatal outcomes, such as the primary composite outcome, was either less than or similar to that for monotherapy with a non-βb drug (Tables 3 and 5). Further research might investigate whether there are differences in placental blood flow and fetal growth according to treatment regimen (monotherapy vs. combined antihypertensive therapy).
Although no significant association was seen between βb use and major perinatal morbidity or mortality, it cannot be inferred that they are "safer" for the fetus. Rather, assuming that the current study was both valid and adequately powered to evaluate major perinatal outcomes, we may conclude that either 1) βbs are prescribed for maternal hypertension when there is less threat to the fetus or mother, while non-βb drugs are used in isolation or in combination with βbs when that threat is greater; or 2) βbs are, in fact, less harmful to the fetus compared to other antihypertensive drugs. Thus, these findings, which are hypothesis generating, should be tested by a study capable of demonstrating causation.
A large international randomized active-control clinical trial is urgently needed to help resolve the controversy surrounding the safety and efficacy for mother and child of treating hypertension during pregnancy. The reasons for such a large double-masked clinical trial are many , including the fact that the condition is common; the choices for therapy are few, unlikely to change for several years and inexpensive; and the time to outcome is less than 40 weeks. Women with a BP greater than 160/100 mm Hg without evidence of preeclampsia or impending delivery could be enrolled.
Randomization could be stratified according to the presence of hypertension before versus after 20 weeks gestation, and treatment might compare a βb to a dihydropyridine calcium channel blocker or methyldopa, for example. Maternal outcomes should include mode of delivery [21, 22], progression to preeclampsia or eclampsia , and drug side effects , while perinatal outcomes should encompass those included in the current study.