HTN in pregnancy: target BP and differences between meds

 there were a couple of articles of note on treatment of mild hypertension in pregnant women.

 

The first assessed the outcomes of women with BP <160/100 to see if they would benefit from a target BP <140/90 (see htn pregnancy treat mild NEJM2022 in dropbox, or DOI: 10.1056/NEJMoa2201295 ), the Chronic Hypertension and Pregnancy (CHAP) project

 

Details:

-- 2408 pregnant women in an open-label, randomized trial done at 70 recruiting sites in the US, from 2015-2021

-- mean age 32, 28% non-Hispanic white/48% non-Hispanic Black/20% Hispanic, previous pregnancy 83%, BMI 38, gestational age <14wks in 41%

-- diabetes 16%, current smoker 7%, aspirin use 45%

-- blood pressure 134/84, 22% newly diagnosed hypertension/56% prior diagnosis and receiving medication/22% prior diagnosis and not receiving medication

-- all with singleton fetus at gestational ages <23 weeks, randomized to BP meds typically used in pregnancy (first-line antihypertensives: labetalol or extended-release nifedipine; or amlodipine or methyldopa if preferred by the patient) vs no meds unless severe hypertension developed (systolic BP >160 mmHg, or diastolic BP >105 mmHg)

-- women randomized to the active treatment group received labetalol (62%) or nifedipine (36%), and 3% received other medications

-- 89% in the active treatment group, and 24% in the control group reported taking medications regularly

-- mean blood pressure at follow-up was systolic 129.5 mmHg in the active treatment group and 132.6 mmHg in the control group, difference of -3.1 mmHg; diastolic 79.1 mmHg versus 81.5 mmHg, for a difference of -2.3 mmHg

-- exclusion criteria included severe hypertension, or blood pressure level requiring more than one medication to control, known secondary hypertension, multiple fetuses, prespecified high-risk coexisting illnesses or complications necessitating treatment to a lower blood pressure, and obstetric conditions that increased fetal risk

    -- women were randomized even when on an antihypertensive, which was stopped at randomization unless blood pressure exceeded 160/105 mmHg (and then were excluded from the study)

    -- in those on the active treatment group, medication was escalated as needed to achieve BP control of <140/90mmHg up to the maximum recommended dose, then a second medication was added (preferably nifedipine or labetalol)

-- primary outcome: composite of preeclampsia with severe features occurring up to two weeks after birth, medically-indicated preterm birth at <35 weeks’ gestation, placental abruption, or fetal or neonatal dath

-- safety outcome: small-for-gestational-age (SGA) birth <10^th percentile for gestational age

-- secondary outcomes: composites of serious neonatal or maternal complications, preeclampsia, and preterm birth

 

Results:

--primary outcome event:

    -- active treatment: 353 of 1170 patients (30.2%)

    -- control group: 427 of 1155 patients (37.0%)

        -- adjusted risk ratio: 0.82 (0.74-0.92), p<0.001;

        -- number of patients needed to be treated to prevent one primary outcome event was 14.7 (9.4-33.7)

-- individual components of the primary outcome:

    -- preeclampsia with severe features: 227/1170 (23.3%) versus 336/1155 (29.1%): risk ratio 0.80 (0.70-0.92)

    -- medically-indicated preterm birth <35wks gestation: 143/1170 (12.2%) versus 193/1155 (16.7%): risk ratio 0.73 (0.60-0.89)

    -- neither placental abruption nor fetal/neonatal death <28 days were statistically significant between the groups, though there were very small numbers of events

-- incidence of serious maternal complications:

    -- active treatment: 11.2%

    -- control group: 10.4%

        -- adjusted risk ratio: 1.04 (0.82-1.31), p=0.76 (not nearly statistically significant)

-- incidence of severe neonatal complications:

    -- active treatment: 2.0%

    -- control group: 2.6%

        -- risk ratio 0.77 (0.45-1.30)  (not nearly statistically significant)

-- incidence of any preeclampsia:

    -- active treatment: 24.4%

    -- control group: 31.1%

        -- risk ratio 0.79 (0.69-0.89)

-- incidence of preterm birth:

    -- active treatment: 27.5%

    -- control group 31.4%

        --risk ratio 0.87 (0.77-0.99)

-- incidence of SGA Infants:

    -- neither infants <10^th percentile nor <5th% percentile had statistically significant difference by treatment group

-- development of severe maternal hypertension:

    -- 436 of 1208 patients (36%) in the active treatment group vs 531 of 1200 patients (44%) in the control group, treatment effect 0.82 (0.74-0.90)

-- subgroup analyses: primary outcome in prespecified subgroups (all of these had overlapping confidence intervals):

    -- more often in those who were diagnosed with prior hypertension and receiving medications; diabetes at baseline; and lower BMI

-- no difference in those having cesarean sections, gestational age at delivery, or cardiovascular complications (very low numbers, even in the composite)

 

Commentary:

-- this study was done because there was uncertainty about what the target blood pressure was for pregnant women with mild hypertension. It has been clear that blood pressure meds do decrease the frequency of developing severe hypertension (defined as blood pressure >160/110 mmHg), though other Issues of maternal or fetal problems have not been investigated thoroughly, and there may be an increased risk for SGA infants with treatment as found in some studies

-- chronic hypertension develops in the US in 2% of pregnancies, and is associated with 3-5 times the risk of preeclampsia, placental abruption, preterm birth or SGA infants, perinatal death, as well as a 5-10 times the risk of maternal death, heart failure, stroke, pulmonary edema, or acute kidney injury

-- the main findings in the study were that pregnant women with mild hypertension but on medications to bring the blood pressure to <140/90 mmHg had better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, and there was no increased risk of SGA infants. in particular, women who received active treatment had lower primary outcome events of preeclampsia with severe features, medically-indicated preterm birth at <35 weeks' gestation, placental abruption or fetal/neonatal death. And that approximately 15 patients would need to be treated to avert one primary outcome event. And without apparent harm by the treatment.

-- strengths of the CHAP study include the its multi-center involvement with significant diversity of the patients enrolled

-- another article also appeared recently finding that labetalol seems to be the preferred med for nonsevere hypertension (see https://www.ahajournals.org/doi/epub/10.1161/HYPERTENSIONAHA.121.18415 ). in brief:

    -- 61 RCTs with 6923 women, all given labetalol, other b-blockers (though there are studies suggesting that labetalol is best-in-class since it may preserve uteroplacental blood flow better than others), methyldopa, calcium channel blockers, or multidrug therapy. all studies had meds vs placebo or no meds

    -- all of the meds reduced the development severe hypertension

    -- labetalol (vs placebo/no med) was associated with decreased proteinuria/preeclampsia, OR 0.73 (0.54-0.99); also decreased fetal/newborn death rates with OR 0.54 (0.30-0.98)

    -- labetalol was associated with decreased proteinuria/preeclampsia vs calcium channel blockers with OR 0.63 (0.41-0.96) and vs methyldopa with OR 0.66 (0.44-0.99)

        -- but, note wide confidence intervals, and this was a network meta-analysis assessing outcomes from different studies, many of single agent vs placebo/none (ie, different trials in different settings and comparing outcomes, which may well be comparing apples to oranges/not so rigorous; though several studies were head-to-head comparisons). would be best to have a large study with direct med comparisons, but it would seem that given equipotency regarding developing severe hypertension, but pretty convincing data on differences in maternal/fetal outcomes, that labetalol might be considered first choice (and it was notable in the above CHAP mild hypertension study, 2/3 of women were on labetalol). 

Limitations:

-- this was an open label study, meaning that the women and clinicians knew if meds were taken, and this could affect the measured endpoints and limit generalizability

-- the spread of blood pressure between those in the active treatment versus control group was not large, only 3.1/2.3 mmHg. This small difference is likely to decrease the occurrence of both adverse effects of higher blood pressure (maternal and infant) as well as potential adverse effects of lower blood pressure (eg SGA). though their finding of significant differences with such small changes is quite impressive. it would have been better and the results likely more profound if there were a larger difference between the active treatment vs no treatment groups

 

so, this CHAP intervention study did find significant maternal/neonatal outcomes with treatment of mild hypertension and targeting a goal of <140/90 mmHg, even without large differences in the actual blood pressure achieved in the active treatment vs control groups. And there is a reasonably strong suggestion that the preferred drug is labetalol for medical management in pregnancy. The role of nonpharmacologic treatment is largely not evidence-based. And some prior suggestions for bedrest and low salt diets may be harmful (bed rest leading to deconditioning, increased thromboemboli, bone loss, significant psychosocial effects; mild salt restriction may be beneficial but more aggressive restrictions have not been tested and could be harmful)

geoff

 

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