Antihypertensives in pregnant women with mild chronic hypertension.
Paulino Vigil-De Gracia, MD.
Complejo Hospitalario Dr. AAM Caja de Seguro Social. Investigador
distinguido del Sistema Nacional de Investigación, SENACYT Panamá,
e-mail: pvigild@hotmail.com
Disclosure: ¨The authors report no conflict of interest¨
Funding: NO
Word count: Abstract: 94 Main Text: 1085
Running Title: Treatment of pregnancy with chronic hypertension.
Abstract
Pregnant women with chronic hypertension have increased worldwide and
with it more maternal and perinatal complications such as hypertensive
crisis, preeclampsia, placental abruption, growth restriction,
prematurity, perinatal mortality. In addition to correct diagnosis and
strict follow-up during the pregnancy, antihypertensive drugs have been
controversially used. An adequate randomized controlled study recently
published shows the benefit of antihypertensives. The antihypertensive
drug used seems to be the explanation why previous studies were not
conclusive in denoting benefits. The drugs that have shown benefits are
beta-blockers (labetalol), calcium channel blockers (nifedipine,
amlodipine) and with minimal effectiveness methyldopa.
Keywords: Chronic hypertension, pregnancy, antihypertensive drugs,
labetalol, methyldopa.
Pregnant women with chronic hypertension increase considerably in the
world. This group of patients and especially the black population have a
higher risk of presenting obstetric complications such as preeclampsia,
placental abruption, growth restriction, prematurity, perinatal
mortality. In addition, there are more maternal risks such as acute
pulmonary edema, kidney damage, heart failure, stroke and death.1,2. The management of the patient with chronic
hypertension requires follow-up, evaluations and the main management
focuses on giving antihypertensive drugs. When these patients become
pregnant or chronic hypertension is diagnosed for the first-time during
pregnancy, there was no convincing evidence on the usefulness and
necessity of giving antihypertensive treatments if the hypertension is
not severe, which is usually defined as a blood pressure of
<160/110 mm Hg. A recently published study shows convincing
evidence on the need to give antihypertensive drugs in this population
group.3. Until before this study 3,
a Cochrane systematic review (CSR) 4 including in the
meta-analysis 58 studies (5909 women) showed controversial results that
prevented a clear recommendation, also a randomized study5 of adequate quality published in 2015, in which
strict blood pressure control was done or not, it failed to prove
benefits in perinatal or maternal outcomes, except less severe
hypertension in the group with strict control of blood pressure. The
findings of the CSR 4 and the study by Tita et al.3 show that the possible explanation for the
controversial findings is the drugs used to treat hypertension.
Most of the randomized studies examining the effectiveness of drugs in
the management of pregnant women with non-severe chronic hypertension
have small numbers of patients. There are only 4 studies that have
evaluated at least 300 patients, two of them analyzed in CSR4 (one in the USA in 1990 with 300 women and the other
in Pakistan in 2016 with 314 women), the study by Magge et al.5 published in 2015 with 981 women and the study by
Tita et al. 3 published in the year 2022 with 2408
pregnant women. The study by Magee et al. 5, used
antihypertensives in both groups, without randomization to the type of
antihypertensives and therefore is not analyzed in the CSR4 and the study by Tita et 3 was
published after the CSR 4. We currently have three big
studies: a systematic review with 5909 women, a randomized study with
981 patients using antihypertensives in both groups, and a randomized
study with 2408 women comparing using versus not using
antihypertensives. Due to the relevance of the topic and the findings of
these three studies, a narrative description and comments are necessary.
The outcomes of maternal and perinatal complications according to the
medication used to manage hypertension are described according to the
findings of each of the three studies, table 1.
Hypertensive crisis (systolic blood pressure ≥160 mm Hg and/or diastolic
blood pressure ≥ 110 mmHg): The reduction in hypertensive crises using
antihypertensives was demonstrated in the CSR 4 and in
the two big and randomized studies already mentioned3,5. The study by Magee et al. 5,
for the strict control of hypertension, labetalol was used as the main
antihypertensive, however, methyldopa was used in more than 40% of the
population studied. The findings show that there is a significant
decrease in hypertensive crises. The CSR 4 showed a
decrease in hypertensive crises independent of the antihypertensive
used, but a better result is observed when using beta-blockers. In
addition, the CRS shows that in two studies (310 women) with methyldopa,
hypertensive crises were also reduced. The Tita et al study3 shows a significant decrease in hypertensive crises
and they used labetalol, nifedipine and amlodipine in 99% of patients
in the treatment group, methyldopa was only used in 0.3%. The results
of these investigations suggest benefits in avoiding hypertensive crises
using beta-blockers, calcium channel blockers and methyldopa.
Preeclampsia/severe preeclampsia and premature birth: The study by Tita
et 3 shows significant decrease in severe preeclampsia
and births before 35 weeks and the CSR 4 showed a
decrease in preeclampsia only when using beta-blockers and a slight
increase is observed when using calcium channel blockers, this
systematic review does not find a decrease in preterm deliveries. The
study by Magee et al. 5 showed no benefit in those
outcomes. The findings of these studies show us that using methyldopa as
an antihypertensive does not reduce preeclampsia or prematurity.
Placental abruption, fetal/perinatal death: The CSR 4and the other two randomized studies 3,5 did not find
any change in these findings, so there seems to be no benefit for these
variables when antihypertensives are used in pregnant women with
mild/moderate chronic hypertension. Nevertheless, the Tita et al study3 shows a significant decrease when adding both
findings as a component of the set of primary results.
Neonatal complications (respiratory distress syndrome, bronchopulmonary
dysplasia, retinopathy of prematurity, necrotizing enterocolitis,
intraventricular hemorrhage grade 3 or 4, hypoglycemia, bradycardia,
seizure, hypotension): The study by Tita et al 3 does
not show differences in these variables when giving you antihypertensive
treatment, nor did the study by Magee et al. 5. The
CSR 4 shows similar results to the two randomized
studies, except that less respiratory distress syndrome is observed at
the expense of the group that received antihypertensive treatment with
beta-blockers.
Small for gestational age: This is a result that has been questioned as
a possible adverse effect of antihypertensives, however, the CSR4 and the two randomized studies 3,5they found no change in fetal growth.
Cesarean section: Cesarean births did not vary significantly in the two
randomized studies 3,5, however, in a sub-analysis of
the CSR 4 shows that there is a significantly higher
chance of cesarean section if the antihypertensive used is methyldopa,
this emerges from the analysis of 13 studies with 1330 women.
Conclusion: Antihypertensives generate benefits in pregnant women with
mild chronic hypertension. The main antihypertensives used in these
patients are labetalol, nifedipine, amlodipine, and methyldopa; these
drugs reduce severe hypertension. Preeclampsia and especially severe
preeclampsia is reduced by beta-blockers and calcium channel blockers.
Using methyldopa there is no decrease in preeclampsia, there is a
greater possibility of cesarean section and there are side effects such
as sedation, depression, dizziness. In addition, the randomized
controlled trial that includes the largest number of pregnant women with
mild chronic hypertension, demonstrating several benefits with
antihypertensives, did not use methyldopa. Methyldopa should not be
considered as an antihypertensive in pregnant women with mild chronic
hypertension due to its minimal usefulness and the existence of other
more effective drugs.
Table 1.
Antihypertensives used in chronic hypertension without hypertensive
crisis