Objective
Despite high rates of hypertension in pregnancy, the effects of hypertension have not been separated appropriately from the effects of the medications that are used. We evaluated the safety of exposure to antihypertensive medications during pregnancy, while accounting for disease effects.
Study Design
A population-based retrospective cohort study was performed that compared all pregnancies of women with hypertension who were either exposed or unexposed to antihypertensive medications. A computerized database of the medications that were dispensed to pregnant women from 1998-2008 was linked with computerized databases that contained maternal and infant hospitalization records from the district hospital during the same period.
Results
During the study period, 100,029 deliveries occurred; of those, 1964 pregnant women experienced chronic hypertension, and 620 neonates (0.6%) were exposed to at least 1 antihypertensive medication (methyldopa or atenolol) during pregnancy. A higher rate of intrauterine growth restriction (7.2% vs 2.1%, respectively; adjusted odds ratio [OR], 4.37; 95% confidence interval [CI], 3.00–6.36; P < .001), small for gestational age (3% vs 1.7%, respectively; adjusted OR, 2.23; 95% CI, 1.27–3.92; P = .005), and preterm deliveries (<37 weeks, 22.9% vs 8.0%, respectively; adjusted OR, 3.69; 95% CI, 2.90–4.69; P < .001) were noted among the pregnancies of women who were exposed to antihypertensive medications during the third trimester. Importantly, a similar association was detected when we compared women with chronic hypertension who were not treated during pregnancy (n = 1074) to women who had no chronic hypertension and who were unexposed to antihypertensive medications (n = 97,820).
Conclusion
Chronic hypertension with or without treatment during pregnancy is an independent and significant risk factor for adverse perinatal outcomes such as intrauterine growth restriction, small for gestational age, and preterm delivery.
Chronic hypertension is defined as blood pressure that exceeds 140/90 mm Hg at <20 weeks’ gestation or that persists longer than the usual postpartum period (12 weeks after delivery). It is a serious medical condition that complicates 1-5% of all pregnancies and that is associated with an increased risk for maternal and fetal morbidity and death. The most common maternal complication that involves 25% of the cases is superimposed preeclampsia. Other possible maternal complications include placental abruption, the need for cesarean delivery, and even death. The most common fetal complications are intrauterine growth restriction (IUGR), small-for-gestational-age (SGA) newborn infants, and prematurity. The incidence of these adverse effects is related to the degree and duration of hypertension and to the involvement of other organs. Studies have shown that, even after adjustment for superimposed preeclampsia as a risk factor for fetal and maternal morbidities, pregnancies that are complicated with chronic hypertension have higher rates of cesarean deliveries, IUGR, perinatal mortality, and postpartum hemorrhage. Several risk factors that have been reported to aggravate the prevalence of chronic hypertension include maternal obesity, diabetes mellitus, heredity, and racial factors. Another risk factor is advanced maternal age.
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The common drugs that are used in the treatment of chronic hypertension during pregnancy are methyldopa or atenolol. Methyldopa is an α2 adrenergic agonist. Activation of these receptors in the central nervous system inhibits sympathetic output that leads to a decrease in blood pressure. Atenolol is a selective β 1 adrenergic inhibitor with a negative chronotropic and inotropic effect on the myocardium. A number of studies have documented the efficacy of treatment for chronic hypertension during pregnancy; nevertheless, an important question that has not yet been resolved is the independent effects of nontreated hypertension. Despite high rates of hypertension in pregnancy, the effects of hypertension have not been separated appropriately from those of the medications that have been used. Because of the increasing rates of maternal obesity and the trend to postpone pregnancies to older ages, there is an increasing incidence of chronic hypertension, which might contribute to maternal and fetal morbidities. The objective of the present study was to separate the effects of hypertension from its treatments on adverse pregnancy outcomes.
Methods
This was a retrospective cohort study that involved members of “Clalit Health services” in southern Israel. Clalit is the largest health maintenance organization in Israel, in which 70% of the district population (which includes 70% of women 15-49 years old) is insured. The population of the Southern District of Israel is slightly greater than one-half a million citizens. Soroka Medical Center (SMC) is the district hospital in which practically all deliveries of the region take place. All infants are examined by a board-certified neonatologist.
The clinical, medication, and demographic data of Clalit members are stored in the Clalit data warehouse and can be queried at the level of an individual member. This database contains information about dispensing date, the Anatomical Therapeutically Classification code of the drug (including the commercial and generic names), dose schedule of drugs administration, and dose dispensed in defined daily dose (the assumed average maintenance dose per day).
Two computerized SMC databases that draw information directly from original sources were used. All patient records at SMC originate from a single database that includes demographic information and hospitalization dates that are generated at the time of the woman’s admission to the hospital and of the infant’s birth. The database of the Obstetrics and Gynecology Department includes information on maternal medical conditions during pregnancy and delivery, maternal age, gestational age at delivery (in days since last menstrual period), perinatal death, parity, ethnic group, self-reported smoking status during pregnancy, infant birthweight, and Apgar score at 1 and 5 minutes. The diagnoses are reviewed routinely by a trained medical secretary before entry into the database. The other electronic SMC database that was used in the present study was the Demog- International Classification of Diseases, Ninth Revision (ICD9) database, which includes demographic and medical diagnoses during hospitalization; the latter is drawn directly from the medical records. Additional infant diagnoses that were recorded on discharge are coded and included into their Demog-ICD9 record. All diagnoses are classified according to the ninth revision of the ICD.
Women from 15-49 years old who were registered with Clalit and who lived in the southern district of Israel who gave birth at SMC were included. The study period was January 1998 to August 2008, during which 100,029 deliveries took place. Approximately one-half of the infants in the district were born to Jewish parents and one-half of the infants were born to Bedouin parents. The southern district of Israel is populated by 2 distinct ethnic groups, the Jewish and the Bedouins Arabs. Because consanguinity is practiced widely in the Bedouin population, their babies are at higher risk for congenital malformations. The 3 databases (1 from Clalit and 2 from SMC) described earlier were encoded and linked by a personal identification number to create a registry of medications that were dispensed during pregnancy and the pregnancy outcomes.
We investigated the relationship between exposure to antihypertensive drugs during pregnancy and perinatal outcomes, specifically IUGR, preterm delivery (PTD; <37 weeks’ gestation), congenital malformations, and low birthweight (LBW; <2500 g). The exposed group included women to whom antihypertensive (methyldopa or atenolol) drugs were dispensed during the first trimester of pregnancy (≤13 weeks’ gestation). We also assessed methyldopa and atenolol individually. The unexposed group comprised all women without diagnosis of chronic hypertension and who were not exposed to antihypertensive drugs through the first or the third trimester during the study period. The nontreated hypertension group included all women with a diagnosis of chronic hypertension who were not treated for hypertension during the index pregnancy.
Congenital malformations data were obtained from SMC databases. We used the definitions of major congenital malformations that had been developed by the Centers for Disease Control and Prevention Metropolitan Atlanta Congenital Defects Program. This program has been conducting surveillance for birth defects since 1967, and its definitions have been validated in several previous studies. Chromosomal diseases were excluded. The following pregnancy outcomes were investigated in both live neonates and stillborn infants: major malformations, perinatal death, PTD, LBW (<2500 g), very LBW (<1500 g), and Apgar score at 1 and 5 minutes after birth (categorized as Apgar ≤7 or ≥8), and preeclampsia. The following potential confounders were included in the statistical analysis: maternal age, parity, self-reported smoking in pregnancy, maternal diabetes mellitus, lack of prenatal care, and ethnicity (ie, Jewish or Bedouin Moslem). The study was approved by the institutional Helsinki Ethics Committee for Human Investigations. No written informed consent was required.
The statistical analyses were performed with the SPSS package (version 18; SPSS Inc, Chicago, IL). The exposed group was compared with the unexposed by means of chi-square test or Fisher’s Exact test for differences in categoric variables and the Student t test for differences in continuous variables. Multivariate logistic regression models were constructed to identify independent risk factors that were associated with adverse pregnancy outcomes. Multivariate logistic regression models were performed to investigate whether greater exposure was associated with increased risk of IUGR, PTD, congenital malformations, and SGA. Odd ratios (ORs) and their 95% confidence intervals (CIs) were computed.
Results
During the study period, 100,029 deliveries occurred. Six hundred twenty women (0.6%) with chronic hypertension were exposed to atenolol or methyldopa or both during the index pregnancy; 271 women (0.2%) were exposed to atenolol or methyldopa or both during the first trimester of pregnancy; 114 women (0.11%) were exposed to methyldopa, and 188 women (0.18%) were exposed to atenolol. One thousand seventy-four women (1.07%) experienced chronic hypertension during pregnancy but were not exposed to antihypertensive medication. Five hundred fifteen infants who were exposed to antihypertensive drugs in utero for maternal indications other than hypertension were excluded from the cohort.
Characteristics of the mother exposed and unexposed to antihypertensive medications are presented in Table 1 . Of the infants who were born, 4623 infants were born with congenital malformations; of which, 18 infants (6.6%) had been exposed to either methyldopa or atenolol during the first trimester (adjusted OR, 1.30; 95% CI, 0.84–2.01). Exposure to antihypertensive drugs (atenolol or methyldopa) during the third trimester was associated with PTD, LBW, low Apgar score, IUGR, SGA, and preeclampsia ( Tables 2 and 3 ). When the data were assessed separately, both atenolol and methyldopa were associated with these adverse pregnancy outcomes as well ( Tables 2 and 3 ).
| Characteristic | Exposure to antihypertensive medication during the first trimester of pregnancy | Exposure to antihypertensive medication during the third trimester of pregnancy | ||||
|---|---|---|---|---|---|---|
| No (n = 97,820) | Yes (n = 271) | P value | No (n = 97,820) | Yes (n = 433) | P value | |
| Ethnic group, n (%) | < .001 | < .001 | ||||
| Jews | 34,475 (35.2) | 135 (49.8) | 34,475 (35.2) | 213 (49.2) | ||
| Bedouins | 63,345 (64.8) | 136 (50.3) | 63,345 (64.8) | 220 (50.8) | ||
| Maternal age, y b | 28.51 ± 5.8 | 34.85 ± 5.5 | < .001 | 28.5 ± 5.8 | 33.4 ± 5.5 | < .001 |
| Maternal diabetes mellitus, n (%) | 5691 (5.8) | 68 (25.1) | < .001 | 5691 (5.8) | 121 (27.9) | < .001 |
| Smoking, n (%) | 2302 (2.4) | 5 (1.8) | .726 | 2302 (2.4) | 6 (1.4) | .243 |
| Parity, n b | 3.5 ± 2.6 | 5.2 ± 3.6 | < .001 | 3.7 ± 2.6 | 4.7 ± 3.3 | < .001 |
a Women with nontreated hypertension were not included;
| Variable | Exposure to antihypertensive medication during the third trimester of pregnancy, n (%) a | Exposure to methyldopa during the third trimester of pregnancy, n (%) | Exposure to atenolol during the third trimester of pregnancy, n (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| No (n = 97,820) | Yes (n = 433) | P value | No (n = 97,820) | Yes (n = 340) | P value | No (n = 97,820) | Yes (n = 107) | P value | |
| Preterm delivery | 7836 (8.0) | 99 (22.9) | < .001 | 7836 (8.0) | 86 (25.3) | < .001 | 7836 (8.0) | 18 (16.8) | < .001 |
| Low birthweight | 10,001 (10.2) | 104 (24.0) | < .001 | 10,001 (10.2) | 84 (24.7) | < .001 | 10,001 (10.2) | 25 (23.4) | < .001 |
| Perinatal death | 1379 (1.4) | 9 (2.1) | .158 | 1379 (1.4) | 9 (2.6) | .035 | 1379 (1.4) | 0 (0.0) | — |
| Apgar score ≤7 | |||||||||
| At 1 min b | 5790 (6.1) | 55 (12.9) | < .001 | 5790 (6.1) | 43 (12.8) | < .001 | 5790 (6.1) | 15 (14.2) | .001 |
| At 5 min c | 1026 (1.1) | 10 (2.3) | .012 | 1026 (1.1) | 10 (3.0) | .001 | 1026 (1.1) | 0 | — |
| Intrauterine growth restriction | 2096 (2.1) | 31 (7.2) | < .001 | 2096 (2.1) | 24 (7.1) | < .001 | 2096 (2.1) | 9 (8.4) | < .001 |
| Small for gestational age | 1704 (1.7) | 13 (3.0) | .005 | 1704 (1.7) | 8 (2.4) | .06 | 1704 (1.7) | 6 (5.6) | < .001 |
| Preeclampsia | 1093 (1.1) | 60 (13.9) | < .001 | 1093 (1.1) | 53 (15.6) | < .001 | 1093 (1.1) | 10 (9.3) | < .001 |
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