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OBSTETRICS
pregnancy is an independent and significant risk factor for adverse perinatal outcomes such as intrauterine growth restriction, small for gestational age, and preterm delivery.
Key words: atenolol, chronic hypertension, methyldopa, pregnancy
Cite this article as: Orbach H, Matok I, Gorodischer R, et al. Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. Am J Obstet Gynecol
2013;208:301.e1-6.
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.1,2
The most common maternal complica-
From the Departments of Public Health (Drs Orbach, Daniel, and Levy), Pediatrics (Dr
Gorodischer), and Obstetrics and Gynecology (Drs Sheiner and Wiznitzer), Faculty of Health
Sciences, Ben-Gurion University of the Negev; Soroka Medical Center (Drs Gorodischer,
Sheiner, and Wiznitzer); and Clalit Health Services (Southern District) (Drs Gorodischer and
Wiznitzer), Beer-Sheva, Israel; the Center for Clinical Epidemiology, Lady Davis Research
Institute, Jewish General Hospital, and the Department of Epidemiology, Biostatistics, and
Occupational Health, McGill University, Montreal, QC (Dr Matok), and the Motherisk Program,
Division of Clinical Pharmacology-Toxicology, Department of Pediatrics, The Hospital for Sick
Children, and University of Toronto, Toronto, ON (Dr Koren), Canada; and the BeMORE (BenGurion Motherisk Obstetric Registry of Exposure) collaboration (Drs Matok, Gorodischer,
Daniel, Koren, and Levy).
Received July 31, 2012; revised Nov. 1, 2012; accepted Nov. 13, 2012.
The authors report no conflict of interest.
Presented as a poster at the annual meeting of the Canadian Society of Pharmacology and
Therapeutics, Montreal, QC, Canada, May 25-27, 2011.
Reprints: Amalia Levy, MPH, PhD, Public Health Department, Faculty of Health Sciences, BenGurion University of the Negev, POB 653, Beer Sheva 84105. Israel.lamalia@bgu.ac.il.
0002-9378/$36.00 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.11.011
tion that involves 25% of the cases is superimposed preeclampsia.2 Other possible maternal complications include
placental abruption, the need for cesarean delivery, and even death.3,4 The most
common fetal complications are intrauterine growth restriction (IUGR),
small-for-gestational-age (SGA) newborn infants, and prematurity.4-6 The incidence of these adverse effects is related
to the degree and duration of hypertension and to the involvement of other organs.7 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.8 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.8
301.e1
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M ETHODS
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.18,19 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 de301.e2
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fined 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 womans
admission to the hospital and of the infants 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.
Obstetrics
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Research
TABLE 1
Characteristic
No (n 97,820)
No (n 97,820)
Yes (n 271)
P value
Yes (n 433)
.001
P value
.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)
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
b
28.51 5.8
Maternal age, y
34.85 5.5
.001
28.5 5.8
33.4 5.5
.001
5691 (5.8)
121 (27.9)
.726
2302 (2.4)
6 (1.4)
.001
................................................................................................................................................................................................................................................................................................................................................................................
5691 (5.8)
68 (25.1)
Smoking, n (%)
2302 (2.4)
5 (1.8)
.001
................................................................................................................................................................................................................................................................................................................................................................................
.243
................................................................................................................................................................................................................................................................................................................................................................................
b
3.5 2.6
Parity, n
5.2 3.6
.001
3.7 2.6
4.7 3.3
.001
................................................................................................................................................................................................................................................................................................................................................................................
a
Women with nontreated hypertension were not included; Data are given as mean SD.
b
R ESULTS
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 sev-
TABLE 2
No
(n 97,820)
Yes
(n 433)
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)
1379 (1.4)
9 (2.6)
1379 (1.4)
0 (0.0)
Variable
P
value
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
.158
.035
................................................................................................................................................................................................................................................................................................................................................................................
Apgar score 7
.......................................................................................................................................................................................................................................................................................................................................................................
b
.001
5790 (6.1)
43 (12.8)
10 (2.3)
.012
1026 (1.1)
31 (7.2)
.001
2096 (2.1)
At 1 min
5790 (6.1)
55 (12.9)
At 5 min
1026 (1.1)
Intrauterine growth
restriction
2096 (2.1)
1704 (1.7)
13 (3.0)
Preeclampsia
1093 (1.1)
60 (13.9)
.001
5790 (6.1)
10 (3.0)
.001
1026 (1.1)
24 (7.1)
.001
2096 (2.1)
9 (8.4)
.001
15 (14.2)
.001
.......................................................................................................................................................................................................................................................................................................................................................................
c
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
.005
1704 (1.7)
8 (2.4)
.001
1093 (1.1)
53 (15.6)
.06
1704 (1.7)
6 (5.6)
.001
1093 (1.1)
10 (9.3)
.001
................................................................................................................................................................................................................................................................................................................................................................................
.001
................................................................................................................................................................................................................................................................................................................................................................................
a
Exposed at least 1 time to atenolol or methyldopa; b 2333 infants had no 1-minute Apgar score; c 2232 infants had no 5-minute Apgar score.
301.e3
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TABLE 3
Crude and adjusted odds ratios for pregnancy adverse outcomes after exposure
of fetuses to antihypertensive medications in the third trimester of pregnancya
Variable
Preterm delivery
3.40 (2.724.27)
3.69 (2.904.69)
3.89 (3.044.97)
4.19 (3.225.45)
2.32 (1.403.86)
2.68 (1.574.56)
Low birthweight
2.78 (2.223.46)
3.68 (2.894.67)
2.88 (2.253.69)
3.77 (2.894.94)
2.68 (1.714.19)
3.89 (2.426.25)
Perinatal death
1.48 (0.772.88)
1.62 (0.833.15)
1.90 (0.983.70)
2.05 (1.054.02)
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Apgar score 7
.......................................................................................................................................................................................................................................................................................................................................................................
At 1 min
2.29 (1.723.04)
2.03 (1.522.72)
2.28 (1.653.14)
1.95 (1.402.70)
2.56 (1.484.42)
2.65 (1.524.61)
At 5 min
2.21 (1.184.14)
2.27 (1.204.28)
2.83 (1.505.32)
2.84 (1.505.38)
Intrauterine growth
restriction
3.52 (2.445.09)
4.37 (3.006.36)
3.47 (2.295.27)
4.32 (2.826.61)
4.19 (2.128.31)
5.19 (2.5910.39)
Small for
gestational age
1.75 (1.003.04)
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
2.23 (1.273.92)
1.36 (0.672.75)
1.01 (1.001.02)
3.35 (1.477.65)
4.80 (2.0711.10)
................................................................................................................................................................................................................................................................................................................................................................................
Preeclampsia
14.24 (10.7718.82)
12.74 (9.5317.03)
16.34 (12.1222.04)
14.24 (10.4319.45)
9.12 (4.7517.54)
9.38 (4.8418.16)
................................................................................................................................................................................................................................................................................................................................................................................
The models were controlled for maternal age, ethnicity, smoking, diabetes mellitus, twin pregnancies, lack of prenatal care and parity.
a
Women with nontreated hypertension were not included in the analysis; b Women who were treated with atenolol during the third trimester of pregnancy were not included in the analysis; c Women
who were treated with methyldopa during the third trimester of pregnancy were not included in the analysis.
C OMMENT
In this large cohort study, we found that
chronic hypertension with or without
TABLE 4
Comparison of the risk for preterm delivery, small for gestational age, and intrauterine growth restriction
among women without hypertension, women with hypertension who were not treated, and women with
hypertension who were treated with atenolol or methyldopa during the third trimester of pregnancy
Odds ratio (95% confidence interval)
Variable
Preterm delivery
Intrauterine growth
restriction
Preeclampsia
Without hypertension
Reference
Reference
Reference
Reference
Nontreated hypertension
1.89 (1.592.25)
2.06 (1.442.95)
2.09 (1.512.89)
7.02 (5.548.89)
3.23 (2.574.05)
2.25 (1.293.94)
4.40 (3.026.40)
12.82 (9.5817.14)
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
The models were controlled for maternal age, ethnicity, smoking, diabetes mellitus, twin pregnancies, lack of prenatal care and parity.
Orbach. Hypertension/antihypertensive drugs in pregnancy/perinatal outcomes. Am J Obstet Gynecol 2013.
301.e4
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self from the potential adverse effects of
the medications that are used. Several
studies have shown that chronic hypertension in pregnancy is associated with
fetal complications such as SGA, PTD,
IUGR, and fetal death4-6; our findings
corroborate those results. Studies have
also shown that women with chronic hypertension that is treated with atenolol
had higher rates of IUGR and PTD,
which are findings that are also corroborated by results of our study (Table
2).22-25 We found that women with
chronic hypertension who were treated
with methyldopa during the third trimester of pregnancy exhibited higher
rates of SGA and PTD. There were differences in the outcome of PTD and preeclampsia between patients who were
treated with methyldopa and those
treated with atenolol (27% vs 17% and
16% vs 9%, respectively), although exposure to atenolol during the third trimester was associated more with SGA
compared with methyldopa (5.6% vs
2.4%). Methyldopa has been used in
many institutions as the drug of choice
for gestational hypertension; therefore,
it is unlikely that women with more severe hypertension were treated with
methyldopa, as opposed to atenolol.
These observations should be further
investigated.
No statistical difference was found
when early treatment in early pregnancy
was compared with treatment in late
pregnancy, which might be because their
hypertension was pregnancy-induced
and started in late pregnancy.
In our population, women with chronic
hypertension who were treated with either atenolol or methyldopa or both
had higher rates of LBW, SGA, PTD,
and IUGR, even after adjustment for
maternal age, ethnicity, smoking, diabetes mellitus, twin pregnancy, lack of
prenatal care, and parity. Adjustment
for confounders can address their
effects on the outcomes but cannot
differentiate between the effects of
the antihypertensive drugs and the hypertension effects on the outcomes.
Confounding by indication (in this
case, hypertension) cannot be adjusted
in the model and should be recognized
as a limitation. However, because we
had a large group of women with hypertension who were not treated with
medications, we could show that most
of the adverse outcomes occurred even
without the drugs. Our study is unique
in having a large cohort of women with
hypertension who were not treated
pharmacologically during the index
pregnancy, which provided a rare opportunity to separate the effect of the
medications from those of the medical
condition. Because we had no data
about the severity of the hypertension,
we assumed that the groups who were
treated by atenolol or methyldopa or
both had experienced more severe hypertension than did the group of
women with hypertension who were
not treated. This may explain the
higher rates of complications such as
LBW or SGA, PTD and IUGR among
the treated women and support the argument that adverse pregnancy outcomes such as LBW, SGA, PTD, and
IUGR in women with chronic hypertension mainly are due to the adverse
effects of the hypertension itself and
not of the medications. Moreover, the
fact that the group of women who were
treated with atenolol and the group of
women who were treated with methyldopa had both shown higher rates of
LBW, SGA, PTD, and IUGR, although
the mechanism of action of the 2 drugs
are completely different, further supports the argument that adverse pregnancy outcomes in women with
chronic hypertension mainly are due
to the effect of the hypertension itself
and not these medications.
In conclusion, with the use of a population-based and relatively large cohort that
separated the role of hypertension from
that of the medications that were used, our
study supports the major adverse effects of
hypertension itself on pregnancy outcome,
rather than atenolol and methyldopa. f
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