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BACKGROUND AND OBJECTIVES: β blockers are widely used in the treatment of hypertensive abstract
disorders during pregnancy. These medications cross the placenta and may cause
physiologic changes in neonates exposed in utero. We sought to define the risks of neonatal
hypoglycemia and bradycardia associated with maternal exposure to β blockers at the time
of delivery in a large, nationwide cohort of Medicaid beneficiaries.
METHODS: We used a cohort of 2 292 116 completed pregnancies linked to liveborn infants
of Medicaid-enrolled women from 2003 to 2007. We examined the risks of neonatal
hypoglycemia and neonatal bradycardia associated with maternal exposure to β blockers
at the time of delivery. Propensity score matching was used to control for potential
confounders including maternal demographics, obstetric and medical conditions, and
exposure to other medications.
RESULTS: There were 10 585 (0.5%) pregnancies exposed to β blockers at the time of delivery.
The risk of neonatal hypoglycemia was 4.3% in the β blocker–exposed neonates versus
1.2% in the unexposed; the risk of neonatal bradycardia was 1.6% in the exposed versus
0.5% in the unexposed. After controlling for confounders, risk remained elevated for both
neonatal hypoglycemia and bradycardia among exposed pregnancies versus unexposed
(adjusted odds ratio, 1.68, 95% confidence interval, 1.50–1.89 and adjusted odds ratio, 1.29,
95% confidence interval, 1.07–1.55, respectively).
CONCLUSION Our findings suggest that neonates born to mothers exposed to β blockers in
late pregnancy, including labetalol, are at elevated risk for neonatal hypoglycemia and
bradycardia.
NIH
aDivisionof Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, and cDivision of WHAT’S KNOWN ON THIS SUBJECT: β blockers are
Endocrinology, Diabetes and Metabolism, Department of Medicine, Brigham and Women’s Hospital, Harvard commonly used to treat hypertensive disorders
Medical School, Boston, Massachusetts; bDepartment of Anesthesiology, Critical Care, and Pain Medicine, during pregnancy. β blockers can cross the placenta
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and dDepartment of
Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
and may cause physiologic changes in neonates
exposed in utero.
Dr Bateman conceptualized and designed the study and drafted the initial manuscript; Drs
Patorno, Desai, Seely, Mogun, Fischer, Hernandez-Diaz, and Huybrechts conceptualized and
WHAT THIS STUDY ADDS: β blockers, including
designed the study and reviewed and revised the manuscript; Ms Mogun designed the study, labetalol, cause an elevated risk for both neonatal
performed the data and statistical analysis, and critically reviewed the manuscript; Dr Maeda hypoglycemia and bradycardia among neonates
designed and performed the validation component of the study and reviewed and revised exposed during late pregnancy compared with
the manuscript; and all authors approved the final manuscript as submitted and agree to be unexposed pregnancies.
accountable for all aspects of the work.
DOI: 10.1542/peds.2016-0731
Accepted for publication Jun 15, 2016 To cite: Bateman BT, Patorno E, Desai RJ, et al. Late
Pregnancy β Blocker Exposure and Risks of Neonatal
Hypoglycemia and Bradycardia. Pediatrics. 2016;138(3):
e20160731
that our results are vulnerable to the causal pathway from β blocker RESULTS
surveillance bias (which would occur exposure to the outcomes, they
if infants born to mothers treated may also be proxies for the severity The cohort included 2 292 116
with β blockers were screened more of the underlying indication. Finally, completed pregnancies linked to
often for hypoglycemia). Fourth, we explored 3 alternative definitions liveborn infants, of which 10 585
we restricted to term deliveries to of outcome: (1) requiring recording (0.5%) pregnancies were exposed
examine whether there was effect of the outcomes of interest in the to β blockers at the time of delivery.
modification by term delivery. infant claims from day of birth Labetalol was the most commonly
Fifth, we excluded patients with to day of life 30 ≥2 times (which used β blocker (n = 6748), followed
β blockers dispensed from 5 months may increase the specificity of the by metoprolol (n = 1485) and
after the LMP to delivery who did outcomes definition in some cases); atenolol (n = 1121).
not have a β blocker with days (2) defining the outcome based on
supply overlapping delivery from inpatient claims only (which most β blocker–exposed patients were
the reference group to minimize the closely matches the outcomes more likely to be older, white, and
potential for misclassification defined in our validation study); have diagnoses that represent
of the unexposed. Sixth, we excluded and (3) defining the presence of the indications for the medication.
neonates with preterm delivery, outcomes using diagnoses recorded They were also more likely to have
who were small for gestational in both maternal and infant claims preexisting or gestational diabetes
age, had low birth weight, or (as claims for the infant are and to deliver preterm. After
experienced intrauterine hypoxemia/ sometimes instead applied to the matching on the basis of the PS,
birth asphyxia. Although these maternal claims). these differences were no longer
conditions cannot be determinants All analyses were performed by present, with the absolute difference
of treatment and may, in fact, in using SAS 9.3 (SAS Institute, Inc, in the prevalence of all measured
some instances be intermediates on Cary, NC). confounders <3% (Table 1).
TABLE 3 The Association Between Exposure to Specific β Blockers and the Risks of Neonatal Hypoglycemia and Neonatal Bradycardia
Exposed Nonexposed OR (95% CI)
Outcomes Total Outcomes Total
Labetalol
Neonatal hypogylcemia
Unadjusted 345 6748 27 228 2 281 531 4.46 (4.00–4.98)
Propensity-score matched 344 6730 593 20 190 1.78 (1.55–2.04)
Neonatal bradycardia
Unadjusted 124 6748 11 659 2 281 531 3.65 (3.05–4.36)
Propensity-score matched 123 6730 276 20 190 1.34 (1.08–1.67)
Metoprolol
Neonatal hypogylcemia
Unadjusted 49 1485 27 228 2 281 531 2.83 (2.13–3.76)
Propensity-score matched 49 1484 91 4452 1.64 (1.15–2.33)
Neonatal bradycardia
Unadjusted 12 1485 11 659 2 281 531 1.60 (0.91–2.81)
Propensity-score matched 12 1484 61 4452 0.59 (0.32–1.09)
Atenolol
Neonatal hypogylcemia
Unadjusted 30 1121 27 228 2 281 531 2.28 (1.59–3.28)
Propensity-score matched 30 1121 59 3363 1.54 (0.99–2.4)
Neonatal bradycardia
Unadjusted 12 1121 11 659 2 281 531 2.11 (1.2–3.73)
Propensity-score matched 12 1121 31 3363 1.16 (0.60–2.27)
Neonatal hypoglycemia occurred crude estimate (OR, 1.29; 95% CI, and atenolol (OR, 1.16; 95% CI,
in 4.3% of offspring of pregnancies 1.07–1.55). 0.60– 2.27).
exposed to β blockers compared
Results across each of the sensitivity
with 1.2% of pregnancies that We examined separately the 3 most analyses conducted were similar
were unexposed, such that the OR commonly prescribed β blockers to those from the main analysis,
associated with β blocker exposure (Table 3). The risk estimates for although for some analyses, in the
was 3.76 (95% CI, 3.42–4.13) (Table neonatal hypoglycemia in the setting of widened CI, the lower
2). After matching, the risk of neonatal PS-matched cohorts were similarly bound of the 95% CI intersected the
hypoglycemia was substantially increased in association with null (Table 4).
attenuated but remained elevated exposure to each of the agents,
(OR, 1.68; 95% CI, 1.50–1.89). including labetalol (OR, 1.78; 95%
CI, 1.55– 2.04), metoprolol (OR, 1.64; DISCUSSION
Neonatal bradycardia occurred in 95% CI, 1.15–2.33), and atenolol
In this large cohort study that
1.6% of the infants born to mothers (OR, 1.54; 95% CI, 0.99–2.40). Risk included ∼2.2 million pregnancies,
exposed to β blockers and in 0.5% estimates for neonatal bradycardia over 10 000 of which were exposed
of those born to mothers who across the specific β blockers in to β blockers around the time of
were unexposed (OR, 3.08; 95% CI, the PS-matched cohorts were less delivery, we observed an ∼70%
2.64–3.60). In the PS-matched cohort, consistent, although the CIs for some increase in the risk of neonatal
the risk of neonatal bradycardia estimates were wide: labetalol (OR, hypoglycemia and a 30% increase
also remained, albeit attenuated by 1.34; 95% 1.08–1.67), metoprolol in the risk of neonatal bradycardia
approximately threefold from the (OR, 0.59; 95% CI, 0.32–1.09), in infants born to mothers taking
Address correspondence to Brian T. Bateman, MD, MSc, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham &
Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120. E-mail: bbateman@partners.org
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2016 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of
Health. The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the
National Institutes of Health (Bethesda, Maryland) under award K08HD075831 (Dr Bateman), the National Heart Lung and Blood Institute at the National Institutes
of Health under grant K24HL096141 (Dr Seely), and the National Institute of Mental Health under grant K01MH099141(Dr Huybrechts). The Medicaid Analytic
eXtract pregnancy cohort was supported by Agency for Healthcare Research and Quality grant R01HS018533. The content is soley the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of Health. Funded by the National Institutes of Health (NIH).
POTENTIAL CONFLICT OF INTEREST: Dr Hernandez-Diaz has consulted for AstraZeneca and UCB for unrelated projects, and served as investigator on grants
to the Brigham & Women’s Hospital from Lilly and Pfizer. The Pharmacoepidemiology Program at the Harvard School of Public Health is supported by Pfizer,
Takeda, Bayer, and Asisa. Drs Huybrechts and Bateman are investigators on grants to the Brigham & Women’s Hospital from Lilly and Pfizer, and Dr Bateman is
an investigator on grants from Baxalta, unrelated to the topic of this manuscript. The other authors have indicated they have no potential conflicts of interest to
disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-1691.
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