Antihistamine Use During Pregnancy and Selected Birth Defects

1
Antihistamine Use During Pregnancy and Selected
Birth Defects

• Gilboa SM, Olshan AF, Werler MM, Correa A, and
  the National Birth Defects Prevention Study
• National Center on Birth Defects and
  Developmental Disabilities, Centers for Disease
  Control and Prevention

The findings and conclusions of this presentation
are those of the authors, and do not necessarily
represent the views of the Centers for Disease
Control and Prevention.
2
Antihistamines

• H1-receptor antagonists
• Indications for use
• Upper respiratory infections
• Allergic rhinitis (seasonal allergies)
• Nausea and vomiting
• Other

3
Antihistamines

• No antihistamines labeled to date meet the FDA
  requirement for pregnancy category A
• Most antihistamines classified in pregnancy
  category B or C
• Prescription and over-the-counter formulations
• Sedating (first generation) and non-sedating
  (second and third generation) products

4
Antihistamine Use During Pregnancy

• Over-the-counter formulations (Werler et al.
  2005)
• National Birth Defects Prevention Study controls
  8
• Slone Birth Defects Study 15
• Non-specified formulations
• Baltimore-Washington Infant Study controls (Rubin
  et al. 1993)

5
Antihistamines and Birth Defects

• Collaborative Perinatal Project (Heinonen et al.
  1977)
• Uniform-malformations by hospital
• Crude relative risks
• Hospitalized-standardized relative risks
• Survival and race-standardized relative risks

Crude RR Adjusted RR
Antinauseants, antihistamines, phenothiazines 1.10 1.05
Brompheniramine 2.04 1.98
Chlorpheniramine 1.20 1.12
Diphenhydramine 1.19 1.17
Doxylamine succinate 1.04 0.97
Meclizine 1.09 0.98
Adapted from Heinonen et al. 1977, Table 23.2,
page 324
6
Antihistamines and Birth Defects

• Baltimore-Washington Infant Study (Ferencz et al.
  1993)
• No association between CVM as a group and any use
  of antihistamines from 3 months before pregnancy
  through first trimester
• Meta-analysis (Seto et al. 1997)
• Primarily anti-nausea medications
• 24 studies over 200,000 women
• Summary estimate 0.76 (0.60-0.94)

7
Research Objectives

• To describe patterns of antihistamine use before
  and throughout pregnancy.
• To investigate the association between maternal
  use of antihistamines between the month before
  conception and the end of the first trimester of
  pregnancy, and the risk for selected birth
  defects.

8
National Birth Defects Prevention Study (NBDPS)

• Case-control design
• Estimated date of delivery, October
  1,1997-December 31, 2002
• AR, CA, IA, MA, NJ, NY, TX, CDC/Atlanta
• Cases
• Live births, stillbirths or terminations
• Over 30 major structural birth defects
• Chromosomal anomalies and single-gene disorders
  excluded
• Controls
• Live births
• Selected from hospital data or vital records
• Interview administered between 6 weeks and 24
  months post-delivery
• Medication data derived from Slone Drug Dictionary

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Birth Defects

• Neural tube defects
• Anencephaly
• Spina bifida
• Hydrocephalus
• Cataract
• Anotia/microtia
• Cardiac defects
• Oral clefts
• Cleft palate
• Cleft lip w/wo cleft palate
• Esophageal atresia
• Intestinal atresias
• Ileal, Jejunal, Multiple
• Duodenal
• Biliary atresia
• Anorectal atresia
• Hypospadias
• Limb reduction defects
• Craniosynostosis

• Cardiac defects
• Heterotaxia
• Conotruncal defects
• Tetralogy of Fallot
• D-Transposition of the great arteries
• Atrioventricular septal defect
• Total anomalous pulmonary venous return
• Left ventricular outflow tract obstructions
• Hypoplastic left heart syndrome
• Coarctation of the aorta
• Aortic stenosis
• Right ventricular outflow tract obstructions
• Pulmonary atresia
• Pulmonic valve stenosis
• Septal defects
• Ventricular septal defect, perimembranous
• Ventricular septal defect, muscular
• Atrial septal defect, secundum
• Atrial septal defect, OS/NOS

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Antihistamines Exposure Definition

• Antihistamine components (n54)
• Categorized into 13 classes
• Exposure Any exposure during
• B1 (month before pregnancy) or
• P1 (first month of pregnancy) or
• P2 (second month of pregnancy) or
• P3 (third month of pregnancy)
• No Exposure No exposure during
• B1 and P1 and P2 and P3

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Analysis

• Restriction to mothers with completed interviews
• Restriction to case groups with gt50 cases
• Crude and multivariable analyses
• Stratification by indication
• Respiratory illness
• Nausea and vomiting during pregnancy
• Other
• Presentation of results with at least 5 exposed
  cases

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Multivariable Modeling

• Selection of model covariates based on results of
  descriptive analyses
• Time-varying covariates used exposure window
  B1-P3
• Final adjustment set for all analyses
• Maternal age
• Maternal education
• Maternal race/ethnicity
• Study center
• Time between delivery and interview
• Antioxidant intake (vitamins E and/or C)
• Alcohol use
• Household income

Using indicator variables for multiple level
factors. Dichotomous variables unless otherwise
specified.
13
Results
14
Antihistamine Exposure Prevalence Among Controls

• Any use three months before conception through
  third trimester
• 660/4094 16
• Any use one month before conception through first
  trimester
• 410/4094 10

15
Antihistamine Use By Month of Pregnancy
16
Maximum Duration of Use
gt25 used loratadine
Frequency of Use
17
Antihistamine Use B1-P3 Among Controls (n4094)
Antihistamine N ()
Any antihistamine 410 (10)
Promethazine 99 (2.4)
Pheniramine 91 (2.2)
Diphenhydramine (Benadryl ) 69 (1.7)
Loratadine (Claritiin ) 66 (1.6)
Doxylamine 51 (1.2)
Fexofenadine (Allegra ) 23 (0.6)
Cetirizine (Zyrtec ) 15 (0.4)
Triprolidine 13 (0.3)
Antihistamine NOS 10 (0.2)
Clemastine 6 (0.1)
Dimenhydrinate 6 (0.1)
Hydroxyzine 5 (0.1)
Meclizine 1 (0.02)
18
Maternal Age
Maternal Race/Ethnicty
19
Prepregnancy BMI Category
Antioxidant and Folic Acid Use
20
Results

• Of 514 comparisons made (14 antihistamines X 39
  birth defects)
• 31 (n168) had at least 5 exposed cases
  available for analysis
• No statistically significant associations for
• ? Cetirizine ? Clemastine
• ? Dimenhydrinate ? Fexofenadine
• ? Hydroxyzine ? Loratadine
• ? Promethazine ? Triprolidine
• ? Antihistamine NOS

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Results (with at least 5 exposed cases)

• Any antihistamine associations
• Spina bifida (aOR 1.46 95 CI 1.05, 2.02)
• Intestinal atresia (aOR 1.78 95 CI 1.10,
  2.88)
• Transverse limb reductions (aOR 1.49 95 CI
  1.04, 2.15)
• Diphenhydramine associations
• Spina bifida (aOR 2.19 95 CI 1.12, 4.28)
• Hydrocephaly (aOR 3.64 95 CI 1.58, 8.37)
• RVOTO (aOR 2.23 95 CI 1.20, 4.14)
• Cleft lip w/wo cleft palate (aOR 1.86 95 CI
  1.63, 3.00)
• Craniosynostosis (aOR 2.86 95 CI 1.55,
  5.25)
• Gastroschisis (aOR 2.64 95 CI 1.26, 5.56)

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Results (with at least 5 exposed cases)

• Doxylamine associations
• Spina bifida (aOR 2.28 95 CI 1.17, 4.43)
• HLHS (aOR 3.94 95 CI 1.91, 8.11)
• Meclizine association (5 exposed cases/1 exposed
  control)
• Cleft palate (aOR 30.72 95 CI 3.49, 270.67)
  
• Pheniramine association
• Cleft lip w/wo cleft palate (aOR 1.68 95 CI
  1.12, 2.51)

23
Limitations

• Self-reported medication use
• Recall bias unlikely
• Low exposure prevalence for specific
  antihistamines
• Multiple comparisons possibility of chance
  findings
• Would have expected approximately 8 statistically
  significant associations by chance alone
• No clear biological mechanism to explain
  associations
• Adverse effects in animal studies for meclizine,
  hydroxyzine, fexofenadine, diphenhydramine
• Several studies of diphenhydramine clearance in
  sheep maternal-fetal-placental unit

24
Conclusions

• Prevalence of antihistamine use consistent with
  the literature
• Limited evidence of association between
  antihistamine use and selected birth defects

25
Next Steps

• Further explore duration and frequency of use
• Long-term/chronic users
• Stratification by
• Sedating and non-sedating formulations
• Drug generations
• Year
• Use of updated analytic tools for births
  1997-2003
• N5008 controls
• Estimated exposure prevalence B1-P3 11

26
Thank you.
27

• Category B Either animal studies have not
  demonstrated a fetal risk BUT there are no
  controlled studies in pregnant women, OR animal
  studies have shown an adverse effect that was not
  confirmed in controlled studies in women in the
  first trimester.
• Category C Either studies in animals have shown
  adverse effects on the fetus and there are no
  controlled studies in women, or studies in women
  and animals are not available.

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Antihistamines and Birth Defects

• Loratadine (Claritin )
• Swedish Medical Birth Registry (Kallen et al.
  2001)
• Hypospadias risk (OR2.39 95 CI1.43-3.38)
• Israeli Teratogen Information Service
  (Diav-Citrin et al. 2003)
• No increased risks for hypospadias comparing
  loratadine exposed with 2 different control
  groups
• Other antihistamine exposed
• Unexposed controls
• MMWR evaluation (CDC, 2004)
• No increased risks for hypospadias using NBDPS
  data