Claritin^®

Evaluation of an Association Between 
Loratadine and Hypospadias — United States, 1997--2001 

Morbidity and Mortality Weekly Report 53(10);219-221, 19mar04

[See abstracts at bottom]

Hypospadias is a birth defect that affects approximately seven in 1,000 male infants in the United States. In affected infants, the urethral opening is located along the underside of the penis, scrotum, or perineum; the condition usually is corrected by surgery. Hypospadias is classified in order of increasing severity as first, second, or third degree. In 2002, a study in Sweden noted that among male infants born to women who while pregnant had taken loratadine (Claritin®), a nonsedating antihistamine commonly used for seasonal allergies, hypospadias prevalence was twice that of the general population (1). However, insufficient data were available to determine the severity of the hypospadias cases, and the study did not control for confounding variables (e.g., family history of hypospadias or maternal age). In 2003, a prospective study using data from four countries indicated that five of 142 pregnancies in women exposed to loratadine resulted in infants with major malformations, a prevalence consistent with that of the general population; none had hypospadias (2). To further assess any potential association between loratadine and hypospadias, CDC analyzed data from the National Birth Defects Prevention Study (NBDPS). This report summarizes the results of that analysis, which determined that no increased risk for second- or third-degree hypospadias existed among women who used loratadine in early pregnancy (Table). These results might be useful for women and health-care providers to address concerns about loratadine use and hypospadias. 

NBDPS is an ongoing, multistate, case-control study of environmental and genetic risk factors for major birth defects that can be used in response to public health concerns regarding rare drug exposures and birth defects (3,4). Infants are identified through birth defect surveillance systems in eight states; mothers undergo a detailed interview by telephone in English or Spanish. For this analysis, the case population was defined as male infants with second- or third-degree hypospadias. Infants with first-degree hypospadias are not included in NBDPS because the mildest form of hypospadias is much less completely ascertained by routine surveillance. Infants were excluded if they had 1) known or suspected chromosome abnormalities, 2) single gene conditions, or 3) other recognized multiple congenital anomaly phenotypes. The control population consisted of live-born male infants with no major birth defects, selected at random from the same populations as the case group. Excluded from the analysis were 86 infants whose mothers had incomplete interviews and 30 infants (28 in the case population and two in the control population) who had fathers or brothers with hypospadias. The study populations consisted of 563 male infants with hypospadias and 1,444 male infant controls; all were born during October 1, 1997--June 30, 2001. 

Exposure was defined as any maternal use of loratadine from 1 month before pregnancy through the first trimester. To control for confounding by indication, exposure to other nonsedating or sedating antihistamines during the same period also was assessed. Potential confounding factors tested by multivariate logistic regression analysis included maternal age, maternal race/ethnicity (i.e., non-Hispanic white, non-Hispanic black, Hispanic, and other), birth month, and state of residence at delivery. 

Of 563 male infants with hypospadias, 46 (8.2%) had multiple major birth defects that were not recognized phenotypes, and 517 (91.8%) had hypospadias with no other major birth defects. Among the 1,957 mothers of infants in the case and control populations, 33 (1.7%) reported using loratadine during the exposure period. Univariate analyses showed no association between this use of loratadine and hypospadias (Table). Use of nonsedating antihistamines (including loratadine) and sedating antihistamines also were not associated with hypospadias. Multivariate adjusted odds ratio estimates did not vary significantly from the univariate estimates. In addition, no association between loratadine use and hypospadias was determined when cases with multiple major defects were excluded or when different exposure periods were examined. 

Reported by: M Werler, ScD, Slone Epidemiology Center, Boston Univ School of Public Health, Massachusetts. C McCloskey, MD, Center for Drug Evaluation and Research, Food and Drug Administration. LD Edmonds, MSPH, R Olney, MD, MA Honein, PhD, Div of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities; J Reefhuis, PhD, EIS Officer, CDC. 

Editorial Note:

The findings in this report indicated that hypospadias was not associated with use of loratadine during the period from 1 month before pregnancy through the first 3 months of pregnancy. During 1998--1999, loratadine was the drug most advertised directly to consumers (5) and was used by 3% of women of childbearing age (6). In November 2002, loratadine was approved by the Food and Drug Administration for over-the-counter use (7). Antihistamines are used widely by the general population, including women of childbearing age, 20%--30% of whom have allergic conditions, primarily rhinitis and sinusitis (8). Because an estimated 50% of all pregnancies in the United States are unintended (9), women frequently are exposed inadvertently to medications before learning they are pregnant. 

This report is subject to at least two limitations. First, NBDPS does not track all birth defects. Because first-degree hypospadias is excluded, the potential association between this mildest form of hypospadias and loratadine could not be assessed. Second, women are interviewed about their pregnancy exposures after delivery, and recall of drug use might be different among mothers of infants with major birth defects compared with mothers of infants without major birth defects. 

The results of this analysis might be useful for women and health-care providers to address concerns about loratadine use and hypospadias. These results do not provide definitive information on the overall safety of loratadine. Women should continue to consult their health-care providers before using any medications during pregnancy. Future studies of medications and birth defects, possibly using NBDPS, are needed to address some of the current knowledge gaps on the effects of medication use during pregnancy. 

Acknowledgments 

This report is based in part on contributions by CA Hobbs, MD, Univ of Arkansas for Medical Sciences, Little Rock, Arkansas. GM Shaw, DrPH, S Carmichael, PhD, California Birth Defects Monitoring Program, Emeryville, California. PA Romitti, PhD, Univ of Iowa, Iowa City, Iowa. K Kelley, Slone Epidemiology Center, Boston Univ School of Public Health; M Anderka, MPH, Massachusetts Dept of Public Health. M Royle, PhD, New Jersey Dept of Health and Senior Svcs. C Druschel, PhD, New York State Health Dept. M Canfield, PhD, P Langlois, PhD, Texas Dept of Health. 

References

1. Källén B. Use of antihistamine drugs in early pregnancy and delivery outcome. J Matern Fetal Neonatal Med 2002;11:146--52. [See abstracts below]

2. Moretti ME, Caprara D, Coutinho CJ, et al. Fetal safety of loratadine use in the first trimester of pregnancy: a multicenter study. J Allergy Clin Immunol 2003;111:479--83. 

3. Yoon PW, Rasmussen SA, Lynberg MC, et al. The national birth defects prevention study. Public Health Rep 2001;116(suppl 1):32--40. 

4. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res Part A Clin Mol Teratol 2003;67:193--201. 

5. Findlay SD. Direct-to-consumer promotion of prescription drugs: economic implications for patients, payers and providers. Pharmacoeconomics 2001;19:109--19. 

6. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002;287:337--44. 

7. Food and Drug Administration. FDA approves OTC Claritin. FDA Consum 2003;37:3. 

8. Schatz M, Zeiger RS. Diagnosis and management of rhinitis during pregnancy. Allergy Proc 1988;9:545--54. 

9. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;30:24--9, 46. 

TABLE. Risk for hypospadias in male infants associated with exposure to loratadine and nonsedating and sedating antihistamines — National Birth Defects Prevention Study, United States, October 1997–June 2001

                            Exposed*           Not exposed†     
Medication             Cases	Controls    Cases	Controls	OR§    (95% CI¶)	AOR**    (95% CI)
Loratadine               11	22	    547		1,410		1.29†† (0.62–2.68)	0.96   (0.41–2.22
Nonsedating
  antihistamines
  (including loratadine) 17	33	    541		1,392		1.33   (0.73–2.40)	0.95   (0.48–1.89
Sedating
  antihistamines         43	104	    489		1,258		1.06   (0.73–1.54)	1.02   (0.68–1.53

* Infants whose mothers reported using the medication during the period from 1 month before pregnancy through the first trimester.
† Infants whose mothers did not report using the medication during the period from 3 months before pregnancy until delivery.
§ Odds ratio.
¶ Confidence interval.
** Adjusted odds ratio. Adjusted for birth month, maternal age, maternal race/ethnicity, and state of residency at delivery.
†† This analysis had 80% power to detect OR of >2.3, using a one-sided test.

source: http://www.cdc.gov/mmwr/PDF/wk/mm5310.pdf 18mar04

Abstracts of papers by Dr. Källén:

Delivery outcome after the use of meclozine in early pregnancy.  Eur J Epidemiol. 2003;18(7):665-9.
Kallen B, Mottet I. ,Tornblad Institute, University of Lund, Lund, Sweden. embryol@embryol.lu.se 

In some countries, including Sweden, no risk is considered to exist with the use of meclozine for nausea and vomiting in pregnancy (NVP), but in other countries warnings against use during pregnancy are given. Rat tests indicate a teratogenic risk and published epidemiological studies are of restricted size. Delivery outcome was studied in 16,536 women who reported the use of meclozine in early pregnancy and was compared with all 540,660 women who gave birth. Information on drug usage was obtained prospectively in early pregnancy. Risk factors for using meclozine were young maternal age, to have had a previous child, not to smoke, to have a low body mass index. The use of some other drugs (antihypertensives, thyroxine, anticonvulsants) decreased the use of meclozine. Maternal diagnoses of preeclampsia or diabetes were less frequent when the woman had used meclozine. The twinning rate was increased and the sex distribution of the infants low (female excess). Preterm birth, low birth weight, short body length, and small head circumference occurred at a reduced rate after meclozine use, notably for boys. Also the rate of congenital malformations was reduced. If anything, delivery outcome is better than expected when the mother used meclozine. These beneficial effects are probably secondary to NVP. Meclozine can apparently be used without risk at this condition.

Use of antihistamine drugs in early pregnancy and delivery outcome.  J Matern Fetal Neonatal Med. 2002 Mar;11(3):146-52. 
Comment in: J Matern Fetal Neonatal Med. 2002 Mar;11(3):145.
Kallen B., Tornblad Institute, University of Lund, Sweden.

OBJECTIVE: To study the impact of antihistamine use in early pregnancy on delivery outcome. METHODS: Using prospectively collected information on drug use in early pregnancy, delivery outcome was studied among 17 266 women with 17 776 deliveries and 18 197 infants. The analysis was performed according to the main reason for antihistamine use: nausea and vomiting in pregnancy and allergy. RESULTS: In the nausea and vomiting in pregnancy group, we found a significant increase in twin births and a significant reduction in preterm births, low birth weight and being small-for-gestational age among singletons. The perinatal death rate was reduced and the rate of congenital malformations was normal. A reduction was seen in the occurrence of congenital cardiovascular defects after the use of antihistamines. The odds ratio for specified cardiac defects, with the exception of ventricular and atrium septal defects, after the use of antihistamines for nausea and vomiting in pregnancy (0.54) was significantly lower than that for non-cardiovascular congenital malformations (0.95). No statistically significant effects on delivery outcome were seen after the use of antihistamine drugs for allergy. However, there was a non-significant tendency for a reduced risk for cardiovascular defects (odds ratio 0.71). CONCLUSIONS: The beneficial effects on delivery outcome observed are most probably related to the underlying nausea and vomiting in pregnancy. There is no clear teratogenic effect of the antihistamines studied.

Exposure to drugs and other possibly harmful factors during the first trimester of pregnancy. Comparison of two prospective studies performed in Sweden 10 years apart. Acta Obstet Gynecol Scand. 1976;55(5):395-405. 
Kullander S, Kallen B, Sandahl B.

474 women in mid-pregnancy, interviewed at ten different hospitals in Sweden, were questioned on a number of social and medical items: e.g., drug use, contraceptive technique used before pregnancy, exposure to possibly deleterious factors in the environment. The study, compared with a similar study made ten years earlier in Sweden, showed little or no difference in the use of iron and/or vitamin preparations, analgesic drugs, antibiotics, or endocrine drugs; but a drastic reduction is noted in the use of psychotropic drugs and of antihistaminic drugs. A marked decrease in frequency of first trimester X-ray exposures can be found, but no marked changes in smoking habits. Appr. 18% of the women used contraceptive pills within 6 months of becoming pregnant---3 had used them during early pregnancy. About 4% (18 women) had used IUD---one became pregnant with a Cu-UID (intra-uterine device inpregnated with copper). This type of study can provide some information on the prevalence of relatively common factors, but it must be considerably extended in order to permit an analysis of rare events, e.g., use of most drugs.

PIP: 474 women in midpregnancy were interviewed at 10 different hospitals in Sweden to determine the type of exposure to drugs and other possibly harmful factors during the first trimester of pregnancy, and to compare these responses with those obtained in a similar study 10 years earlier. The 1st study was performed in the city of Malmo during 1963-1965 and involves 6376 women. Information in this study was accumulated for the whole of the pregnancy. A comparison of age distribution and civil status shows a marked change over the 10-year period. Fewer women in the 2nd study are less than 20 years of age (p less than .001) and a greater number are unmarried but living with the infant's father. Reproductive history is also influenced by age and civil status. Contraceptive information for the 6-month period prior to the pregnancy is recorded only for the 2nd study. 52% were without contraceptives. 38% of those using a contraceptive used the pill, and 49% used condoms, 8% IUDs, 2% used a diaphragm, and the rest used a variety of other techniques. The comparison showed little difference in the use of iron and/or vitamin supplements, analgesic drugs,antibiotics, or endocrine drugs; but a drastic reduction was noted in the use of psychotropic drugs and of antihistimines. A decrease in the frequency of X-ray exposure in the first trimester was also seen, while smoking habits were unchanged.