A population-based retrospective cohort study was conducted, including all women 15 to 49 years of age who were registered in Clalit Health Services and had a delivery or a pregnancy termination due to medical reasons at Soroka Medical Center (SMC) between 1 January 1999 and 30 December 2009. Clalit Health Services is the largest health maintenance organization in the country, in which 70% of the women in the southern district of Israel 15 to 49 years of age are insured. SMC is the regional hospital, where 98% of the deliveries take place (25
Almost 70% of the population in southern Israel are Jewish and 25.4% are Bedouin Muslim. The Bedouin population composes only 3.5% of the total population of the state of Israel; however, they account approximately half of the births in southern Israel due to a high birth rate (total fertility rate of 7.5 for the Bedouin population versus 2.7 for the Jewish population) (25
Compared to central Israel, which is the most populated and well-developed area of the state, most settlements in the southern district are ranked at low to average socioeconomic levels (27
). The Israeli Central Bureau of Statistics (CBS) uses a socioeconomic scale of clusters ranked from 1 to 10, in which clusters 1 to 3, clusters 4 to 7, and cluster 8 to 10 represent low, average, and high socioeconomic ranks, respectively. Data published by the CBS show, for example, that 86% of the Jewish settlements in the southern district are ranked in clusters 4 and 5, while only 13% of the Jewish settlements in central Israel are ranked within those clusters. Similarly, 42% of the Jewish settlements in central Israel are ranked in clusters 6 and 7, whereas only 2% of the Jewish settlements in the south are ranked at that level. Furthermore, 42% of the Arabic settlements in central Israel are ranked in the low socioeconomic clusters (clusters 1 to 3), while 100% of the Bedouin settlements in the south are ranked in the low socioeconomic clusters (27
We linked 3 computerized databases which draw information directly from original sources—two from Soroka Medical Center (SMC) and one from Clalit Health Services. The SMC's Department of Obstetrics and Gynecology deliveries database includes maternal demographic information, including mother's age and ethnic group (Jewish or Bedouin Muslim), parity, health status during pregnancy and delivery, self-reported smoking status during pregnancy, gestational age at delivery, and delivery results (perinatal death, infant's birth weight, and Apgar score at 1 and 5 min). The diagnoses are reviewed routinely by a trained medical secretary before entry into the database.
Information regarding major malformations diagnosed in newborns or infants until the age of 12 months was collected from the Demog-ICD9 database, which includes demographic and medical information for patients admitted to SMC. Information on drugs dispensed to mothers during the first trimester of pregnancy was collected from the Clalit Health Services medication database, which includes information on the date the drug was dispensed, the anatomical therapeutic chemical (ATC) classification codes of the drugs (including the commercial and generic names), the dose schedule, and the dose dispensed, in terms of the defined daily dose (DDD) (28
) (i.e., the assumed average maintenance dose per day). A fourth database, which included data on medical pregnancy terminations, was assembled manually from the registry of the Committee for Termination of Pregnancies at Soroka Medical Center.
The four databases were encoded and linked by personal identification numbers (numbers that are given at birth by the Interior Ministry and used throughout life) to create a registry of medications dispensed during the first trimester of pregnancy and of pregnancy outcomes. We used the unique identification number of the hospitalization given at SMC to the mother and to the newborn to link the mother and the infant's identification number.
The study was approved by the local institutional ethics committee in accordance with the principles of the Declaration of Helsinki. In accordance with Ministry of Health regulations, the institutional ethics committee did not require written informed consent because the data were obtained anonymously from medical files, with no participation of patients.
The exposure groups were defined as exposure to any macrolide (erythromycin, azithromycin, clarithromycin, or roxithromycin) during the first trimester of pregnancy, or during the third trimester of pregnancy. The unexposed groups were infants or fetuses that were not exposed to any macrolide during the first or third trimester, respectively. The analysis also investigated specific macrolide drugs. An infant or fetus was defined as “exposed” if a macrolide was dispensed to the mother during the first 13 weeks of pregnancy (first trimester group) or during the last 12 weeks of pregnancy (third trimester group). The first day of the last menstrual period was defined as the first day of gestation.
First-trimester exposure to macrolide was also characterized by the total number of defined daily doses (DDD) dispensed. The DDD for macrolides is as follows (28
): erythromycin, 1 g; erythromycin ethyl succinate, 2 g; azithromycin, 0.5 g; clarithromycin, 1 g; roxithromycin, 0.3 g. The total defined daily doses dispensed during the first trimester were stratified into three categories: 1 to 5, 6 to 10, and 11 and more.
We investigated the risk of major malformations after exposure to macrolides during the first trimester of pregnancy for live births and stillbirths and for pregnancy terminations due to medical reasons. We used the definitions of major and minor congenital malformations developed by the Metropolitan Atlanta Congenital Defects Program of the Centers for Disease Control and Prevention (CDC) (29
). Chromosomal diseases were excluded. In subclass analyses of major malformations, the following specific defects were examined (ICD9 codes are in parentheses): anencephaly (740); spina bifida (741); other anomaly of the nervous system (742); anomalies of the eye (743; anomalies of the ear, face, and neck (744); bulbus cordis anomalies and anomalies of cardiac septal closure (745); other anomalies of the heart (746); other anomalies of the circulatory system (747); anomalies of the respiratory system (748); cleft palate and lip (749); other anomalies of the upper alimentary tract (750); other anomalies of the digestive system (751); genital anomalies (752); anomalies of the urinary system (753); musculoskeletal deformities (754); other anomalies of the limbs (755); other musculoskeletal anomalies (756); and anomalies of the integument (757).
In a separate analysis we investigated the risk of pyloric stenosis (ICD9 code 7505) or intussusception (ICD9 code 5600) in infants exposed to macrolides during the last 12 weeks of pregnancy.
We used the SPSS program, version 17 (IBM SPSS; Somers, NY), for statistical analysis. Characteristics of mothers from the exposed and unexposed groups were compared by the chi square or Fisher exact test for categorical variables and the Student t test for continuous variables. We used a multivariate logistic-regression model to determine whether exposure to macrolides was independently associated with an increased risk of major congenital malformations adjusting for maternal age, parity, ethnic group (i.e., Jewish versus Bedouin Muslim), pregestational diabetes mellitus, and year of birth or medical pregnancy termination. A categorical multivariate logistic-regression model was constructed to determine whether greater exposure in terms of defined daily dose (DDD) was associated with an increased risk for major congenital malformations. Odd ratios and 95% confidence intervals were computed. Similar methods were used to estimate the risks of pyloric stenosis or intussusceptions after third-trimester exposure to macrolides.