This study included data on deliveries with estimated due dates between October 1997 and December 2004 obtained from the National Birth Defects Prevention Study (NBDPS), a multistate case-control study of more than 30 different birth defects. The study design was approved by the institutional review boards of the participating study centers and by the Centers for Disease Control and Prevention. Details on the study methodology and the surveillance systems in the 10 states that contributed data to this analysis have been published previously.22,23
In brief, 7 of the 10 states included liveborn, stillborn (fetal deaths at ≥ 20 weeks' gestation), and prenatally diagnosed and electively terminated cases (Arkansas, California, Georgia, Iowa, North Carolina, Texas, and Utah), 1 state included only liveborn and stillborn cases (Massachusetts), and 2 states included only liveborn cases (New Jersey and New York). Each state randomly selected approximately 100 nonmalformed liveborn controls per study year from birth certificates (Arkansas in 2000-2004, Georgia in 2001-2004, Iowa, Massachusetts, North Carolina, New Jersey, and Utah) or from birth hospitals (Arkansas in 1997-1999, California, Georgia in 1997-2000, New York, and Texas) to represent the population from which cases were derived. This analysis is restricted to all male controls. Case information obtained from multiple hospital reports and medical records was entered into a standardized database.
This study included only cases of second- or third-degree hypospadias, that is, with the urethral opening at the penile shaft, scrotum, or perineum (modified British Pediatric Association codes 752.606, 752.607, 752.626, and 752.627). Medical record information (including operative reports when available) with anatomic descriptions or diagrams by pediatricians, urologists, geneticists, pathologists, or other health care providers was reviewed by a clinical geneticist at each study center who determined whether to include or exclude cases in the NBDPS database. Cases described as chordee alone, mild hypospadias (ie, first-degree, coronal, or glandular), hypospadias not otherwise specified, epispadias, or ambiguous genitalia without further description were excluded. Infants with recognized single gene disorders, female karyotypes, or chromosomal abnormalities also were excluded. Each case received a final review by a single clinical geneticist (R.O.) to ensure that cases from each study center met standard eligibility criteria. This geneticist also classified each case as isolated, if there was no concurrent major anomaly or only a minor anomaly (eg, sacral/pilonidal dimple), or multiple, if there was at least 1 unrelated accompanying major anomaly and in another organ system.24
Maternal interviews were conducted using a standardized, computer-based telephone questionnaire in English or Spanish, no earlier than 6 weeks and no later than 24 months after the infant's estimated date of delivery (EDD). Final EDD was based on the mother's self-report; if this was not available, then EDD was estimated from information in the medical record (< 2% of subjects). Interviews were conducted with the mothers of 1165 cases (77% of eligibles) and 3000 controls. (The participation rate in the mothers of all controls was 75%; the rate in the mothers of male-only controls was not available.) The mean time from delivery to interview was 13.2 months in the mothers of cases and 8.9 months in the mothers of controls.
Exposure to corticosteroid medications was determined by asking the mothers whether they experienced various types of illnesses and injuries (eg, respiratory illness, infections) and what medications they used to treat them. The mothers were also asked to describe the specific illness or injury that they experienced. In a final section, the mothers reported the use of any other medications not reported in the preceding illness/injury-specific sections; indication was not recorded in this section. For each medication, information on start and stop dates of use and frequency of use was recorded. Those women who knew only either the start date or stop date of use, but not both, were asked about the duration of use. Medication exposure was assessed during the period extending from 4 weeks before conception through 18 weeks after conception. The date of conception was derived by subtracting 266 days from the EDD. A central coding facility assigned a drug code to each medication exposure, using the Slone Epidemiology Center Drug Dictionary. These codes were used to identify the primary components in each medication. Route of administration (eg, topical, systemic) was assigned based on exact wording from the mother's report or on the known formulation of the medication. Indication was assigned based on injury or illness reported in conjunction with the corticosteroid medication.
The following covariates were considered for inclusion in multivariate models given a possible association with the risk of hypospadias or reported corticosteroid use: maternal education (less than high school diploma, high school diploma, 1 to 3 years of college, 4 or more years of college), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other), age (< 25, 25 to 34, ≥ 35 years at the time of conception), number of previous live births (0, 1, 2 or more), folic acid–containing supplement intake (any vs none from 1 month before through 3 months after conception), smoking (any vs none from 1 month before through 3 months after conception), body mass index (underweight, normal weight, overweight, or obese),25
subfertility (ie, any fertility-related treatments or procedures), and study site. The subfertility variable was based on a positive response to any of the following 3 questions: (1) “Did you have any surgical procedures [to help you become pregnant]?”; (2) “In the 2 months before you became pregnant with [baby's name], did you take any medications to help you become pregnant?”; and (3) “Did you have any other procedures to help you become pregnant?”
We first examined the association between the risk of hypospadias and corticosteroid use versus no corticosteroid use during the periconceptional period (ie, 4 weeks before conception through 14 weeks after conception). We initially used this time window, which both precedes and includes the time of urethral and genital tubercle development, because some of the potential effects of corticosteroid medications extend beyond the actual period of use (eg, adrenal suppression). We then examined associations with more specific time windows of exposure, route of administration, and medication components. We also explored associations with corticosteroid use starting at 15 to 18 weeks after conception (i.e., after urethral closure would have been completed), to help identify possible reporting errors. ORs were estimated only if there were at least 2 exposed cases and 2 exposed controls in a particular comparison. To estimate relative risks, maximum likelihood estimates of ORs and their corresponding 95% CIs were calculated from logistic regression models using SAS version 9.1 (SAS Institute, Cary, North Carolina). Covariates were included in the models if their inclusion resulted in at least a 10% change in the OR for the association of any corticosteroid use with hypospadias; they were tested one at a time because of the limited number of exposed subjects.
We also examined whether the association of corticosteroid use varied depending on whether or not the mother took folic acid–containing supplements during the periconceptional period, using a cross-product term in the logistic model.Most of the women who took supplements used a prenatal formulation.26
Experimental studies have shown that vitamin B6
and folic acid, both of which are contained in prenatal vitamin formulations, are protective against the teratogenic effects of corticosteroids,27,28
possibly because they suppress the activity of glucocorticoid receptors.29,30
We reexamined final estimates separately for subjects with birth weight ≥ 2500 g, (because it is possible that infants with normal birth weight are etiologically distinct from those with low birth weight.31,32
), cases that were isolated, cases from singleton births, and cases with no first-degree family history of hypospadias (ie, the father or any brothers).