Abstract
Clubfoot, a common major structural malformation, develops early in gestation. Epidemiologic studies have identified higher risks among boys, first-born children, and babies with a family history of clubfoot, but studies of risks associated with maternal exposures are lacking. We conducted the first large-scale, population-based, case-control study of clubfoot with detailed information on maternal medication use in pregnancy. Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina during 2007–2011. Cases were 646 mothers of children with clubfoot without other major structural malformations (i.e., isolated clubfoot); controls were mothers of 2,037 children born without major malformations. Mothers were interviewed within 12 months of delivery about medication use, including product, timing, and frequency. Odds ratios were estimated for exposure to 27 medications in pregnancy months 2–4 after adjustment for study site, infant sex, first-born status, body mass index (weight (kg)/height (m)2), and smoking. Odds ratios were less than 1.20 for 14 of the medications; of the remainder, most odds ratios were only slightly elevated (range, 1.21–1.66), with wide confidence intervals. The use of antiviral drugs was more common in clubfoot cases than in controls (odds ratio = 4.22, 95% confidence interval: 1.52, 11.73). Most of these results are new findings and require confirmation in other studies.
Keywords: clubfoot, malformation, medications, pregnancy
Clubfoot is a structural defect in which the bones of the foot and ankle are fixed in malposition. Specifically, the foot is inwardly rotated and pointed downward, and the forefoot is pronated toward the heel. These malpositions affect mobility and require treatment. Correction is achieved in a majority of cases with serial casting and possibly tenotomy, splinting, or more invasive surgery (1). Clubfoot recurs within families but does not follow a strict Mendelian inheritance pattern (2). It is sometimes accompanied by other structural anomalies, including neural tube defects and bilateral renal agenesis, but it most often occurs as an isolated congenital anomaly without any family history (1).
Clubfoot can be visualized by ultrasonography at 12 weeks' gestation and, thus, is considered to develop early in pregnancy, though its pathogenesis is not known. One hypothesis is vascular disruption, based on epidemiologic, radiological, surgical, and pathological observations (3–10). Clubfoot might also be secondary to neurological or connective tissue maldevelopment (11, 12). Genetic factors involved in limb signaling pathways have also been implicated (13). Known risk factors include maternal smoking during pregnancy and primiparity (14–16). Although various environmental exposures and medical conditions have been suggested in single studies (17–25), these have not been confirmed as risk factors. Some studies of specific medications in relation to a wide variety of birth defects have reported associations with clubfoot (26–28), but maternal medication use has not been systematically explored in an epidemiologic study specifically focused on clubfoot.
We sought to identify whether medications commonly used in early gestation are associated with the risk of isolated clubfoot in the first large-scale, population-based case-control study of medical record–confirmed clubfoot. Specific medication classes and agents were examined in relation to clubfoot and according to family history of clubfoot.
METHODS
During the years 2007–2011, a case-control study of clubfoot was conducted in Massachusetts, North Carolina, and parts of New York State. For cases, the birth defect registries in each of these states reported to the study data on all infants less than 11 months of age with a diagnosis of talipes equinovarus or clubfoot without a known chromosomal anomaly, inherited syndrome, bilateral renal agenesis, Potter syndrome, or neural tube defect. For controls, random samples of children born in the same years as cases but without known malformations were identified from birth certificates (in Massachusetts and North Carolina) or birth hospital records (in New York); approximately 4 controls were selected per case. Mothers were interviewed by telephone within 12 months after delivery about pregnancy events and exposures. The institutional review boards at Boston University and the state health departments in Massachusetts, North Carolina, and New York approved the study protocol. Details of the study methods have previously been reported (16).
Mothers of clubfoot cases were asked to provide releases for their children's pediatric and orthopedic records; 77% agreed, and the clubfoot diagnoses were confirmed by orthopedist review of those records. The remaining 23% of cases whose medical records could not be obtained met inclusion criteria on the basis of the mother having reported in the interview 3 or more castings of her child's affected foot or feet. Cases were further classified as “isolated” (i.e., no other major malformations) or “multiple” (i.e., the presence of additional major malformations as reported by the birth defect registry or stated in medical records). Cases with a notation of heart murmur but without supporting evidence of a structural heart abnormality or other cardiac abnormality were considered isolated.
Case and control mothers were asked about demographic factors, including sex of the child and maternal age, years of education, marital status, race/ethnicity, number of previous pregnancies and births, height, and prepregnancy weight. Specific questions about medication use involved the use of prompts by indication and product; for each medication reported, details were obtained on timing, frequency, and duration of use. Mothers were also asked if any of the babies' relatives were born with clubfoot and, if so, which relatives.
On the basis of the timing of clubfoot development, the exposure window of interest is lunar months (LMs) 2–4, which is 29–112 days after the first day of the last menstrual period. For each medication, exposure was defined as any use in LMs 2–4, with the exception of fertility medications for which the exposure window was the 28 days before to 56 days after the last menstrual period, because this spans the typical exposure period, after which there were no exposures. For comparison purposes, nonexposure was defined as no use from the last menstrual period to the end of pregnancy, with the exception of fertility medications for which no use from 28 days before the last menstrual period through the end of pregnancy constituted the unexposed group. Women whose dates of use were unknown were excluded from both the exposed and nonexposed groups.
Single- and multiple-component medications were classified according to their active ingredients. Comparisons between case and control mothers were made for those specific medications with at least 5 exposed cases and 5 exposed controls. Logistic regression models were used to estimate odds ratios and 95% confidence intervals. Odds ratios were adjusted for study site (Massachusetts, New York, or North Carolina), first born (yes or no), sex (male or female), body mass index (weight (kg)/height (m)2) (≥25 or <25), and maternal smoking through LM 4 (yes or no). Confounding by the use of multiple medications was assessed. Medications with odds ratios less than 0.8 or greater than 1.2 were entered into models, and those that changed the odds ratio estimate by more than 15% were retained. Data on selective serotonin reuptake inhibitors were not presented in this analysis because their relationship with clubfoot was previously reported (29), but their potential confounding effects were evaluated. In analyses of fertility medications, potential confounding by multiple gestations and invasive prenatal testing was assessed in additional and separate subanalyses by restricting the models to singleton births without chorionic villus sampling or amniocentesis. For medications with at least 20 exposed cases, the number of days exposed in LMs 2–4 was examined. Frequency (i.e., number of days per week or month) and duration of use were combined to calculate the number of exposure days, which was then categorized as none, 14 or fewer days, more than 14 days, or unknown.
Cases and controls with a sibling or parent affected with clubfoot were considered to have a positive family history. Medication use was also examined within the larger subgroup without a positive family history of clubfoot.
RESULTS
The mothers of 72% of cases and 63% of controls were eligible and participated in the study. Among the 677 clubfoot cases, 95% had no other major structural malformations and were included in the present analysis of isolated clubfoot. These 646 cases were compared with the 2,037 control subjects. Compared with controls, a higher percentage of cases were male, non-Hispanic white, from the Massachusetts study site, first born, and with mothers who smoked or had a body mass index value of 25 or more (Table 1). Cases were more than 15 times as likely as controls to have a parent or sibling affected with clubfoot.
Table 1.
Distribution of Demographic and Reproductive Factors Among 646 Isolated Clubfoot Cases and 2,037 Control Subjects in Massachusetts, New York, and North Carolina, 2007–2011
| Descriptive Factor | Cases (n = 646) |
Controls (n = 2,037) |
||
|---|---|---|---|---|
| No. | % | No. | % | |
| Child's sex | ||||
| Male | 466 | 72.1 | 1,006 | 49.4 |
| Female | 180 | 27.9 | 1,031 | 50.6 |
| Maternal age, years | ||||
| <20 | 19 | 2.9 | 107 | 5.3 |
| 20–24 | 132 | 20.4 | 369 | 18.1 |
| 25–29 | 178 | 27.6 | 536 | 26.3 |
| 30–34 | 183 | 28.3 | 568 | 27.9 |
| ≥35 | 134 | 20.7 | 452 | 22.2 |
| Unknown | 0 | 0.0 | 5 | 0.2 |
| Maternal education, years | ||||
| <12 | 80 | 12.4 | 283 | 13.9 |
| 12 | 163 | 25.2 | 456 | 22.4 |
| ≥13 | 403 | 62.4 | 1,297 | 63.7 |
| Mother living with child's father | ||||
| Yes | 553 | 85.6 | 1,730 | 84.9 |
| No | 92 | 14.2 | 305 | 15.0 |
| Unknown | 1 | 0.2 | 2 | 0.1 |
| Race/ethnicity | ||||
| White (non-Hispanic) | 472 | 73.1 | 1,339 | 65.7 |
| Hispanic | 72 | 11.1 | 246 | 12.1 |
| Black | 82 | 12.7 | 342 | 16.8 |
| Other | 20 | 3.1 | 109 | 5.4 |
| Maternal residence | ||||
| New York | 202 | 31.3 | 568 | 27.9 |
| North Carolina | 265 | 41.0 | 1,014 | 49.8 |
| Massachusetts | 179 | 27.7 | 455 | 22.3 |
| First born | ||||
| Yes | 313 | 48.5 | 814 | 40.0 |
| No | 333 | 51.6 | 1,223 | 60.0 |
| Prepregnancy body mass indexa | ||||
| <18.5 | 23 | 3.6 | 87 | 4.3 |
| 18.5–24.9 | 297 | 46.0 | 1,080 | 53.0 |
| 25.0–29.9 | 175 | 27.1 | 451 | 22.1 |
| ≥30.0 | 134 | 20.7 | 360 | 17.7 |
| Unknown | ||||
| Maternal smoking | ||||
| Yes | 111 | 17.2 | 193 | 9.5 |
| No | 535 | 82.8 | 1,844 | 90.5 |
| Clubfoot in parent or sibling | ||||
| Yes | 76 | 11.8 | 15 | 0.7 |
| No | 570 | 88.2 | 2,022 | 99.3 |
a Weight (kg)/height (m)2.
Of the more than 1,000 drugs and vitamins reported by mothers in the study, 27 medications were reported by at least 5 cases and 5 controls during the 84-day period of interest (Table 2). Consideration of the use of multiple medications revealed no appreciable confounding for all but 2 products: guaifenesin was confounded by the use of pseudoephedrine, diphenhydramine, and phenylephrine; and metronidazole was confounded by the use of salicylate, opioids, diphenhydramine, albuterol, and antifungals. After adjustment for sociodemographic factors and smoking, the odds ratio for acetaminophen use was 0.99, whereas odds ratios were slightly elevated for ibuprofen, salicylate, naproxen, and opioid use, but had 95% confidence intervals that included 1.0. The opioid-exposed subjects most frequently reported having taken hydrocodone, codeine, and oxycodone. Oxycodone use was reported by 8 case mothers (1.2%) and 3 control mothers (0.1%), whereas the corresponding proportions for hydrocodone and codeine were similar between cases and controls. The use of morphine, methadone, buprenorphine, fentanyl, propoxyphene, and meperidine was also reported (collectively, in 1.5% of case mothers and 0.6% of control mothers), but numbers for specific agents were too small to examine separately. Adjusted odds ratios for the use of cold, cough, allergy, and asthma medications ranged from 0.71 to 1.16, appearing not to be associated with a greater risk of clubfoot. Among antimicrobials, amoxicillin and antifungal compounds were not associated with greater risk of clubfoot, but risk estimates were elevated for the use of azithromycin (adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI): 0.85, 3.24) and antiviral medications (adjusted OR = 4.22, 95% CI: 1.52, 11.73). A greater than 3-fold higher odds ratio was observed for metronidazole after controlling for sociodemographic factors, smoking, and other medications, but the confidence interval was wide (95% CI: 0.68, 14.06). Suggestions of slightly higher risks were observed for 2 antinausea treatments—promethazine (adjusted OR = 1.39) and ondansetron (adjusted OR = 1.33)—but not for the use of proton pump inhibitors. Five different proton pump inhibitors were reported (omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole), but there were too few women exposed to any 1 medication to estimate odds ratios.
Table 2.
Medication Use in Early Pregnancy in Relation to Isolated Clubfoot Among 646 Isolated Clubfoot Cases and 2,037 Control Subjects in Massachusetts, New York, and North Carolina, 2007–2011
| Medication Use in Lunar Months 2–4 | Isolated Cases (n = 646) |
Controls (n = 2,037) |
Adjusted ORa | 95% CIa | ||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Analgesics | ||||||
| Acetaminophen | 251 | 38.9 | 793 | 38.9 | 0.99 | 0.80, 1.21 |
| Ibuprofen | 68 | 10.5 | 171 | 8.4 | 1.21 | 0.89, 1.66 |
| Naproxen | 8 | 1.2 | 15 | 0.7 | 1.48 | 0.61, 3.62 |
| Opioids | 25 | 3.9 | 47 | 2.3 | 1.56 | 0.92, 2.66 |
| Salicylates | 30 | 4.6 | 70 | 3.4 | 1.30 | 0.82, 2.05 |
| Colds/cough/allergy medications | ||||||
| Cetirizine | 11 | 1.7 | 35 | 1.7 | 0.84 | 0.42, 1.70 |
| Diphenhydramine | 20 | 3.1 | 82 | 4.0 | 0.71 | 0.42, 1.18 |
| Guaifenesin | 15 | 2.3 | 44 | 2.2 | 1.16 | 0.56, 2.41 |
| Loratadine | 17 | 2.8 | 52 | 2.6 | 1.01 | 0.57, 1.79 |
| Phenylephrine | 23 | 3.6 | 69 | 3.4 | 1.03 | 0.62, 1.71 |
| Pseudoephedrine | 26 | 4.0 | 103 | 5.1 | 0.72 | 0.46, 1.14 |
| Antimicrobials | ||||||
| Amoxicillin | 10 | 1.5 | 42 | 2.1 | 0.67 | 0.33, 1.37 |
| Antifungal | 7 | 1.1 | 42 | 2.1 | 0.57 | 0.25, 1.30 |
| Antiviral | 9 | 1.4 | 8 | 0.4 | 4.22 | 1.52, 11.73 |
| Azithromycin | 15 | 2.3 | 26 | 1.3 | 1.66 | 0.85, 3.24 |
| Metronidazole | 5 | 0.8 | 7 | 0.3 | 3.08 | 0.68, 14.06 |
| Antiemetics | ||||||
| Ondansetron | 34 | 5.3 | 91 | 4.5 | 1.33 | 0.87, 2.03 |
| Promethazine | 29 | 4.5 | 78 | 3.8 | 1.39 | 0.87, 2.22 |
| Proton pump inhibitors | 7 | 1.1 | 21 | 1.0 | 1.03 | 0.42, 2.51 |
| Fertility medications | ||||||
| Clomiphene only | 11 | 1.7 | 25 | 1.2 | 1.44 | 0.67, 3.08 |
| Hormones | 28 | 4.3 | 51 | 2.5 | 1.58 | 0.96, 2.57 |
| Other medications | ||||||
| Albuterol | 25 | 3.9 | 89 | 4.4 | 0.78 | 0.49, 1.25 |
| Folic acid | 582 | 90.1 | 1,840 | 90.3 | 0.99 | 0.65, 1.51 |
| Insulin | 9 | 1.4 | 18 | 0.9 | 1.62 | 0.70, 3.74 |
| Marijuana | 19 | 2.9 | 61 | 3.0 | 1.35 | 0.69, 2.65 |
| Oral contraceptives | 16 | 2.5 | 49 | 2.4 | 1.12 | 0.62, 2.03 |
| Thyroid hormone | 19 | 2.9 | 61 | 3.0 | 0.98 | 0.57, 1.68 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Adjusted for study site, first born, sex, body mass index (weight (kg)/height (m)2), and maternal smoking. Guaifenesin was also adjusted for pseudoephedrine, diphenhydramine, and phenylephrine; metronidazole was also adjusted for salicylate, opioid, diphenhydramine, albuterol, and antifungal medications.
Treatments for infertility were associated with slightly elevated adjusted odds ratios for clubfoot. After exclusion of 45 case and 79 control multiple gestations, adjusted odds ratios for clomiphene only and other fertility medications were 1.66 and 1.63, respectively (data not shown). Similarly, the exclusion of 22 cases and 28 controls with invasive prenatal testing resulted in 1.46- and 1.52-fold greater odds ratios for clomiphene only and fertility medications, respectively (data not shown). In addition, 1.62-fold and 1.35-fold unstable elevations in risk were observed for insulin use and marijuana use, respectively. The use of thyroid medications, oral contraceptives, and folic acid were similarly distributed for cases and controls, and adjusted odds ratios ranged from 0.98 to 1.12.
Medication use was also examined in relation to clubfoot among the subset of 570 cases and 2,022 controls without a first-degree family history of clubfoot (Table 3). Odds ratios were similar to those for the overall group. Associations between clubfoot risk and the use of opioids and antiviral drugs remained elevated, with 95% confidence intervals that excluded 1.0.
Table 3.
Medication Use in Relation to Clubfoot Among 570 Isolated Clubfoot Cases and 2,022 Control Subjects With First-Degree Relatives Affected With Clubfoot in Massachusetts, New York, and North Carolina, 2007–2011
| Medication Use in Lunar Months 2–4 | Cases (n = 570) |
Controls (n = 2,022) |
Adjusted ORa | 95% CIa | ||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Analgesics | ||||||
| Acetaminophen | 220 | 38.6 | 789 | 39.0 | 0.98 | 0.79, 1.22 |
| Ibuprofen | 65 | 11.4 | 171 | 8.5 | 1.34 | 0.97, 1.84 |
| Naproxen | 7 | 1.2 | 15 | 0.7 | 1.42 | 0.56, 3.63 |
| Opioids | 24 | 4.2 | 47 | 2.3 | 1.77 | 1.03, 3.03 |
| Salicylates | 27 | 4.7 | 69 | 3.4 | 1.33 | 0.83, 2.15 |
| Colds/cough/allergy medications | ||||||
| Phenylephrine | 14 | 2.5 | 41 | 2.0 | 1.15 | 0.69, 1.93 |
| Pseudoephedrine | 14 | 2.5 | 56 | 2.8 | 0.67 | 0.41, 1.10 |
| Diphenhydramine | 16 | 2.8 | 81 | 4.0 | 0.65 | 0.37, 1.15 |
| Cetirizine | 9 | 1.6 | 35 | 1.6 | 0.78 | 0.36, 1.66 |
| Guaifenesin | 13 | 2.3 | 42 | 2.1 | 1.23 | 0.57, 2.68 |
| Loratadine | 15 | 2.6 | 52 | 2.6 | 1.02 | 0.56, 1.86 |
| Antimicrobials | ||||||
| Amoxicillin | 7 | 1.2 | 41 | 2.0 | 0.53 | 0.23, 1.21 |
| Antifungal | 7 | 1.2 | 40 | 2.0 | 0.68 | 0.30, 1.55 |
| Antiviral | 8 | 1.4 | 8 | 0.4 | 4.02 | 1.40, 11.56 |
| Azithromycin | 14 | 2.5 | 29 | 1.4 | 1.60 | 0.79, 3.22 |
| Metronidazole | 4 | 0.7 | 7 | 0.3 | 2.73 | 0.54, 13.91 |
| Antiemetics | ||||||
| Ondansetron | 32 | 5.6 | 89 | 4.4 | 1.47 | 0.95, 2.27 |
| Promethazine | 25 | 4.4 | 78 | 3.9 | 1.37 | 0.84, 2.24 |
| Proton pump inhibitors | 6 | 1.1 | 20 | 1.0 | 1.05 | 0.40, 2.72 |
| Fertility medications | ||||||
| Clomiphene only | 9 | 1.6 | 25 | 1.2 | 1.39 | 0.61, 3.14 |
| Hormones | 24 | 4.2 | 49 | 2.4 | 1.56 | 0.93, 2.62 |
| Other medications | ||||||
| Albuterol | 22 | 3.9 | 88 | 4.4 | 0.78 | 0.47, 1.27 |
| Folic acid | 514 | 90.2 | 1,827 | 90.4 | 1.01 | 0.64, 1.57 |
| Insulin | 9 | 1.6 | 18 | 0.9 | 1.84 | 0.80, 4.24 |
| Marijuana | 14 | 2.5 | 26 | 1.3 | 1.35 | 0.66, 2.73 |
| Oral contraceptives | 14 | 2.5 | 49 | 2.4 | 1.10 | 0.59, 2.05 |
| Thyroid hormone | 18 | 3.2 | 60 | 3.0 | 1.08 | 0.62, 1.89 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Adjusted for study site, first born, sex, body mass index (weight (kg)/height (m)2), and maternal smoking. Guaifenesin was also adjusted for pseudoephedrine, diphenhydramine, and phenylephrine; metronidazole was also adjusted for salicylate, opioid, diphenhydramine, albuterol, and antifungal medications.
For medications taken by mothers of at least 20 cases, the number of days of use in pregnancy (i.e., ≤14 or >14 days) was compared between cases and controls (Table 4). Although odds ratios were higher for use of more than 14 days compared with use of 14 or fewer days for some medications, no adjusted odds ratio exceeded 1.71, and 95% confidence intervals overlapped considerably. After exclusion of the 147 (23%) cases whose diagnoses were not confirmed by medical records, odds ratios were the same as or within 10% of the corresponding odds ratios for cases overall (data not shown).
Table 4.
Number of Days of Medication Exposure in Lunar Months 2–4 in Relation to Isolated Clubfoot Among 646 Clubfoot Cases and 2,037 Control Subjects in Massachusetts, New York, and North Carolina, 2007–2011
| No. of Days Exposed, by Medication Used During Lunar Moinths 2–4a | Cases (n = 646) |
Controls (n = 2,037) |
Adjusted ORb | 95% CIb | ||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| Acetaminophen | ||||||
| ≤14 | 152 | 23.9 | 467 | 23.2 | 1.01 | 0.80, 1.28 |
| >14 | 105 | 16.5 | 317 | 16.5 | 1.06 | 0.80, 1.39 |
| Albuterol | ||||||
| ≤14 | 10 | 1.5 | 40 | 2.0 | 0.58 | 0.26, 1.27 |
| >14 | 12 | 1.9 | 47 | 2.3 | 0.70 | 0.36, 1.37 |
| Diphenhydramine | ||||||
| ≤14 | 9 | 1.4 | 47 | 2.3 | 0.54 | 0.26, 1.13 |
| >14 | 10 | 1.6 | 23 | 1.1 | 1.33 | 0.61, 2.88 |
| Folic acid | ||||||
| ≤14 | 8 | 1.3 | 16 | 0.8 | 1.58 | 0.61, 4.07 |
| >14 | 536 | 86.6 | 1,699 | 87.4 | 0.97 | 0.68, 1.40 |
| Ibuprofen | ||||||
| ≤14 | 37 | 5.8 | 114 | 5.7 | 1.09 | 0.72, 1.64 |
| >14 | 14 | 2.2 | 31 | 1.5 | 1.22 | 0.62, 2.41 |
| Ondansetron | ||||||
| ≤14 | 7 | 1.1 | 23 | 1.1 | 1.02 | 0.43, 2.45 |
| >14 | 20 | 3.1 | 60 | 3.0 | 1.27 | 0.74, 2.18 |
| Opioids | ||||||
| ≤14 | 11 | 1.7 | 24 | 1.2 | 1.44 | 0.67, 3.12 |
| >14 | 10 | 1.6 | 22 | 1.1 | 1.65 | 0.81, 3.35 |
| Phenylephrine | ||||||
| ≤14 | 23 | 3.6 | 65 | 3.2 | 0.86 | 0.48, 1.55 |
| >14 | 5 | 0.8 | 9 | 0.4 | 1.70 | 0.55, 5.24 |
| Promethazine | ||||||
| ≤14 | 6 | 0.9 | 33 | 1.6 | 0.68 | 0.28, 1.66 |
| >14 | 26 | 3.6 | 74 | 3.6 | 1.24 | 0.78, 2.01 |
| Pseudoephedrine | ||||||
| ≤14 | 19 | 2.9 | 97 | 4.8 | 0.62 | 0.35, 1.11 |
| >14 | 7 | 1.1 | 25 | 1.1 | 0.80 | 0.33, 1.92 |
| Salicylates | ||||||
| ≤14 | 13 | 2.0 | 23 | 1.1 | 1.71 | 0.80, 3.65 |
| >14 | 12 | 1.9 | 31 | 1.5 | 1.17 | 0.59, 2.33 |
Abbreviations: CI, confidence interval; OR, odds ratio.
a Study subjects with unknown days of exposure were excluded.
b Adjusted for study site, first born, sex, body mass index (weight (kg)/height (m)2), and maternal smoking.
DISCUSSION
In this first epidemiologic study of clubfoot with special emphasis on medication use, many medications commonly used in pregnancy were not associated with isolated clubfoot. Further, although slightly higher odds ratios were observed for some analgesics, antimicrobials, antiemetics, fertility agents, insulin, and marijuana, the respective 95% confidence intervals were also compatible with no association or a moderately higher risk. The lack of a clear dose-response effect for the number of days exposed detracts from a putative causal relationship between these medications and isolated clubfoot. Antiviral exposure was less common but was more strongly associated with isolated clubfoot overall and isolated clubfoot without a positive history in first-degree relatives.
Exposure to vasoconstrictive medications was previously postulated to induce vascular disruption in developing fetuses (30, 31). Although pseudoephedrine, phenylephrine, and albuterol each have α-adrenergic properties that cause vasoconstriction (32), there was little evidence of associations between exposure to these agents and greater risk of clubfoot. The nonsteroidal antiinflammatory drugs ibuprofen, salicylates, and naproxen, on the other hand, may be vasoactive in the developing fetus as a result of prostaglandin inhibition, and the modest (albeit unstable) associations observed for the use of those medications may provide some evidence in support of a vascular disruption pathogenesis. These medications could also affect foot development through other pathways. On the other hand, it is worth noting that another class of analgesics—opioids—is not considered to be vasoactive but was more strongly associated with clubfoot risk. The possibility of confounding by indication is a relevant concern, because the nonsteroidal antiinflammatory drugs and opioids noted above were used largely for pain. The observed null odds ratio for acetaminophen (the drug most commonly used for pain) could be considered evidence against such confounding. However, pain is not likely to be 1 entity, with widely varying causes and severity.
Another postulated pathogenetic pathway is that clubfoot is a sequela to a primary central nervous system (CNS) abnormality. In cases with well-characterized CNS abnormalities, such as neural tube defects and caudal dysplasia, clubfoot is common, suggesting that other clubfoot occurrences could be secondary to abnormal innervation. Drugs that affect the CNS include opioids, promethazine, other antihistamines, ondansetron, marijuana, and selective serotonin reuptake inhibitors, which were, for the most part, associated with slightly higher risks of clubfoot. In contrast, odds ratios for the over-the-counter antihistamines—diphenhydramine, loratadine, and cetirizine—that also affect the CNS were not elevated for any use in LMs 2–4, but the use of diphenhydramine for 14 or more days was associated with a very slightly higher odds ratio of 1.33. The Collaborative Perinatal Study reported higher relative risks for clubfoot and the antihistamines pheniramine, diphenhydramine, and doxylamine (27). We speculate as to whether the observed pattern of higher odds ratios for CNS-active drugs supports abnormal neurulation as the primary defect in clubfoot. Though these medications do cross the placenta, it is not clear how they could affect neurulation in the fetus, particularly the development specific to distal lower limbs, in the absence of a structural brain or spinal anomaly. Nevertheless, further research on this possible pathogenetic and etiological pathway seems warranted.
Assisted reproductive technologies have been associated with greater risk of birth defects overall and certain specific birth defects (33), but the modestly elevated odds ratios observed in the present study for the use of clomiphene and fertility hormones are the first to be reported for clubfoot. Women who undergo assisted reproductive technologies may be more likely to have multiple gestations or early prenatal testing, such as chorionic villus sampling or early amniocentesis, which are associated with clubfoot risk (4, 16, 33, 34). However, none of these factors accounted for the higher odds ratios for clomiphene and fertility hormone use, which remained after the exclusion of such women.
The relatively strong association of the use of antiviral medications with clubfoot risk has not been previously described and requires confirmation. Antiviral agents interfere with DNA transcription (32), and there is some evidence of adverse effects on fetal development (32, 35). However, our risk estimate was based on only 9 exposed cases and 8 exposed controls; further, we did not have sufficient information on specific medications within this class to estimate drug-specific risks (4 cases and 3 controls were exposed to antiherpetics; 3 cases and 4 controls were exposed to the neuraminidase inhibitor oseltamivir; 1 case and 1 control were exposed to antiretrovirals; and 1 case was exposed to an unspecified antiviral).
The modestly higher odds ratios for promethazine and ondansetron have not previously been reported, but a positive association was reported for hyperemesis (22) without consideration of types of treatment. Diabetes was not associated with clubfoot risk in a report from Iowa (25), in contrast to the modestly elevated odds ratio for insulin observed in the present study. A slightly lower clubfoot risk was reported for folic acid supplementation in 1 study (23), whereas we observed no association for women who supplemented for more than 14 days in early pregnancy.
Strengths of this study include the large number of cases derived from population-based birth defect surveillance systems, confirmation of clubfoot diagnoses by an orthopedic surgeon, standardized and detailed collection of exposure information, and detailed classification of medications. Despite the large case group, the study lacked statistical power to detect small, null, or protective associations of rare exposures. Retrospective recall of exposures is a potential limitation of this study. However, it is difficult to imagine that differential recall would explain the elevated odds ratios observed for some medications in this study when null or inversely associated odds ratios were observed for many other exposures. Selection bias might explain the observed positive associations, particularly because the participation rates were 72% for cases and 63% for controls. If exposed case mothers were more likely to participate, and/or exposed control mothers were less likely to participate, higher odds ratios would be falsely elevated. Such bias is not likely to explain the observed elevated odds ratios for antiviral medications and metronidazole, but it could explain the observed odds ratios that were more moderately elevated. Uncontrolled confounding by unmeasured or imperfectly measured factors is a possibility. Finally, the observed findings could be due to chance and require confirmation.
In conclusion, our findings offer some evidence that the use of certain specific medications in early pregnancy might increase the risk of clubfoot, though we were not able to rule out the possibility of no associations. Among the many exposures considered, elevated risks, with confidence bounds that excluded 1.0, were observed for opioids and, more strongly, for antiviral drugs. Specific areas for future research should include confirmation of positive associations between CNS-active medications and clubfoot risk in epidemiologic studies, as well as basic research investigations of the biological plausibility of CNS-active drugs affecting neural development in the fetus and a pathogenetic mechanism for clubfoot through abnormal neurulation.
ACKNOWLEDGMENTS
Author affiliations: Slone Epidemiology Center at Boston University, Boston, Massachusetts (Martha M. Werler, Mahsa M. Yazdy, Allen A. Mitchell); Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, Massachusetts (James R. Kasser, Susan T. Mahan); North Carolina Birth Defects Monitoring Program, State Center for Health Statistics, Raleigh, North Carolina (Robert E. Meyer); Massachusetts Birth Defects Monitoring Program, Massachusetts Department of Public Health, Boston, Massachusetts (Marlene Anderka); and Congenital Malformations Registry, New York State Department of Health, Albany, New York (Charlotte M. Druschel).
Support for this work was provided by the Eunice Kennedy Shriver National Institute for Child Health and Human Development (grant RO1-HD051804).
We thank Lisa Crowell and Mary Beth Pender, who served as interviewers; Michelle Heinz and Eileen Mack, who served as research assistants; Michael Bairos, Oleg Starobinets, and Elie Sirotta, who served as database analysts; and Dr. Katherine E Kelley.
Conflict of interest: M.M.W. sits on the advisory boards of several studies that evaluate reproductive outcomes in association with medications taken for various autoimmune disorders; these studies are sponsored by the manufacturers of the medications. The products (and manufacturers) are teriflunomide (Sanofi S.A.), Enbrel (Amgen, Inc.), Actemra (Genentech, Inc.), Cimzia (UCB, Inc.), Humira (Abbott Laboratories), and Orencia (Bristol-Myers Squibb Co.). None of these medications was investigated in the present study, and no conflict is perceived from these relationships. S.T.M.'s husband is a synthetic organic chemist and was employed by Pfizer, Inc., until July 2011 with a severance until July 2012 and holds less than $500 in stock options. He is no longer involved in pharmaceutical research. Dr. Mitchell serves on a Pregnancy Registry advisory council for a biological treatment for multiple sclerosis by Biogen Idec, Inc., which is not examined in this paper and therefore presents no conflict. The Slone Epidemiology Center receives research support from various pharmaceutical companies, some of which may make products covered by this study. None of the companies provided support for, had any role in, or had awareness of the present analysis.
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