Table I.

Case-series reports of methotrexate exposure from the National Birth Defects Prevention Study, 1997–2009

Birth defect(s)a	Time of exposureb,c	Reported indication for methotrexate use	Gestational age (weeks)	Maternal age at delivery (years)	Maternal race/ethnicity	Maternal diabetes and pre-pregnancy BMI categoryd	Use of folic acid- containing multivitaminc
Perimembranous ventricular septal defect, atrial septal defect	Preconception	None	37	26	Non-Hispanic Black	No diabetes, overweight	Month 2 – end of pregnancy
Secundum atrial septal defect	Preconception	Neoplasm of endocrine glands	38	35	Non-Hispanic White	No diabetes, overweight	Month 4 – end of pregnancy
Tetralogy of Fallot	Preconception	None	35	37	Non-Hispanic White	No diabetes, normal weight	Preconception – Month 7
Total anomalous pulmonary venous return, atrial septal defect	Preconception	None	36	36	Asian/Pacific Islander	Gestational diabetes, obese	Preconception – end of pregnancy
Valvar pulmonary stenosis, secundum atrial septal defect	Preconception	None	40	29	White, Native American	No diabetes, obese	Month 2 – end of pregnancy
Secundum atrial septal defect	Preconception - Week 1	None	38	22	Non-Hispanic White	No diabetes, normal weight	Preconception – end of pregnancy
Cleft palate	Preconception - Week 2	None	38	24	Non-Hispanic Black	No diabetes, overweight	Month 2 – end of pregnancy
Tetralogy of Fallot	Preconception - Week 2	Rheumatoid arthritis	38	35	Hispanic	No diabetes, normal weight	Month 3 – end of pregnancy
Secundum atrial septal defect	Preconception - Week 3	None	38	33	Non-Hispanic White	Gestational diabetes, overweight	Month 2 – end of pregnancy
Multiple congenital diaphragmatic hernias (Bochdalek, Morgagni, hiatal)	Preconception - Week 4	None	22	26	Non-Hispanic White	No diabetes, obese	Preconception – end of pregnancy
Third degree hypospadias	Preconception - Week 6	Systemic lupus erythematosus	41	39	Non-Hispanic Black	No diabetes, overweight	Preconception – end of pregnancy
VACTER (thoracic hemivertebrae, tracheo- esophageal fistula, esophageal atresia, ectopic kidney, and cardiac [double-inlet left ventricle with mitral atresia, transposed great arteries, and hypoplastic ascending aorta])	Preconception - Week 9	None	34	24	Non-Hispanic White	No diabetes, normal weight	Month 2 – end of pregnancy
Bilateral foot ectrodactyly, metopic craniosynostosis	Week 5	None	37	30	White, Hispanic	No diabetes, normal weight	Preconception – end of pregnancy
Third degree hypospadias	Week 5	None	29	29	Non-Hispanic White	No diabetes, obese	Preconception – end of pregnancy
Right microtia, muscular ventricular septal defect	1 dose between weeks 6–10	None	33	31	Hispanic	Gestational diabetes, obese	Month 1 – end of pregnancy
Valvar pulmonary stenosis	Week 22	None	33	36	Hispanic	No diabetes, normal weight	Preconception – end of pregnancy
Control	Preconception	None	35	34	Non-Hispanic White	No diabetes, normal weight	Preconception – end of pregnancy
Control	Preconception	Polyarticular juvenile rheumatoid arthritis	39	33	Non-Hispanic White	Gestational diabetes, obese	Preconception – end of pregnancy
Control	Preconception - Week 1	None	36	36	Non-Hispanic White	No diabetes, overweight	Preconception – end of pregnancy
Control	Preconception - Week 2	None	39	29	Non-Hispanic White	No diabetes, overweight	Preconception – end of pregnancy

^aBirth defect diagnoses organized by cases appearing first followed by controls; within sub-group, cases and controls arranged chronologically by timing of exposure; congenital heart defects in bold

^bExposure defined as any reported maternal use of methotrexate

^cPreconception defined as the period from three months prior to conception through the estimated date of conception. Week refers to gestational week. Month refers to gestational month.

^dBody mass index (BMI) categories: 18.5–24.9 mg/kg² - normal, 25.0–29.9 - overweight, >29.9 - obese