Risk Factor: C*
Class: Respiratory drugs/ Antitussives
Fetal Risk Summary
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 563 of whom had 1st trimester exposure to codeine (1, pp. 287295). No evidence was found to suggest a relationship to large categories of major or minor malformations. Associations were found with six individual defects (1, pp. 287295, 471). Only the association with respiratory malformation is statistically significant. The significance of the other associations is unknown. However, independent confirmation is required for all associations found in this study.
Respiratory (8 cases) Genitourinary (other than hypospadias) (7 cases) Down’s syndrome (1 case) Tumors (4 cases) Umbilical hernia (3 cases) Inguinal hernia (12 cases) For use anytime during pregnancy, 2,522 exposures were recorded (1, p. 434). With the same qualifications, possible associations with four individual defects were found (1, p. 484): Hydrocephaly (7 cases) Pyloric stenosis (8 cases) Umbilical hernia (7 cases) Inguinal hernia (51 cases) In an investigation of 1,427 malformed newborns compared to 3,001 controls, 1st trimester use of narcotic analgesics (codeine most common) was associated with inguinal hernias, cardiac and circulatory system defects, cleft lip and palate, dislocated hip and other musculoskeletal defects (2). Second trimester use was associated with alimentary tract defects. In a large retrospective Finnish study, the use of opiates (mainly codeine) during the 1st trimester was associated with an increased risk of cleft lip and palate (3,4). Finally, a survey of 390 infants with congenital heart disease matched with 1,254 normal infants found a higher rate of exposure to several drugs, including codeine, in the offspring with defects (5). Although all four of these studies contain several possible biases that could have affected the results, the data serve as a possible warning that indiscriminate use of codeine may present a risk to the fetus.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 7,640 newborns had been exposed to codeine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 375 (4.9%) major birth defects were observed (325 expected). Specific data were available for six defect categories, including (observed/expected) 74/76 cardiovascular defects, 14/13 oral clefts, 4/4 spina bifida, 25/22 polydactyly, 15/13 limb reduction defects, and 14/18 hypospadias. Only with the total number of defects is there a suggestion of an association between codeine and congenital defects, but other factors, including the mother’s disease, concurrent drug use, and chance may be involved.
Use of codeine during labor produces neonatal respiratory depression to the same degree as other narcotic analgesics (6). The first known case of neonatal codeine addiction was described in 1965 (7). The mother had taken analgesic tablets containing 360480 mg of codeine/day for 8 weeks prior to delivery.
A second report described neonatal codeine withdrawal in two infants of nonaddicted mothers (8). The mother of one infant began consuming a codeine cough medication 3 weeks prior to delivery. Approximately 2 weeks before delivery, analgesic tablets with codeine were taken at a frequency of up to six tablets/day (48 mg of codeine/day). The second mother was treated with a codeine cough medication consuming 90120 mg of codeine/day for the last 10 days of pregnancy. Apgar scores of both infants were 810 at 1 and 5 minutes. Typical symptoms of narcotic withdrawal were noted in the infants shortly after birth but not in the mothers.
[* Risk Factor D if used for prolonged periods or in high doses at term.]
Breast Feeding Summary
Codeine passes into breast milk in very small amounts that are probably insignificant (9,10 and 11). The American Academy of Pediatrics considers codeine to be compatible with breast feeding (12).
- Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
- Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol 1981;58:33644.
- Saxen I. Associations between oral clefts and drugs taken during pregnancy. Int J Epidemiol 1975; 4;3744.
- Saxen I. Epidemiology of cleft lip and palate: an attempt to rule out chance correlations. Br J Prev Soc Med 1975;29:10310.
- Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:4339.
- Bonica JJ. Principles and Practice of Obstetric Analgesia and Anesthesia. Philadelphia, PA:FA Davis, 1967:245.
- Van Leeuwen G, Guthrie R, Stange F. Narcotic withdrawal reaction in a newborn infant due to codeine. Pediatrics 1965;36;6356.
- Mangurten HH, Benawra R. Neonatal codeine withdrawal in infants of nonaddicted mothers. Pediatrics 1980;65:15960.
- Kwit NT, Hatcher RA. Excretion of drugs in milk. Am J Dis Child 1935;49:9004.
- Horning MG, Stillwell WG, Nowlin J, Lertratanangkoon K, Stillwell RN, Hill RM. Identification and quantification of drugs and drug metabolites in human breast milk using GC-MS-COM methods. Mod Probl Paediatr 1975;15:739.
- Anonymous. Drugs in breast milk. Med Lett Drugs Ther 1974;16:257.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.