Opioid Use in Pregnancy Linked to Birth Defects

March 10, 2011 — Opioid use just before conception or in early
pregnancy has been associated with an increased risk for birth defects,
including hypoplastic left heart syndrome, one of the most critical
heart defects.
According to an ongoing, population-based study conducted by the
Centers for Disease Control and Prevention (CDC), women receiving opioid
analgesic treatment in early pregnancy had a 2- to 3-fold increased
risk of delivering infants with conoventricular septal defects,
atrioventricular septal defects, hypoplastic left heart syndrome, spina
bifida, or gastroschisis.
"It's important to acknowledge that although there is an increased
risk for some types of major birth defects from an exposure to opioid
analgesics, that absolute risk for any individual woman is relatively
modest," principal investigator Cheryl S. Broussard, PhD, from the CDC's
National Center on Birth Defects and Developmental Disabilities, said
in a news release.
"However, with very serious and life-threatening birth defects like
hypoplastic left heart syndrome, the prevention of even a small number
of cases is very important," she said.
The study was published online February 24 in the American Journal of Obstetrics and Gynecology.


Leading Cause of Death

According to the study authors, previous research has shown that
opioid analgesic use and abuse have been increasing in recent years but
their effects on the developing fetus are poorly understood.
Studies that looked at their potential effects have been plagued by insufficient sample sizes and inconsistent results.
Major birth defects affect about 3% of the 4 million live births each
year in the United States and are the leading cause of infant deaths,
the study team notes. Congenital heart defects are the most common type
of birth defect, affecting nearly 1% of US births, and are the main
contributor to infant mortality attributable to birth defects.
"Despite evidence of adverse fetal effects with maternal codeine use
and the paucity of data on the effects of maternal use of other opioids,
such treatment is often assumed to be safe during pregnancy," the study
authors note.
To examine whether maternal therapeutic use of opioid analgesics in
early pregnancy is associated with birth defects, the investigators
analyzed data from the National Birth Defects Prevention Study, an
ongoing, population-based, case-control study for infants born October
1, 1997, through December 31, 2005, in 10 states.
This study focuses on infants with birth defects of unknown causes,
so those with recognized chromosomal abnormalities or single-gene
disorders are excluded.


Risk-Benefit Must Be Weighed

Mothers were interviewed between 6 weeks and 2 years after the
estimated date of delivery and queried about various maternal health
factors, pregnancy history information, dietary and drug exposures, and
sociodemographic characteristics.
Exposures were assessed for the period from 3 months before conception through the end of pregnancy.
The researchers defined opioid exposure as maternal report of one or
more opioids taken for therapeutic reasons. These included codeine,
hydrocodone, meperidine, oxycodone, propoxyphene, morphine, tramadol,
methadone, hydromorphone, fentanyl, or pentazocine. The exposure window
of interest was the period from 1 month before to 3 months after
conception.
The investigators found that therapeutic opioid use was reported by
2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. The most
commonly prescribed opioids included codeine (34.5%), hydrocodone
(34.5%), oxycodone (14.4%), and meperidine (12.9%).
Codeine and hydrocodone exposure were slightly more common among
cases, and oxycodone and meperidine were slightly more common among
controls.
Treatment was statistically significantly associated with
conoventricular septal defects (odds ratio [OR], 2.7; 95% confidence
interval [CI], 1.1 – 6.3), atrioventricular septal defects (OR, 2.0; 95%
CI, 1.2 – 3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4 –
4.1), spina bifida (OR, 2.0; 95% CI, 1.3 – 3.2), or gastroschisis (OR,
1.8; 95% CI, 1.1 – 2.9) in infants, the investigators report.
Codeine and hydrocodone accounted for most of the statistically
significant findings, the study authors note, but these drugs were also
the most commonly used, representing 69% of all reported exposures.
It's possible, the study authors say, that some of the findings may
be due to chance. "Our results should be treated with caution and
deserve further investigation," they write.
They did not have information on medication dose so were unable to
assess dose-response relationships. In addition, illicit drug use was
not assessed.
"It is critical that health care providers weigh the benefits of
these medications along with their potential risks when discussing
analgesic treatment options with patients who are or may become
pregnant, including reproductive-aged women who are not planning a
pregnancy but might be at risk of an unintended pregnancy," the study
authors write.
The study authors have disclosed no relevant financial relationships.

Am J Obstet Gynecol. Published online February 24, 2011. Abstract



Clinical Context



Major birth defects affect approximately 3% of the 3 million
US live births each year, and congenital heart defects are common and
affect nearly 1% of births as a main contributor to infant mortality.
Opioids are often prescribed with nonopioid analgesics in women before
conception, and it is unclear if maternal therapeutic use is associated
with congenital heart defects and other congenital defects.
This is a case-control, population-based study of live births to
examine the role of maternal opioids in congenital heart defects and
other birth defects.









Study Highlights

• Included were infants born between 1997 and 2005 in the National
  Birth Defects Prevention Study, a multisite population-based,
  case-control study of more than 30 types of major structural birth
  defects focusing on exposures immediately before and during pregnancy.
  
• Excluded were known chromosomal abnormalities, single gene
  disorders, noncardiac and nonstructural defects, and physiologic rather
  than structural defects such as patent foramen ovale.
  
• Simple heart defects were discrete or well-recognized single entities, whereas complex defects were combination defects.
  
• Control infants were infants of mothers who did not have birth
  defects born in the same period and from the same region or states.
  
• Mothers participated in structured telephone interviews between 6
  weeks and 2 years after birth, with average of 11 months after delivery
  for cases and 9 months for controls.
  
• Mothers were asked about medication use for each specific
  illness or indication, such as surgery. They were also asked to report
  start and stop dates, duration and frequency of opioid use, and calendar
  dates or pregnancy months.
  
• Logistic regression was used to calculate ORs for birth defects.
  
• Of 17,449 mothers of case infants, 2.6% reported analgesic opioid use between 1 month before and 3 months after conception.
  
• Among the control infants, 2.0% of mothers reported similar use.
  
• The most commonly reported opioids were codeine (34.5%), hydrocodone (34.5%), oxycodone (14.4%), and meperidine (12.9%).
  
• Lower maternal education, prepregnancy obesity, and periconceptional smoking were more frequent among case mothers.
  
• In the 66% of women whose treatment was linked to a reason,
  opioids were used for surgical procedures (41%), infections (34%),
  chronic diseases (20%), and injuries (18%).
  
• The primary analysis included a total of 7724 infants with 1 or more of 15 defects.
  
• The combined risk for all eligible congenital heart defects was 1.4.
  
• Maternal opioid use was associated with infants with
  conoventricular septal defect (OR, 2.7; 95% CI, 1.1 - 6.3),
  atrioventricular septal defect (OR, 2.0; 95% CI, 1.2 - 3.6), atrial
  septal defect, hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4 -
  4.1), tetralogy of Fallot, and pulmonary valve stenosis.
  
• The highest OR was for hypoplastic left heart syndrome (OR, 3.7) when the exposure period definition was tightened.
  
• Oxycodone was only significantly associated with pulmonary valve stenosis.
  
• Maternal opioid use between 1 month before and 3 months after
  conception was also associated with the risk for spina bifida (OR, 2.0;
  95% CI, 1.3 - 3.2) but no other neural tube defects.
  
• There were significant associations with hydrocephaly (OR, 2.0),
  glaucoma or anterior chamber eye defects (OR, 2.6), and gastroschisis
  (OR, 1.8; 95% CI, 1.1 - 2.9).
  
• Limiting the exposure definition to the first 2 months after conception produced similar results.
  
• The authors concluded that opioid use before and after
  conception was associated with an increased risk for congenital heart
  defects and noncardiac birth defects.
  
• They urged caution in considering use of opioids among women of reproductive age who may become pregnant.
  

Clinical Implications

• Maternal use of opioids 1 month before to 3 months after
  conception is associated with an increased risk for congenital heart
  defects.
  
• Maternal use of opioids 1 month before to 3 months after
  conception is associated with an increased risk for noncardiac birth
  defects, such as spina bifida, hydrocephaly, anterior chamber eye
  defects, and gastroschisis.