Pregnant Women And Neonates

Life is not about the end of the story where you put down the book with a satisfied sigh.  It is about all the chapters in between that make your heart race,bring a smile and make you cry as you work your way deliously exhausted  to the end where you get to say,
                                    "  That Was a Great Story."

The continued use of heroin during pregnancy, with its attendant risks of infection, overdose, and intrauterine withdrawal, is life threatening to both the woman and the fetus. Research on the safety and efficacy of buprenorphine in pregnant women and neonates is scarce, however. If a patient is pregnant or is likely to become pregnant during the course of opioid addiction treatment, the physician must consider whether buprenorphine is an appropriate option for treatment. Physicians should weigh all the risks and benefits of treatment with buprenorphine against all the risks associated with the continued use of illicit opioids. Methadone is currently the standard of care in the United States for the treatment of opioid addiction in pregnant women. Methadone has been shown to be safe and effective for both pregnant women and neonates.

The FDA classifies buprenorphine as a Pregnancy Category C drug. The FDA Pregnancy Labeling Task Force, whose long-term goal is to determine how animal toxicologic information contributes to clinically meaningful information in pregnancy, assigns a human prescription drug to Pregnancy Category C

 (1) if animal reproduction studies have shown an adverse effect on the fetus
 (2) if there are no adequate and well-controlled studies in humans, and
(3) if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

In addition to considering the FDA warnings pertaining to the use of buprenorphine in pregnant women, physicians also must consider the risks of infectious diseases and lifestyle issues (e.g., poor nutrition, lack of prenatal care) when addressing the needs of these patients.

Effects of Buprenorphine in Pregnancy

Data on the pharmacokinetics of buprenorphine in pregnant women and neonates are extremely limited (Johnson et al. 2003a ; Marquet et al. 1997). Likewise, data are limited regarding the clinical use of buprenorphine for the maintenance treatment of opioid addiction in pregnant women. The literature in this area generally consists of case reports and a small number of prospective studies; there have been no controlled clinical trials.

In case reports from European and Australian sources on the use of buprenorphine in opioid-addicted pregnant women, doses have ranged from 0.4 to 24 mg per day. In these limited reports, pregnancies have generally progressed normally, with low rates of prematurity or other problems. Maternal clinical laboratory data in these reports generally have been within normal limits; or were deemed either clinically nonsignificant at levels expected during pregnancy, when outside normal limits, or were due to factors other than the medication. For a complete review of the published literature on the use of buprenorphine in the treatment of opioid addiction in pregnant women, see (Johnson et al. 2003a ).

Infants of Mothers Treated With Buprenorphine

Buprenorphine and its metabolite norbuprenorphine have been found in high concentrations in the blood, urine, and meconium of the neonates of women maintained on buprenorphine (Johnson et al. 2003a ; Marquet et al. 1997).

The published literature includes information on at least 309 infants born to women maintained on buprenorphine treatment. Although not systematically studied, a neonatal abstinence syndrome (NAS) has been reported in 191 of these 309 infants, with approximately one-half of those with NAS requiring treatment. In more than 40 percent of the cases, however, evaluation of the abstinence syndrome was confounded by other drug use by the mothers. Overall, although no randomized controlled trials have been reported, the NAS associated with buprenorphine has been reported to be less intense than that observed with methadone.

One prospective open-label study (Fischer et al. 2000) found signs of NAS in 7 of 15 neonates exposed to buprenorphine in utero. Of these 15 neonates, 3 had moderate signs of NAS that required treatment, 4 had mild signs of NAS that required no treatment, and 8 had no signs of NAS. A second prospective open-label study (Johnson et al. 2003a ) reported NAS in 3 of 3 neonates; however, none required treatment with medications.

NAS from buprenorphine generally appears within the first 2 days of life, peaks within 3 or 4 days, and lasts for 5 to 7 days. Few infants were reported to have had a withdrawal syndrome for 6 to 10 weeks.

Similar to the treatment of Neonatal Abstinence Syndrome following exposure to methadone, several different medications (including chlorpromazine, phenobarbital, benzodiazepine, paregoric elixir, and morphine drops) have been used successfully to treat the NAS associated with buprenorphine.

The American Academy of Pediatrics recommends tincture of opium as the medication of choice for treatment of neonatal opioid withdrawal symptoms (American Academy of Pediatrics Committee on Drugs 1998).

Breast Feeding While on Buprenorphine Treatment

The limited human pharmacokinetic data show that buprenorphine passes into the breast milk of lactating women at a plasma-to-milk ratio of approximately 1. As a result, and because of the poor oral bioavailability of buprenorphine, the nursing infant will be exposed to only 1/5–1/10 of the total amount of buprenorphine available.

The literature includes reports on approximately 40 to 50 women who were maintained on buprenorphine and who breastfed after delivery (Johnson et al. 2003a ; Lejeune et al. 2001; Loustauneau et al. 2002; Marquet et al. 1997).

These reports indicate that buprenorphine present in breast milk does not appear to suppress NAS. Additionally, NAS has not been observed after the cessation of breastfeeding by women who were maintained on buprenorphine (Loustauneau et al. 2002).

Although the Subutex® and Suboxone® package inserts state that breastfeeding is not advised in mothers treated with these medications, it is the consensus of the panel that any effects of these medications on the breastfed infant would be minimal and that breastfeeding is not contraindicated. However, given the limited literature in this subject area, physicians are advised to use their professional judgment in their recommendations.

The Buprenorphine/Naloxone Combination in Pregnancy

The panel notes that there is a question whether the buprenorphine/naloxone combination is or is not recommended for use in pregnancy. Naloxone is labeled by FDA as a Pregnancy Category B drug. The FDA Pregnancy Labeling Task Force assigns a human prescription drug to Pregnancy Category B (1) if animal reproduction studies have failed to demonstrate a risk to the fetus and (2) if there are no adequate and well-controlled studies in pregnant women.

 Despite the fact that naloxone is classified as a Pregnancy Category B drug, it should be used with caution in pregnant women who are addicted to opioids. Because both mother and fetus will be dependent on the opioids used by the mother, administration of naloxone could precipitate withdrawal in both.

If  it  is  determined  that buprenorphine  is the only acceptable option for the treatment of a pregnant woman, and she understands the issues and risks, then she should be treated with buprenorphine monotherapy so as not to risk fetal exposure to naloxone.

It should be noted that use of buprenorphine monotherapy, because of its greater potential for abuse, necessitates more frequent monitoring of patients and of their medication supplies.

 To prevent abuse and diversion of the buprenorphine monotherapy formulation, quantities of take-home supplies and quantities provided via prescription should be smaller compared to treatment with the buprenorphine/naloxone combination formulation.


Never Forget For a Single Minute;
You Didn't Grow Under My Heart...But in it!

Summary

Buprenorphine is classified by FDA as a Pregnancy Category C drug. Data from controlled studies on the use of buprenorphine in pregnant women are needed. The available evidence does not show any causal adverse effects on pregnancy or neonatal outcomes from buprenorphine treatment, but this evidence is from case series not from controlled studies.

Methadone is currently the standard of care in the United States for the treatment of heroin addiction in pregnant women. Pregnant women presenting for treatment of opioid addiction should be referred to specialized services in methadone maintenance treatment programs.

If such specialized services are refused by a patient or are unavailable in the community, maintenance treatment with the buprenorphine monotherapy formulation may be considered as an alternative.

 In such circumstances, it should be clearly documented in the medical record that the patient has refused methadone maintenance treatment, or that such services were unavailable; that she was informed of the risks of using buprenorphine, a medication that has not been thoroughly studied in pregnancy; and that she understands those risks.

Reference: (1) Clinical Guidelines For The Use of Buprenorphine In The Treatment of Opioid Addiction TIP 40 Chapter 5 

Written And Edited By:  Deborah Shrira      Updated:  8 May 2007