This drug should be used during pregnancy only if the benefit clearly outweighs the risk to the fetus.

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned

Risk summary: The majority of available data from clinical trials, observational studies, case series, and case reports on use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone.

Comments:
-Prolonged use of opioids during pregnancy can result in physical dependence in the neonate; women should be advised of the risk of neonatal abstinence syndrome and ensure that appropriate treatment will be available.
-Due to pharmacokinetic differences during pregnancy (significantly lower trough plasm concentrations, shorter half-life than after delivery), the methadone dose may need to be increased or dosing interval decreased to achieve therapeutic effectiveness.
-This drug should not be used during and immediately prior to labor, when short acting analgesics or other analgesic techniques are more appropriate.
-Reports indicate pregnant patients involved in methadone maintenance programs have improved prenatal care (leading to reduced incidence of obstetric and fetal complications and neonatal morbidity and mortality) compared to those using illicit drugs; several factors, including maternal drug use, nutrition, infection and psychosocial circumstances, complicate the interpretation of investigations of the children exposed to methadone during pregnancy.
-Information regarding dose and duration of methadone use during pregnancy is limited, and most maternal exposure in these studies appears to occur after the first trimester of pregnancy.
-Animal reproduction studies of subcutaneous methadone administered during early gestation produced neural tube defects (i.e., exencephaly and cranioschisis) at doses equivalent to 2 times the human daily oral dose (HDD); advise pregnant patients of the potential risk to a fetus.
-Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged opioids use during pregnancy.
-NOWS presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs usually occur in the first days after birth; duration and severity of NOWs may vary.
-Observe newborns for signs of NOWS and manage accordingly.

Clinical Considerations:
-Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death, as well as continued or relapsing illicit opioid use.
-Higher doses or administering the daily dose in divided doses may be necessary during pregnancy.
-Closely monitor for withdrawal signs and symptoms and adjust the dose as necessary.

Labor or Delivery:
-Opioid-dependent patients on methadone maintenance therapy may require additional analgesia during labor.
-Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Infertility:
-Advise patients that chronic opioid use may cause reduced fertility; it is not known whether these effects are reversible.

Animal Data: Administration to pregnant animals during organogenesis and through lactation of doses comparable to or less than the human daily oral dose (HDD) resulted in decreased litter size, increased pup mortality, decreased pup weights, developmental delays, and long-term neurochemical changes in the brain of offspring that correlate with persistent altered behavioral responses. Administration to male rodents prior to mating with untreated females resulted in increased neonatal mortality and significant differences in offspring behavioral tests at exposures comparable to and less than the HDD.
In a study in pregnant mice, a single subcutaneous dose of 22 to 24 mg/kg methadone (approximately equivalent to the HDD) administered on Gestation Day 9 produced exencephaly in 11% of the embryos.

Human Data:
-The majority of available data from clinical trials, observational studies, case series, and case reports on methadone use in pregnancy do not indicate an increased risk of major malformations specifically due to methadone. Findings regarding specific major malformations, decreased fetal growth, premature birth and Sudden Infant Death Syndrome have been inconsistent. Children with prenatal methadone exposure have been reported to demonstrate mild but persistent performance deficits on psychometric and behavioral tests, and visual abnormalities.
In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant patients were randomized to buprenorphine (n=86) or methadone (n=89) treatment (average gestational age of 18.7 weeks at enrollment in both groups). Treatment was discontinued before the end of pregnancy in 33% of the buprenorphine group and 18% in the methadone group. Among those who remained in treatment until delivery, there was no difference between methadone-treated and buprenorphine-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine- exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference), or secondary outcomes (birth weight and length, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among those who discontinued treatment before delivery are not known. Because of the imbalance in discontinuation rates between the methadone and buprenorphine groups, the study findings are difficult to interpret.

Neonatal opioid withdrawal syndrome is an expected and treatable outcome of prolonged use during pregnancy. Several studies have reported decreased fetal growth in infants born to narcotic-addicted women treated with methadone during all or part of their pregnancy; however, this growth deficit does not appear to persist into later childhood. Mild but persistent deficits in performance on psychometric and behavioral tests have been demonstrated. There is conflicting data on whether the risk of sudden infant death syndrome is increased. There are no controlled studies of methadone use in pregnant women.

The effect of this drug on fertility is unknown. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential; it is not known whether these effects on fertility are reversible. Reproductive function in human males may be decreased; reduced ejaculate volume, seminal vesicle and prostate secretions have been reported as well as reductions in serum testosterone levels, sperm motility, and abnormalities in sperm morphology. In animal studies, methadone produces a significant regression of sex accessory organs and testes of male animals, and administration to pregnant animals reduced fetal blood testosterone and androstenedione in male offspring.

AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

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Peak methadone levels occur about 4 to 5 hours after an oral dose. A breastfed infant would receive approximately 17.4 mcg/kg/day based on average milk consumption of 150 mL/kg/day; this is approximately 2% to 3% the oral maternal dose. Methadone concentrations from 50 to 570 mcg/L were observed in assays of breast milk from mothers maintained on oral methadone doses of 10 to 80 mg/day. Cases of sedation and respiratory depression in breastfed infants exposed to methadone have been received. There is no information on use of parenteral methadone in breastfeeding, or the safety of high dose methadone typically used for chronic pain management.

Pregnant mothers need to know when they should or should not breastfeed; a stable mother being treated for opioid use disorder is encouraged to breastfeed, although there are situations where breastfeeding is not recommended (e.g., the mother is HIV-positive, has tuberculosis, has cracked or bleeding nipples, is hepatitis C-positive, has returned to illicit drug use including cannabis). If breastfeeding is being considered, counseling should include:
-How to identify respiratory depression and sedation in their babies and when it may be necessary to seek immediate medical care; mothers should be aware that methadone will be transferred to breast milk.
-The possibility that the baby may experience methadone withdrawal if breast-feeding is discontinued suddenly; mothers should discuss discontinuation of breast-feeding with the baby's healthcare team.
-Use of other substances of abuse will expose the baby to additional risks; if other substances of abuse are being used, mothers should not breast-feed.

Use is considered acceptable; caution is recommended

Excreted into human milk: Yes

Comments:
-Initiation of methadone postpartum, or increasing the maternal dosage to greater than 100 mg/day (therapeutically or by abuse) poses a risk of sedation and respiratory depression in the breastfed infant, especially if the infant was not exposed to methadone in utero.
-Women who received methadone maintenance during pregnancy and are stable should be encouraged to breastfeed unless there is another contraindication; nursing mothers will need ongoing support during this period.
-Breastfed infants should be monitored closely for signs of increased sleepiness, breathing difficulties, and limpness; breastfeeding may decrease, but not eliminate neonatal withdrawal symptoms in infants exposed in utero.
-Breastfed infants of mothers using methadone should be weaned gradually to prevent development of withdrawal symptoms.
-Based on two small clinical studies, methadone was present in low levels in human milk, but the exposed infants did not show adverse reactions
-There have be rare case reports of sedation and respiratory depression in infants exposed to methadone through breast milk.

See references