Managing Pain During Pregnancy and Lactation

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Acetaminophen

NSAIDs have both analgesic and anti-inflammatory properties and are commonly used for musculoskeletal pain. Although the exact mechanism of action is uncertain, NSAIDs decrease pain by acting as non-selective inhibitors of cyclooxygenase (COX) and then inhibiting prostaglandin synthesis. During pregnancy, prostaglandins modulate many key processes, including stimulation of uterine activity, maintaining patency of the fetal ductus arteriosus (essential for adequate in utero blood flow), and promoting fetal urine production (which contributes to the level of amniotic fluid in the second and third trimesters). As expected, alteration of prostaglandin metabolism then has varied effects on the pregnancy, depending on the timing and duration of use. For example, short-term use of indomethacin in the second trimester is effective for the treatment of pain caused by degenerating fibroids; use for long periods (more than 48 hours) in the third trimester has been associated with narrowing of the ductus arteriosus ^, and oligohydramnios. To complicate this picture further, aspirin, the prototypical NSAID, is used in a therapeutic manner in low doses (80–160 mg/day) to decrease the incidence of pregnancy complications in certain high-risk groups but is associated with premature narrowing of the ductus arteriosus at higher doses. Therefore NSAID use in pregnancy must be carefully planned to achieve the proposed benefit and avoid fetal risk. In general, if NSAID use is indicated, the duration should be short (less than 48 hours) without monitoring fetal ductus flow and amniotic fluid volume. All NSAID use for pain should be discontinued by 34 weeks of gestation to prevent pulmonary hypertension in the newborn.

NSAIDs are among the most commonly used drugs during the first trimester of pregnancy. ^, Over the counter use of this medication is very common in this population. With their use so common, many women may not realize that there is potential for deleterious effects on them or their developing fetuses. Furthermore, as the age of first-time mothers increases, more women are likely to take NSAIDs for conditions such as joint and musculoskeletal pain. The effects of NSAID exposure on the fetus in the third trimester are well documented, associated with premature narrowing of the ductus arteriosus leading to pulmonary hypertension in the newborn. However, there is controversy as to the risk associated with maternal exposure and other congenital anomalies.

There is no role for routine use of NSAIDs for pain in pregnancy other than that related to rheumatologic disease or uterine fibroids. In the largest published series of NSAID use during pregnancy to date, Ostensen and Ostensen have detailed a series of 88 women with rheumatic disease, comparing the outcome in 45 who received NSAID therapy during pregnancy with 43 who were not treated during pregnancy. The most common agents used were naproxen (23/45) and ibuprofen (8/45). NSAIDs were most frequently used during the first and second trimesters because many patients stopped therapy once pregnancy was recognized. Many of the rheumatic conditions remitted later in pregnancy. They found no significant differences in pregnancy outcome (duration of pregnancy and labor, vaginal delivery rate, maternal bleeding requiring transfusion, or incidence of congenital anomalies) or the health status of offspring at long-term follow up (ranging from six months to 14 years). The authors concluded that NSAID therapy limited to periods of active rheumatic disease until weeks 34–36 did not adversely affect the neonate. However, it is noted that women with rheumatic disease have poor pregnancy outcomes in general; thus these outcome data should not be applied to the general obstetric population.

More recently, Ofori and collegues published a case-control study regarding the risk of congenital anomalies in pregnant users of NSAIDs. Using a population-based pregnancy registry from 1997–2003 in Quebec, they identified 93 births with congenital anomalies in 1056 women (8.8%) who filled prescriptions for NSAIDs in the first trimester of pregnancy, compared to 2478 in 35,331 (7%) women who did not. They concluded that there might be a greater risk of having children with congenital anomalies, particularly those related to cardiac septal closure.

Despite the physiologic effects of NSAIDs, the results of the Collaborative Perinatal Project have suggested that first trimester exposure to aspirin does not pose an appreciable teratogenic risk, nor does ibuprofen or naproxen, the most commonly used NSAIDs. Patients who conceive while taking NSAIDs can be reassured that this will not impair pregnancy outcomes. However, NSAIDs can interfere with implantation and placental circulation. In a population-based cohort study, the risk of miscarriage was 1.8 (95% confidence interval [CI] 1.0, 3.2) with any NSAID use and was increased to 8.1 (95% CI 2.8, 23.4) if used for more than one week around the time of conception.

Aspirin has well known platelet-inhibiting properties and, theoretically, may increase the risk of peripartum hemorrhage. Neonatal platelet function is inhibited for up to five days after delivery in aspirin-treated mothers. Although low dose aspirin therapy (60–80 mg/day) has not been associated with maternal or neonatal complications, higher doses appear to increase the risk of intracranial hemorrhage in neonates born prior to 35 weeks of gestation. Low dose aspirin has been used to improve pregnancy outcomes for women with both preeclampsia and anti-phospholipid antibodies. However, as with other NSAIDs, aspirin crosses the placenta. Although it has not been implicated in causing congenital abnormalities, it has been associated with an increased risk of vascular disruptions, particularly gastroschisis. ^, Data from two retrospective meta-analyses suggest that there may be a two- to three-fold increase risk of gastroschisis with aspirin exposure. ^, However, there are reassuring data from over 30,000 women in randomized, control trials of low dose aspirin verses placebo that have not shown any significant risk of intraventricular hemorrhage, other neonatal bleeding, or poor pregnancy outcomes.

Ketorolac is an NSAID available for oral and parenteral administration. According to the manufacturer’s prescribing information, ketorolac did not cause congenital disabilities in the offspring of pregnant rabbits. However, ketorolac administration during labor did lead to dystocia in rodents. Ketorolac shares the platelet-inhibiting properties of other NSAIDs. Although ketorolac has not undergone evaluation for its effects on the fetal ductus arteriosus or renal vasculature, it is likely to have effects similar to those of other NSAIDs. Until more information is available, it may be prudent to choose more extensively studied NSAIDs for use during pregnancy.

Based on our clinical experience and a review of the available literature, we have formulated recommendations for the use of NSAIDs during pregnancy ( Box 45.1 ). NSAIDs use in pregnancy must be carefully planned to achieve benefit and avoid fetal risk. In general, if NSAID use is indicated, the duration should be short (48 hours) in the absence of monitoring fetal ductus flow and amniotic fluid volume. Chronic use of NSAIDs should be avoided in pregnancy, especially in the third trimester. Before the 24 ^th week of pregnancy, the use of NSAIDs should be used with caution. It is preferable to use both low dose and short half-life NSAIDs.

Because of the anti-platelet properties of NSAIDs, many anesthesiologists are concerned about the risk of epidural hematoma formation as a result of epidural catheter placement. To date, there are no outcome studies on which to base practice recommendations. There is no evidence that low dose aspirin therapy or the use of other NSAIDs increases the risk of epidural hematoma formation following spinal or epidural placement. As part of our routine history and physical examination of the parturient, we screen for any evidence of bleeding diathesis or easy bruising and, in their absence, proceed with epidural placement without further laboratory testing. This practice is consistent with the practice guidelines published by the American Society of Regional Anesthesia.

Salicylic acid is excreted into breast milk in breastfeeding women, with higher doses of aspirin resulting in disproportionately higher milk concentrations. If continuous, high dose therapy is considered, an alternate drug would be preferred. With the use of daily, low dose aspirin (75 to 325 mg), no aspirin is excreted into breastmilk, and salicylate levels are low. Caution should still be exercised if more than occasional or short term aspirin use is contemplated during lactation because neonates have very slow elimination of salicylates. High-dose aspirin can lead to rashes, platelet abnormalities, and bleeding in nursing infants. As for the use of NSAIDs for pain management in breastfeeding women, ibuprofen is the preferred agent because of its short half-life and safety profile for use in infants. The doses used for infants are much lower than what is excreted in breast milk. While naproxen is considered compatible with breastfeeding, other agents may be preferred because of the longer half-life. Diclofenac and indomethacin are also considered acceptable, but other agents may be preferred because of minimal data available.

Little information is available on the safety of maternal ketorolac use during lactation. One study has found that ketorolac concentrations ranged from 1%–4% of maternal serum levels in breastmilk. The analysis of the breast milk in 10 women given ketorolac 10 mg PO Q6 hours for four days resulted in clinically insignificant levels that the nursing infant would be exposed to. Considering the bioavailability of ketorolac after oral administration, this would likely result in neonatal blood levels between 0.16% and 0.40% of the maternal dose. Ketorolac is commonly given after Cesarean section. However, the colostrum has very little excreted. The manufacturer indicates a contraindication with breastfeeding; therefore another agent should be considered 24–72 hours after birth when more breast milk is produced.

Acetaminophen is a frequently used painkiller and antipyretic drug among pregnant women. It provides similar analgesia without the anti-inflammatory effects seen with NSAIDs. Acetaminophen has no known teratogenic properties, does not inhibit prostaglandin synthesis or platelet function, and is hepatotoxic only in extreme overdosage. ^, As with most drugs, there are no controlled studies in pregnant women in the first trimester. In animal studies, acetaminophen has not demonstrated fetal risk. Data obtained from 88,142 patients in the Danish National Birth Cohort (1996–2003) who had information on acetaminophen use during the first trimester of pregnancy indicated that ingestion of acetaminophen during pregnancy is not related to an overall increased prevalence of congenital abnormality or an increased prevalence of the most frequent abnormalities. If persistent pain demands the use of a mild analgesic during pregnancy, acetaminophen appears to be a safe and effective first-choice agent. Acetaminophen does enter breast milk, although maximal neonatal ingestion would be less than 2% of a maternal dose. Acetaminophen is considered compatible with breastfeeding.

Opioid Analgesics

Many women of childbearing age are prescribed opioids for intermittent or continual pain management. Much of our present knowledge about the effects of chronic opioid exposure during pregnancy is derived from the study of opioid-abusing patients. Chronic opioid use in pregnancy is associated with low birth weight and decreased head circumference. However, the contribution of comorbidities, including polysubstance abuse and smoking, is not clear. Enrollment and compliance with methadone therapy for opioid dependence improves birth weight and prolongs gestation, supporting the role of therapy during gestation.

Until recently, there was no evidence to suggest a relationship between exposure to any of the opioid agonists or agonist-antagonists during pregnancy and large categories of major or minor malformations. The Collaborative Perinatal Project monitored 50,282 mother-child pairs and included exposures to codeine, propoxyphene, hydrocodone, meperidine, methadone, morphine, or oxycodone. Only codeine was found to have an association with malformation (respiratory), but other studies have not confirmed this. No evidence was found for either agent to suggest a relationship to large categories of major or minor malformations. In the spring of 2011, a study by Broussard and colleagues used data gathered from the National Birth Defects Prevention Study (1997–2005), which consisted of an ongoing multi-site, population-based, case-control study of over 30 types of major structural congenital disabilities. They reported that opioid treatment between one month prior to pregnancy and through the first trimester was associated with a greater risk of conoventricular septal defects, atrioventricular septal defects, hypoplastic left heart syndrome, spina bifida, and gastroschisis. Codeine and hydrocodone represented 69% of all reported exposures. However, these results should be interpreted with caution, as some sample sizes were borderline, and further investigation is necessary. It is important to understand that the increased relative risk of a rare congenital disability with exposure to medications usually only translates into a modest absolute increase in risk above baseline. Healthcare providers must weigh the risks and benefits when prescribing to pregnant women or those of childbearing age.

It is important to note that there is an increased risk warning for neonatal opioid dependence when mothers are treated with opioid medications for prolonged periods during pregnancy. Abrupt cessation of opioids in the opioid dependent patient late in pregnancy can precipitate fetal withdrawal in utero , characterized by fetal tachycardia and fetal death. Therefore pregnant women who are opioid dependent, regardless of whether the use is prescription or illicit, should not undergo acute withdrawal late in pregnancy without careful fetal monitoring. The general recommendation is to offer continuation of narcotic medication (for prescription use) or opioid substitution therapy such as methadone or buprenorphine for women using illicit drugs, with entry into treatment programs. Additional benefits of treatment programs include improved prenatal care, higher birth weight, and reduced infectious risk to the neonate.

Neonates exposed to opioid medications in utero can develop dependence and manifest withdrawal symptoms in the first few days of life, known as neonatal abstinence syndrome (NAS). Characterized in mild cases by irritability and increased tone, severe neonatal withdrawal is associated with poor feeding and seizures. NAS occurs in 30%–90% of infants exposed to heroin, methadone, or buprenorphine in utero ^{, , ,} when mothers are treated for illicit opioid use. Patients requiring methadone to treat chronic pain tend to require lower doses of methadone, and their infants have a lower incidence of NAS, approximately 11%. Most infants who have narcotic withdrawal are symptomatic by 48 hours postpartum, but there are reports of withdrawal symptoms beginning 7–14 days postpartum. Neonates with prenatal exposure to opiates for long periods may require very slow weaning (as slow as a 10% reduction every third day) to prevent withdrawal symptoms. The AAP considers methadone to be compatible with breastfeeding.

Recognition of infants at risk for NAS and institution of appropriate supportive and medical therapy typically results in little short-term consequence to the infant. ^, The long-term effects of in utero opioid exposure are unknown. Chasnoff has considered environmental and socioeconomic factors that influence child development and concluded that no definite data exist to demonstrate long-term developmental sequelae from in utero opioid exposure.

Buprenorphine, a partial μ-opioid agonist and κ-opioid antagonist, is currently used for office-based treatment of opioid dependence but is increasing in use for the treatment of chronic pain. ^, Obstetricians and anesthesiologists will encounter patients treated with buprenorphine with increasing frequency. This drug’s low intrinsic receptor efficacy results in a ceiling effect and a diminished risk of overdose compared with methadone. While methadone has been used for over 40 years in the treatment of opioid dependence, buprenorphine is now advocated as first line therapy. The literature that reports buprenorphine in pregnancy remains limited, but buprenorphine has been found to be superior to methadone in reducing signs of withdrawal in newborns, thus requiring less medication and hospitalization time for the babies. In a randomized, double-blind trial comparing 175 women and infants treated with methadone versus buprenorphine, infants who had prenatal exposure to buprenorphine required significantly less morphine for the treatment of NAS, a significantly shorter period of NAS treatment, and significantly shorter hospitalization than those with prenatal exposure to methadone. However, there was no difference in the number of neonates requiring NAS treatment, peak NAS score, head circumference, or any other neonatal or maternal outcome. ^, However, in buprenorphine-maintained patients, acute pain can be challenging to treat because of the partial antagonist activity at the mu receptor. While treatment of opioid dependence requires only once-daily dosing, opioid dependent patients receiving buprenorphine with mild pain may receive analgesia simply by splitting the same daily dose into dosing intervals every 6 hours.

According to the drug manufacturer insert, buprenorphine is not recommended during breastfeeding. However, it appears to be safe. Because of the low levels in breast milk and the poor oral bioavailability in the infant, the infant is exposed to about 1%–1.4% of the maternal weight-adjusted dose. The risk of breast milk induced addiction appears unlikely, and there is no reason to time breastfeeding to avoid peak levels of buprenorphine. The amount of buprenorphine in the milk may not be sufficient to prevent neonatal withdrawal, and treatment of the infant may be required.

Fentanyl is one of the most common parenteral opioid analgesics administered during the perioperative period. As with all opioid analgesics, administration of fentanyl to the mother immediately prior to delivery may lead to respiratory depression in the newborn. Maternal administration of fentanyl or other opioids may also cause loss of the normal variability in fetal heart rate. Loss of fetal heart rate variability can signal fetal hypoxemia; thus the administration of opioids during labor may deprive obstetric caregivers of a useful tool for assessing fetal wellbeing.

Meperidine undergoes extensive hepatic metabolism to normeperidine, which has a long elimination half-life (18 hours). Repeated dosing can lead to accumulation, especially in patients with renal insufficiency. Normeperidine causes excitation of the central nervous system that manifests as tremors, myoclonus, and generalized seizures. Significant accumulation of normeperidine is unlikely in the parturient who receives single or infrequent doses. However, meperidine offers no advantages over other parenteral opioids.

Although mixed agonist-antagonist opioid analgesic agents are widely used to provide analgesia during labor, they do not appear to offer any advantage over pure opioid agonists. In a blinded randomized comparison of meperidine and nalbuphine during labor, the two agents appeared to provide comparable analgesic effects as well as similar neonatal Apgar and neurobehavioral scores. Use of nalbuphine or pentazocine during pregnancy can lead to NAS. Nalbuphine may also cause a sinusoidal fetal heart rate pattern after maternal administration, thereby complicating fetal assessment.

Low-affinity opioid agonists, such as tramadol (Ultram), are being used with increasing frequency, in part because of a perceived lessening of the abuse and addiction potential. There is no evidence that acute use of tramadol for labor analgesia has any advantages over more traditional opioids. According to the manufacturer’s prescribing information, no drug related teratogenic effects were observed in the progeny of rats treated orally with combination tramadol and acetaminophen at 1.6 times the maximum human daily dose. However, at this dose, embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. The intramuscular application of tramadol in mothers in labor reaches the neonate almost freely, confirming a high degree of placental permeability. The neonate already possesses the complete hepatic capacity for the metabolism of tramadol into its active metabolite. However, the renal elimination of the active tramadol metabolite M1 is delayed, in line with the slow maturation process of renal function in neonates. Neonates born to women who are chronically receiving tramadol during pregnancy carry a risk of withdrawal. There are no studies on the relative rates of NAS comparing tramadol with other opioid analgesics.

Postoperative analgesia for most pregnant women undergoing non-obstetric surgery can be readily provided using narcotic analgesics ( Tables 45.1 and 45.2 ). Fentanyl, morphine, and hydromorphone are all safe and effective alternatives when a potent opioid is needed for parenteral administration. There are a range of safe and effective oral analgesics. For mild pain, acetaminophen alone or in combination with hydrocodone is a good alternative. For moderate pain, oxycodone alone or in combination with acetaminophen is effective. More severe pain may require morphine or hydromorphone, both of which are available for oral administration.

Narcotic analgesics can also be administered into the intrathecal or epidural compartments to provide postoperative analgesia. Such neuraxial administration of hydrophilic agents, e.g. morphine, greatly reduces total postoperative opioid requirements while providing excellent analgesia. Spinal or epidural delivery of opioids can be used to minimize maternal plasma concentrations, thereby reducing placental transfer to the fetus or exposure of the breastfeeding infant.

Maternal use of opioids can result in infant drowsiness, central nervous depression, and even death. Opioids are excreted into breast milk. Pharmacokinetic analysis has demonstrated that breast milk concentrations of codeine and morphine are equal to or somewhat higher than maternal plasma concentrations. Meperidine use in breastfeeding mothers via patient-controlled analgesia (PCA) has resulted in significantly greater neurobehavioral depression of the breastfeeding newborn than equianalgesic doses of morphine. After absorption from the infant’s gastrointestinal tract, opioids contained in ingested breast milk undergo significant first-pass hepatic metabolism. Morphine undergoes glucuronidation to inactive metabolites. Meperidine undergoes N -demethylation to the active metabolite normeperidine. Normeperidine’s half-life is markedly prolonged in the newborn, so that regular breastfeeding leads to accumulation and the resultant risks of neurobehavioral depression and seizures. The AAP considers the use of many opioid analgesics, including codeine, fentanyl, methadone, morphine, and propoxyphene, to be compatible with breastfeeding. There are insufficient data to determine the safety of buprenorphine with breastfeeding. However, the excretion of buprenorphine into breast milk is minimal.

Local Anesthetics

Few studies have focused on the potential teratogenicity of local anesthetics. Lidocaine and bupivacaine do not appear to pose a significant developmental risk to the fetus. In the Collaborative Perinatal Project, only mepivacaine had any suggestion of teratogenicity. However, the number of patient exposures was inadequate to draw conclusions. Animal studies have found that continuous exposure to lidocaine throughout pregnancy does not cause congenital anomalies but may decrease neonatal birth weight. Continuous exposure to local anesthetics is unusual but might be seen with the frequent use of local anesthetic patches or creams, which are used for postherpetic neuralgia and other neuropathic pain states.

Neither lidocaine nor bupivacaine appear in measurable quantities in breast milk after epidural local anesthetic administration during labor. Intravenous infusion of high doses (2–4 mg/min) of lidocaine to suppress cardiac arrhythmias has led to minimal levels in breast milk. Based on these observations, continuous epidural infusion of dilute local anesthetic solutions for postoperative analgesia should result in only small quantities of drug reaching the fetus. The AAP considers local anesthetics to be safe for use in the nursing mother.

Mexiletine is an orally active antiarrhythmic agent with structural and pharmacologic properties similar to those of lidocaine. This agent has shown promise in the treatment of neuropathic pain. Mexiletine is lipid-soluble and freely crosses the placenta. There are no controlled studies in humans of mexiletine use during pregnancy. However, studies in rats, mice, and rabbits using doses up to four times the maximum daily dose in humans have demonstrated an increased risk of fetal resorption but not teratogenicity. Mexiletine appears to be concentrated in breast milk. However, based on expected breast milk concentrations and average daily intake of breast milk, the infant would receive only a small fraction of the usual pediatric maintenance dose of mexiletine. The AAP considers mexiletine use to be compatible with breastfeeding.

Steroids

Corticosteroids may be used commonly in pregnancy in patients with autoimmune disease and those with premature rupture of membranes. There is variability in placental metabolism and transplacental passage of steroids depending on the preparation. Most corticosteroids cross the placenta, although prednisone and prednisolone are inactivated by the placenta, while dexamethasone and betamethasone do not undergo significant metabolism. Fetal serum concentrations of prednisone are less than 10% of maternal levels. No increase in malformations was seen among 145 patients exposed to corticosteroids during their first trimester of pregnancy. The use of corticosteroids during a limited trial of epidural steroid therapy in the pregnant patient probably poses a minimal fetal risk (see further discussion later in this chapter).

In breastfeeding mothers, less than 1% of a maternal prednisone dose appears in the nursing infant over the next three days. This amount of steroid exposure is unlikely to affect infant endogenous cortisol secretion.

Benzodiazepines

Benzodiazepines are among the most frequently prescribed drugs and are often used as anxiolytic agents to treat insomnia and as skeletal muscle relaxants in patients with chronic pain. First trimester exposure to benzodiazepines may be associated with an increased risk of congenital malformations. Diazepam may be associated with cleft lip or cleft palate, and with congenital inguinal hernia. However, epidemiologic evidence has not confirmed the association of diazepam with cleft abnormalities. The incidence of cleft lip and palate remained stable after the introduction and widespread use of diazepam. Epidemiologic studies have confirmed the association of diazepam use during pregnancy with congenital inguinal hernia. Benzodiazepine use immediately before delivery also increases the risk of fetal hypothermia, hyperbilirubinemia, and respiratory depression.

Two other benzodiazepines have been evaluated for teratogenicity. Chlordiazepoxide has been reported to produce a four-fold increase in congenital anomalies, including spastic diplegia, duodenal atresia, and congenital heart disease. ^, However, a study of over 200,000 Michigan Medicaid recipients did not support these earlier findings. Instead, this study found a high co-prevalence of alcohol and illicit drug use in patients receiving benzodiazepines. Benzodiazepine use alone did not appear to be a risk factor for congenital anomalies. Oxazepam use during pregnancy has also been associated with congenital anomalies, including a syndrome of dysmorphic facial features and central nervous system defects. In addition to the risks of teratogenesis, neonates who are exposed to benzodiazepines in utero may experience withdrawal symptoms immediately after birth.

Diazepam and its metabolite desmethyldiazepam in the breastfeeding mother can be detected in the infant’s serum for up to 10 days after a single maternal dose. This is caused by the slower metabolism in neonates than in adults. Clinically, infants who are nursing from mothers receiving diazepam may show sedation and poor feeding. It appears most prudent to avoid any use of benzodiazepines during organogenesis, near the time of delivery, and during lactation.

Anti-depressants

Anti-depressants are often used in the management of migraine headaches, as well as for analgesic and anti-depressant purposes in chronic pain states. Selective serotonin reuptake inhibitors (SSRIs) have become the mainstay for the treatment of depression and are widely prescribed. As with most medications, increased use has been associated with increased reports of adverse effects in pregnancy and neonates. Although initially thought to be safe in early pregnancy, unpublished epidemiologic reports from GlaxoSmithKline have raised concern that paroxetine, one of the most widely prescribed anti-depressants, may be associated with an increase in malformations when used in the first trimester, particularly cardiovascular malformations. This recent retrospective epidemiologic study of 3581 pregnant women exposed to paroxetine or other anti-depressants during the first trimester has suggested an increased risk of overall major congenital malformations for paroxetine than other anti-depressants (odds ratio [OR], 2.20; 95% CI, 1.34–3.63). There was also an increased risk for cardiovascular malformations with the use of paroxetine than other anti-depressants (OR, 2.08; 95% CI, 1.03–4.23); 10 out of 14 infants with cardiovascular malformations had ventricular septal defects. Use late in pregnancy has also recently become a concern, with reports of NAS, including jitteriness or seizures, and pulmonary hypertension in the newborn. While paroxetine is generally discouraged in pregnancy, citalopram, and sertraline are considered an option and have not been associated with congenital disabilities. It is important to note that although the relative risk of adverse outcomes has increased, the incidence of malformations (1%–3%) and pulmonary hypertension (0.5%–1%) remain low, whereas the presence of severe depression in pregnant women is high (15%). As with all medications, the risk of no medication must be carefully weighed against the risk of treatment. Many women will need to remain on anti-depressants throughout pregnancy, and the low incidence of adverse outcomes remains reassuring.

Although tricyclic anti-depressants have had a more limited role in the treatment of depression, they can be of benefit in patients with chronic pain. Amitriptyline is teratogenic in hamsters (encephaloceles) and rats (skeletal defects). Imipramine has been associated with several congenital disabilities in rabbits but not in rats, mice, or monkeys. Although there have been case reports of human neonatal limb deformities after maternal amitriptyline and imipramine use, large human population studies have not revealed association with any congenital malformation, with the possible exception of cardiovascular defects after maternal imipramine use. There have been no reports linking maternal desipramine use with congenital disabilities. Withdrawal syndromes have been reported in neonates born to mothers using nortriptyline, imipramine, and desipramine, with symptoms including irritability, colic, tachypnea, and urinary retention.

Amitriptyline, nortriptyline, and desipramine are all excreted into human milk. Pharmacokinetic modeling has suggested that infants are exposed to about 1% of the maternal dose. In a critical review of the literature regarding the use of anti-depressants during breastfeeding, Wisner and colleagues have concluded that amitriptyline, nortriptyline, desipramine, clomipramine, and sertraline are not found in quantifiable amounts in nurslings and reported no adverse effects. They recommended the use of these agents as the anti-depressants of choice for breastfeeding women. Fluoxetine is also excreted into human milk and has a milk-to-plasma ratio of about 0.3. No controlled studies are available to guide fluoxetine therapy during lactation. However, colic and high infant serum levels have been reported. Maternal doxepin use has also been associated with elevated plasma levels of the metabolite N -desmethyldoxepin and respiratory depression in a nursing infant. The AAP considers all anti-depressants to have unknown risk during lactation.

Duloxetine, a selective norepinephrine reuptake inhibitor (SNRI), is representative of a new class of drug that combines inhibition of serotonin and norepinephrine reuptake. Duloxetine is efficacious for depression and neuropathic pain and may have particular efficacy in diabetic neuropathy. Neonates born to mothers receiving SSRI or SNRI drugs may have a withdrawal reaction, as discussed earlier. Although the relative risks and benefits of breastfeeding when a woman is receiving duloxetine have not been fully evaluated, the manufacturer advises against its use during breastfeeding.

Anti-convulsants

Several anti-convulsant medications are used in chronic pain management. However, most data regarding the fetal risk of major malformation in women taking anti-convulsants are derived from the treatment of epilepsy. Although epilepsy itself is not associated with an increased risk of congenital malformations, some theoretical risk may exist. Despite this, data from anti-convulsant use in epileptic women is used to assess the risk of the same medications when used for pain conditions. The American Academy of Neurology and American Epilepsy Society subcommittee recently undertook a systematic review of the evidence for teratogenic potential and perinatal outcomes among pregnant women on antiepileptic medication. ^, The review found that valproic acid exposure, especially in the first trimester, contributes to neural tube defects, facial cleft, and possibly hypospadias. They also found that neonates of women taking anti-convulsants were also more likely to be small for gestational age and have lower Apgar scores. Treatment with valproic acid is more likely to be associated with major congenital malformation than treatment with carbamazepine or lamotrigine. There is a possible dose relationship for the development of congenital malformations for valproic acid during the first trimester. Though not consistent throughout all studies, a valproic acid dose of greater than 1000 mg daily may be associated with the greatest risk of malformations.

In the same review, carbamazepine was associated with an increased risk of cleft palate, but this was not confirmed by another study focusing specifically on carbamazepine using the European Surveillance of Congenital Anomalies (EUROCAT) database. Though this study did not find an association between carbamazepine and clefts, it did find an association with spina bifida.

Data suggests that topiramate (Topamax) and its generic version increase the risk of cleft lip and cleft palate in babies born to women who use the medication during pregnancy. Its use has also been linked to low birth weight.

Gabapentin is an anti-convulsant that is being used for the treatment of neuropathic pain syndromes. Little information exists about the safety of gabapentin in pregnant women, and thus far, the Gabapentin Registry Study does not show an increased risk for adverse maternal and felt events. In their prescribing information, the manufacturer has reported a series of nine women who received gabapentin during their pregnancies. Four women elected pregnancy termination, four had normal outcomes, and one neonate had pyloric stenosis and an inguinal hernia. Insufficient data exist to counsel patients regarding the fetal risk of gabapentin use during pregnancy.

A drug similar to gabapentin is pregabalin, which combines anti-convulsant activity and affinity to the g-aminobutyric acid receptor. The main applications of pregabalin are for the treatment of pain associated with diabetic neuropathy and postherpetic neuralgia.

Patients contemplating childbearing who are receiving anti-convulsants should have their pharmacologic therapy critically evaluated. Those taking anti-convulsants for neuropathic pain should strongly consider discontinuation during pregnancy, particularly during the first trimester. Consultation with a perinatologist is recommended if continued use of anti-convulsants during pregnancy is being considered. Frequent monitoring of serum anti-convulsant levels and folate supplementation should be initiated, and maternal a-fetoprotein screening may be considered to detect fetal neural tube defects.

The use of anti-convulsants during lactation does not seem to be harmful to infants. Phenytoin, carbamazepine, and valproic acid appear in small amounts in breast milk, but no adverse effects have been noted. There are limited data on both pregabalin and gabapentin.

Ergot Alkaloids

Ergotamine can have significant therapeutic efficacy for the episodic treatment of migraine headaches. However, even low doses of ergotamine are associated with significant teratogenic risk, and higher doses have caused uterine contractions and spontaneous abortion. During lactation, ergot alkaloids are associated with neonatal convulsions and severe gastrointestinal disturbances. Occasionally, methyl-ergonovine is systemically administered to treat uterine atony and maternal hemorrhage immediately after delivery. This brief exposure does not contraindicate breastfeeding.

Caffeine

Caffeine is a methylxanthine often used in combination with analgesics for the management of vascular headaches. It is readily absorbed from the gastrointestinal (GI) tract and crosses the placenta such that concentrations in the fetus are similar to maternal plasma levels. Early studies of caffeine ingestion during pregnancy suggested an increased risk of intrauterine growth retardation, fetal demise, and premature labor, while more recent studies do not. Although the data are not strongly compelling against caffeine use in pregnancy, most obstetricians recommend that pregnant women limit caffeine intake to less than 300 mg per day. To date, there is no evidence for congenital disabilities related to caffeine.

Caffeine use is also associated with certain cardiovascular changes. Ingestion of modest doses of caffeine (100 mg/m ² , a dose similar to that found in two cups of brewed coffee) in caffeine-naïve subjects produces modest cardiovascular changes in mother and fetus, including increased maternal heart rate and mean arterial pressure, increased peak aortic flow velocities, and decreased fetal heart rate. The modest decrease in fetal heart rate and increased frequency of fetal heart rate accelerations may confound the interpretation of fetal heart tracings. Caffeine ingestion is also associated with an increased incidence of tachyarrhythmia in the newborn, including supraventricular tachyarrhythmias, atrial flutter, and premature atrial contractions. Many over-the-counter analgesic formulations contain caffeine (typically in amounts from 30–65 mg/dose), and the use of these preparations must be considered when determining total caffeine exposure.

Moderate ingestion of caffeine during lactation (up to two cups of coffee/day) does not appear to affect the infant. Breast milk usually contains less than 1% of the maternal dose of caffeine, with peak breast milk levels appearing 1 hour after maternal ingestion. Excessive caffeine use may cause increased wakefulness and irritability in the infant.