Management of Nonobstetric Pain During Pregnancy and Lactation

Abstract

Pain management practitioners assist with the treatment of pain in a variety of settings. Despite the common occurrence of pain during pregnancy, major textbooks in both pain management and obstetrics lack any concentrated discussion of the topic. In this review, we discuss the potential for fetal toxicity or teratogenic effects of medications often used to treat pain syndromes, as well as the safety of these medications in the breast-feeding mother. We then present an approach to the diagnosis and treatment of several pain management challenges that may present during pregnancy. Teratology and Toxicity of Medications Used in Pain Management The first tenet in the medical management of the pregnant patient is to minimize the use of all medications and to use nonpharmacologic therapies whenever possible. When opting for drug therapy, the clinician should begin by considering any potential for harm to the mother, the fetus, and the course of pregnancy. The degree of protein binding and lipid solubility of the medication, the speed of maternal metabolism, and the molecular weight all have an impact on the placental transfer of medications from the maternal to the fetal circulation. With the exception of large polar molecules (such as heparin and insulin), nearly all medications reach the fetus to some degree. Approximately 3% of newborns have a significant congenital malformation. Only 25% of fetal malformations have a known genetic cause, and only 2%-3% have a clear environmental link [1]. One of the major limitations in evaluating a medication's potential for causing harm to a developing fetus is the degree of species specificity for congenital defects. A classic example of this specificity is the drug thalidomide; nonprimate studies revealed no teratogenic effects, but severe limb deformities occurred in human offspring when thalidomide was prescribed during pregnancy [2]. The most critical period for minimizing maternal drug exposure is during organogenesis-from the 4th through 10th weeks of pregnancy. Drug exposure before organogenesis usually causes an all-or-none effect: the embryo either does not survive or develops without abnormalities. Drug effects later in pregnancy typically lead to multiple-organ involvement, developmental syndromes, or intrauterine growth retardation [1]. Certain medications may not directly influence fetal organ development but may have the potential to adversely influence the physiology of pregnancy. For example, nonsteroidal antiinflammatory drugs (NSAIDs) may delay the onset of labor, decrease amniotic fluid volume, or place a newborn at risk of pulmonary hypertension. The United States Food and Drug Administration (FDA) has developed a five-category labeling system for all drugs approved in the United States (Table 1). This labeling system rates the potential risk for teratogenic or embryotoxic effects based on available scientific and clinical evidence. Our present knowledge about the adverse effects of uncontrolled pain, as well as the risks of administering medications during pregnancy, is incomplete, and the practitioner is left to weight the risks against the benefits of instituting pharmacologic therapy for each individual.Table 1: FDA Pregnancy Risk Classification Categories for Medications Used in Pain ManagementaMedications in the Breast-Feeding Mother High lipid solubility, low molecular weight, minimal protein binding, and the unionized state all facilitate secretion of medications into breast milk. The neonatal dose of most medications obtained through breast feeding is 1%-2% of the maternal dose [3]. Even with minimal exposure via breast milk, neonatal drug allergy and slower infant drug metabolism must be considered. Only small amounts of colostrum are secreted during the first few postpartum days; thus, early breast feeding poses little risk to the infant whose mother received medications during the delivery period [4]. Most breast milk is synthesized and secreted during and immediately after breast feeding. Taking medications after breast feeding or when the infant has the longest interval between feedings, and avoiding long-acting medications minimizes drug transfer via breast milk [4]. However, effective treatment of chronic pain often requires the use of long-acting medications, particularly opioids. The American Academy of Pediatrics has categorized medications in relation to the safety of their ingestion by breast-feeding mothers [3] (Table 2).Table 2: American Academy of Pediatrics (AAP) Classification of Maternal Medication Use During LactationaMedications Often Used in Pain Management Nonsteroidal Antiinflammatory Drugs Aspirin remains the prototypical NSAID and is the most thoroughly studied of this class of medication. The results of the Collaborative Perinatal Project suggest that first-trimester exposure to aspirin does not pose appreciable teratogenic risk [5]. Prostaglandins seem to trigger labor, and the aspirin-induced inhibition of prostaglandin synthesis may result in prolonged gestation and protracted labor [1]. Aspirin also has well known platelet-inhibiting properties and, theoretically, may increase the risk of peripartum hemorrhage. Neonatal platelet function is also inhibited for up to 5 days after delivery in aspirintreated mothers [6]. Although small-dose aspirin therapy (60-80 mg/d) has not been associated with maternal or neonatal complications, larger doses seem to increase the risk of intracranial hemorrhage in neonates born before 35 wk of gestation [7]. Circulating prostaglandins modulate the patency of the fetal ductus arteriosus. NSAIDs have been used therapeutically in neonates with persistent fetal circulation to induce closure of the ductus arteriosus via inhibition of prostaglandin synthesis. In utero, patency of the ductus arteriosus is essential for normal fetal circulation. Indomethacin has shown promise for the treatment of premature labor [8], but its use has been linked to premature antenatal closure of the fetal ductus arteriosus [9]. Ibuprofen has not been linked to congenital defects. The use of ibuprofen during pregnancy may result in reversible oligohydramnios (reflecting diminished fetal urine output) and mild constriction of the fetal ductus arteriosus [10]. Similarly there are no data to support any association between naproxen administration and congenital defects. Because it shares the renal and vascular effects of ibuprofen, naproxen may diminish ductus arteriosus diameter and cause oligohydramnios [7]. Ketorolac is a relatively new NSAID available for both oral and parenteral administration. According to the manufacturer's prescribing information (Syntex Laboratories, Palo Alto, CA, 1997), it did not cause birth defects 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 [11]. 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. In breast-feeding women, salicylate transport into breast milk is limited by its highly ionized state and high degree of protein binding. Caution should still be used if more than occasional or short-term aspirin use is contemplated during lactation, because neonates eliminate salicylates very slowly [12]. Both ibuprofen and naproxen are also minimally transported into breast milk and are with breast feeding [3]. Indomethacin should be during based on of neonatal and [4]. information is available on the safety of maternal ketorolac use during One that ketorolac from to of maternal in breast milk the of ketorolac after oral this likely result in neonatal between and of the maternal The American Academy of Pediatrics ketorolac to be with breast feeding [3]. Because of the properties of are about the risk of as a result of there are no studies on to is no that small-dose aspirin therapy or use of other NSAIDs the risk of after or of and of the we for any of or and, in their with without similar without the antiinflammatory effects of the NSAIDs. has no known teratogenic does not prostaglandin synthesis or platelet and is only in [7]. persistent pain use of a mild during pregnancy, to be a and effective does breast milk, neonatal ingestion be than of a maternal dose is with breast feeding [5]. of knowledge about the effects of chronic exposure during pregnancy from studies of as are often with other that pose and and human are often associated with drug Pregnancy in studies of mothers must be with when to the risks of a prescribed in the pregnant patient with Most studies suggest that is associated with gestation and birth weight when with of However, both and pregnant with birth and than increase in congenital defects has been in the offspring of The FDA has a risk used at large doses Neonatal in between and of to either or in Neonatal may be more if the maternal dose Most that have are by but there are of days postpartum with exposure to for may very as a to in breast milk seem to in the infant [7]. The American Academy of Pediatrics doses of up to to be with breast feeding [3]. of at risk of neonatal and of and medical therapy typically results in little to the infant The effects of in exposure are both the environmental and that influence development and that there are no data development from in is no to suggest a between exposure to any of the or during pregnancy and large of major or The Collaborative Project of first-trimester exposure to and of first-trimester exposure to [5]. was for either drug to suggest a to large of major or was associated with and Only the association with was to be with defects after exposure persistent ductus arteriosus and of these data from large studies have to with but the is not than that of the for malformations after is for all of the in this and are Risk by the The Collaborative Perinatal Project no congenital associated with or use during pregnancy [5]. In the a of fetal to occurred with no of teratogenic effects [5]. have been no the use of or with congenital defects. However, the Collaborative Perinatal Project the to any of these and are all Risk by the is of the most common parenteral during the with all administration of to the mother immediately before delivery may lead to in the newborn Maternal administration of or other may also cause of the normal in fetal of fetal fetal thus, administration of during labor may of a for fetal metabolism to has a lead to in with renal causes of the system as and of is in the or but no other parenteral opioids. Although are used to during labor, not seem to any In a of and during labor, the drugs to as well as neonatal and Use of either or during pregnancy lead to neonatal may also cause a fetal after maternal fetal are into breast milk. has that breast milk of and are to or than maternal use in breast-feeding mothers via in of the breast-feeding newborn than doses of from the in breast milk significant to to the is prolonged in the newborn that breast feeding to the of and the risks of and The American Academy of Pediatrics use of and to be with breast feeding [3]. for most pregnant be by (Table and are all and effective when a is for parenteral administration. is a of and effective oral for mild pain, or in with is a for pain, or in with is more severe pain may or both of are available for oral for Pain During also be into the or to administration of drugs (such as or delivery of be used to minimize maternal of placental transfer to the fetus or exposure of the breast-feeding studies have on the potential of and not seem to pose significant developmental risk to the In the Collaborative Perinatal Project only any of the of patient was to studies have that exposure to pregnancy does not cause congenital but it may decrease neonatal birth weight in in the breast milk after administration during labor [4]. of large doses of for of to minimal in breast milk on these of for should result in only small of the drug the The American Academy of Pediatrics to be for use in the mother [3]. is a drug with and pharmacologic properties similar to and has shown promise in the treatment of is and the are no studies of use during pregnancy in in and doses up to the dose in have an risk of fetal but not to be concentrated in breast based on breast milk and of breast milk, the infant only a small of the dose of is Risk by the FDA and its use should be during pregnancy. The American Academy of Pediatrics use to be with breast feeding [3]. Most the and are by the [1]. of are than of maternal to during their first of pregnancy, no increase in infant malformations was [5]. The use of during a limited of therapy in the pregnant patient poses minimal fetal risk discussion later in this than of a maternal dose in the infant the days This of exposure is to have an impact on infant secretion are the most prescribed of all drugs and are often used as to treat and as in with chronic pain exposure to may be associated with an risk of congenital may be associated with as well as congenital However, has not the association of with the of and after the and use of studies have the association of use during pregnancy and congenital use immediately before delivery also risks fetal and other have been for has been to a increase in congenital and congenital However, a of more than did not support these this a high of and drug use in use did not to be a risk for congenital use during pregnancy has also been associated with congenital a of and system defects from the risks of neonates to in may immediately after birth In the breast-feeding mother, and its be in infant for up to days after a maternal This is to the slower metabolism in neonates with are from mothers may and feeding most prudent to any use of during the of and during are often used for the management of as well as for and in chronic pain and are all Risk by the The and are FDA Risk and all other medications are is teratogenic in and [7]. has been associated with several congenital defects in but not in or Although there are of human neonatal limb deformities after maternal and large human studies have not revealed an association with any congenital with the exception of defects after maternal use [7]. are no maternal use with congenital defects. have been in neonates born to mothers and with and [7]. and are all into human milk. that are to of the maternal dose In a critical of the use of during breast that and not in amounts in and that no adverse effects been The use of these drugs as the of for breast-feeding is also into human milk and has a milk to of studies are available to therapy during and high infant have been Maternal use has also been associated with of the and in a infant The American Academy of Pediatrics to have risk during [3]. Most data the risk of major in born to are from the treatment of of or the risk of a congenital in their offspring was or that of the defects in the offspring of and and be during maternal associated with use during pregnancy may to defects The fetal has and The of this may be by either fetal genetic or by of the for metabolism Although have a teratogenic may be for fetal malformations pregnant for chronic pain may have a risk of fetal malformations than those the medications for are should have their pharmacologic therapy for pain should their during pregnancy, particularly during the first with a is if use of during pregnancy is considered. of and should be and maternal may be to fetal defects. is a new that is used to treat pain is very little information about the safety of in pregnant or In the prescribing the a of received during their pregnancy. pregnancy and normal and an The use of during does not seem to be to and in small amounts in breast milk, but no adverse effects have been [7]. are no data on use during have significant in the treatment of However, small doses of are associated with significant teratogenic larger doses have and During lactation, are associated with neonatal and severe [7]. is to treat and maternal hemorrhage immediately after This exposure does not breast feeding is often used in for the management of vascular studies of ingestion during pregnancy an risk of intrauterine growth fetal and premature However, these early studies did not for and for these no risks with ingestion of more than was associated with birth weight in amounts between and and use of these must be when ingestion of during to of does not seem to the milk usually than of the maternal dose of with breast milk after maternal use may cause and in the infant is a that has use because of its in the therapy of has been associated with fetal malformations in but not in data in have not any teratogenic effects does not properties with and not likely have effects in a to the risk of use during pregnancy Pregnancy the of this with early exposure to been with a birth This is to the in the and no of defects has been is by the The use of during has not been well One of a administration to breast milk to be only of the maternal Because is from the infant only of the drug by the fetus be Even this exposure be by and all milk for after and other are used in the chronic against and vascular is no that is The fetal effects with maternal of weight, to a decrease in maternal with diminished placental For an of the use of and other during pregnancy, and In the mother doses of up to seem to have minimal neonatal The neonatal exposure at this maternal dose is than of the dose is concentrated in breast milk but still results in in the infant Pain Management pain management we have been to on a of pregnant with uncontrolled this we discuss the evaluation of pain and during pregnancy because these are the most common that we have in Although we have pain during pregnancy it a example of the approach to pain during the course of pregnancy. more common is the patient for during pregnancy. for are in the first of this Pain During Pregnancy and pain at some during pregnancy in of and is common that it is often a normal of pregnancy. The during pregnancy and may to the development of low pain during pregnancy may also a a secreted by the the the and of the developing fetus and This may cause pain by an of Although often low pain during pregnancy, has an of only The of and was by in pregnant and of of pregnant and of at or more The that pregnant not have an of abnormalities. of the fetus on the has been as the cause of One of several that to the development of pain during pregnancy, maternal weight during pregnancy, the weight, the of and of A that before pregnancy the risk of pain, as did and pregnant from the wk of gestation pain occurred in of at some during the pregnancy. The pain into in pain was to the and as pregnancy in the other pain was to either the or the and either or did not during the course of pregnancy. with a occurred in only 1: of pain by a of studied pregnancy. High pain of pregnant low pain of pregnant pain of pregnant with from of pain in pregnancy. with a often the clinician to other causes with both labor and premature of may present with low pain and renal may also present with low should and should be the during low pain with or without to the during is with either or of or or the of or is of Pregnancy is not an to exposure during pregnancy to about congenital and risk of growth or have been associated with fetal exposure to than dose received during a is well this when and of the are has during pregnancy, effective and in the diagnosis of both and Although to be during pregnancy, there are no studies the safety of fetal exposure to during For a and of of the pregnant for the use of studies in the evaluation of the pregnant patient are in for Use of in the and studies to as as in the patient with new onset of low pain by or When the clinical is in and from However, results are in the of a causing of a and of the often used to low pain during pregnancy are in than a did not similar be prescribed pregnancy of may not the of pain during pregnancy the American of and to and low pain during pregnancy with the patient about the common causes of pain during pregnancy. and in the often to to a pain remains to a for evaluation and in and low may be be particularly to the and the of the effects of on the and the of or may also be Although clinical are to pain in a variety of in pain has a limited The safety of use during pregnancy has not been the used in are likely to only in data suggest that is for use during pregnancy and may be in with pain in a limited For pain of the treatment of of of with of the results have also been with the use of a or for with pain of For with pain at of and in of a to support the of a pregnant on the of during pregnancy is are common and often and pain Use of of pregnancy is The for the of to be in with to Although the risk to the fetus after a dose of to be it is that should be for the pregnant patient with the new onset of of in a and with In we that it is to with before of the after treatment may the for is the first to for the management of Although NSAIDs are the of the pharmacologic management of pain in their use during pregnancy remains use of ibuprofen or naproxen to be during the first and [7]. pain may treatment with often for their parenteral administration (Table and several days with the and of a is usually of oral or parenteral seem to pose little risk to the for to Pain During During Pregnancy and 25% of from with the during more often during has been to a in During pregnancy, there is a to increase in of or of during pregnancy begin during pregnancy. that of during pregnancy should a for causes One of with during pregnancy that for and a The is with of intracranial that during pregnancy, and causes of during pregnancy drug most and present with their first severe during pregnancy should a and should be for and For the patient with onset of the of a hemorrhage should be in the of weight should suggest or The of and and may also be in with and For those pregnant with a of before pregnancy and a normal the is to of the minimizing risk to the and of or other environmental should pharmacologic pharmacologic therapy is with or without is and effective Ibuprofen and naproxen both seem to be for use during the first [7]. The short-term use of mild as or in with to little risk (Table When oral and administration of parenteral may be (Table Until more information is available on the safety of during pregnancy, it should be used only after other have should be during pregnancy and A of to of therapy oral or are should that their use is associated with are small for their Although are effective for therapy in the most often used medications of this class and are all FDA with and are all FDA or aspirin mg/d) that may be effective drugs during pregnancy Pain in the with and is an The of to the of the chronic and is the most common maternal in with a of of pain, usually the and A that the clinical course of with was not adversely by their pregnancy, as by the of a period The was and after the first pregnancy and occurred at some during the course of of Most during pregnancy are and are often by or the pain in the or but may also the as pain is also common and may be to in the or be in and with most from to 5 Because evaluation is diagnosis of with other causes for the particularly and the management of in pregnancy has been by Management of during pregnancy is and management with to increase and decrease is essential in those with to an of the management of may the of severe during pregnancy about pregnancy with to or often the pain that the patient is has been shown to the pain of and the of days that are therapy of also be may be when pain is to a limited The of pain the pharmacologic approach to Although may oral or parenteral are often (Table remains the of during pregnancy. Although NSAIDs be particularly for pain, should be used during pregnancy. and or to be for more severe For the patient with severe pain, may be to pain (Table is well and effective for of severe pain and in Administration of via a a of their and that larger doses of may be to pain with In we treat with severe pain with via often the pain of to are to a long-acting oral (such as This approach and are then the to The use of has not been studied in of small-dose the of pain without opioids. the management of a pregnant in the of a pain a In whose pain is to the or and are of may be a about pain in pregnant is limited by the of in the and the risks associated with pharmacologic therapy during pregnancy. with common pain as well as the maternal and fetal risks of pain medications, the pain practitioner to a more pregnancy. A should be to and their into a of The and for their with of and and for their critical of the