PREGNANCY & ANALGESIA

When a pregnant patient needs analgesics

By Mary E. Norton, MD and Juan E. Vargas, MD

Yes, analgesics are everywhere, but that doesn't mean they're without risk. For a balanced assessment of which ones pose the greatest threat, read on.

It's unlikely there's a single adult in America who has not used analgesics at some point in time. As many as 68% of pregnant women use at least one prescription or nonprescription drug during their pregnancy, and no doubt many of these drugs are pain relievers. The challenge, of course, is making sure that these women are getting all the pain relief possible without endangering their unborn.

Unfortunately for more than 90% of the drugs currently in use, there's only limited information on their teratogenic effects, and analgesics are no exception.¹ Our goal here is to review that information, with special emphasis on the safety of common nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotic agents in pregnancy.

When is the fetus at greatest risk?

Over half of the pregnancies in the United States are unplanned, which means many fetuses are being exposed to these agents very early on. As with other drugs, the effects of such exposure depend in large part on their timing. Between fertilization and 14 days postconception (the expected menstrual period), exposure to potential teratogens typically results in either no observable effect or early death and miscarriage. This is often referred to as the "all-or-none" phenomenon, and some recent evidence does link NSAIDs to an increased risk of early spontaneous abortion.²

Weeks 3 through 8 postconception are considered the critical period of embryogenesis, during which the three germ layers give rise to all tissues and organs. Exogenous agents are most likely to cause structural birth defects during this period. Aspirin and indomethacin, when used at standard adult doses, for example, have been linked to gastroschisis (Table 1). Later in gestation, any exposures are less likely to cause structural abnormalities, but more likely to adversely affect function. Examples include constriction of the ductus arteriosus with resultant pulmonary hypertension, effects on platelet function leading to fetal intracranial hemorrhage, and CNS depression and withdrawal following prolonged narcotic exposure in late pregnancy.

TABLE 1
Managing first-trimester exposure to analgesics

The concept of a teratogen therefore extends beyond the common notion that a structural birth defect is the only possible adverse outcome to a harmful agent. Functional impairments, limitations in fetal growth, and subsequent cognitive and behavioral problems are examples included in a broader, more current definition of teratogenicity. This type of adverse outcome has been associated with nonsteroidal anti-inflammatory agents and narcotics in the second and third trimester. Additionally, we know that certain analgesics can induce or aggravate maternal bleeding complications at the time of delivery, potentially compromising the fetus (Table 2).

TABLE 2
How analgesics affect mother and fetus during the second and third trimesters

Non-steroidal anti-inflammatory drugs

NSAIDs act by inhibiting cyclo-oxygenase (COX) enzymes involved in prostaglandin synthesis. There are two isoforms of the enzyme, COX-1 and COX-2. Prostaglandins produced by COX-1 are primarily involved in homeostatic activities, such as maintaining the gastrointestinal mucosal barrier, renal hemodynamics, platelet function, and vascular homeostasis, while COX-2 is mainly induced by acute and chronic inflammation. COX-2 may also be expressed in small amounts under normal conditions in the kidney, small intestine, bone, brain, ovary, uterus, and, late in gestation, the placenta.

Nonselective NSAIDs, like ibuprofen and naproxen, inhibit both COX-1 and COX-2, thereby decreasing both inflammatory and homeostatic prostaglandin production. Acetaminophen, while also an NSAID, is a more selective agent that acts primarily on the CNS. Selective COX-2 inhibitors, such as celecoxib and rofecoxib, have been recently introduced to treat arthritis and acute pain. These agents are less likely to cause GI bleeding, which is relatively common with the nonselective agents.

Early pregnancy exposure to NSAIDs. Rat and rabbit studies have shown that nonselective NSAIDs reduce embryo and fetal survival at maternal doses comparable to adult human doses.³ There's also at least one human study linking NSAIDs taken in the periconception period with spontaneous abortion.² After conception, studies have implicated several of these medications in fetal gastroschisis.^4,5 The association is strongest for aspirin, although some studies also suggest ibuprofen may contribute to the congenital defect; similarly, there's a potential danger from acetaminophen. With that in mind, it's best to avoid exposure to any NSAID during early gestation. There is no other pattern of birth defects consistently reported with any NSAID, although there are no human studies of first-trimester exposure to COX-2 inhibitors.

Bleeding complications. Because NSAIDs inhibit cyclooxygenase, they can impair platelet function and cause bleeding complications in the fetus, newborn, or pregnant woman. Aspirin in particular decreases platelet adhesiveness and aggregation, and infants born after aspirin exposure have an increased risk of bleeding. Minor complications such as petechia and cephalohematoma have been reported in term infants whose mothers took 1 g or more of aspirin in the 5 days prior to delivery, and premature infants whose mothers take aspirin within 1 week of delivery are more likely to develop intracranial hemorrhage (ICH).^6,7 Indomethacin has been linked to ICH in preterm infants after fetal exposure, possibly due to vasoconstriction compounded by a bleeding diathesis.

Standard adult doses (350 mg) of aspirin may adversely affect maternal hemostasis, contributing to antepartum and postpartum hemorrhage.⁸ In the second and third trimesters of pregnancy, 100 mg or less has been used in many thousands of women to prevent fetal growth restriction, pre-eclampsia, and stillbirth in high-risk pregnancies. While no benefits have been firmly established for these indications, at these small doses there is no evidence of harm to the mother or fetus.⁹

All NSAIDs may prolong bleeding time. However, with the exception of aspirin, NSAIDs reversibly inhibit platelet aggregation and therefore their effect lasts only as long as the drug remains in circulation. NSAIDs other than aspirin have not been reported to increase bleeding complications unless the patient has an underlying coagulopathy.

Ductal constriction and pulmonary hypertension. Both animal and human studies have shown that several NSAIDs cause in utero constriction of the ductus arteriosus. The constriction tends to increase with advancing gestational age, and chronic fetal ductal constriction can lead to persistent pulmonary hypertension in the newborn. In utero ductal constriction can also lead to tricuspid regurgitation, and has been reported to result in hydrops and fetal death in some cases.¹⁰

Ibuprofen seems to cause the greatest degree of ductal constriction, but aspirin and indomethacin can also cause significant harm. The effects of acetominophen, on the other hand, appear to be clinically insignificant—although present in animal studies. Selective COX-2 inhibitors have been recently used to treat preterm labor with the hope of avoiding fetal complications such as ductal constriction.¹¹ However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. In the lamb, celecoxib increased the pressure gradient and resistance across the ductus and decreased fetal plasma concentrations of PGE and 6ketoPGF (1 alpha), indicating that these agents do have some effect on the fetal ductus, although it does appear to be less than with indomethacin.^2,12

Due to concerns of ductal constriction and resultant pulmonary hypertension with third-trimester exposure, NSAIDs other than acetaminophen are contraindica-ted after 32 weeks of gestation. Between 24 and 32 weeks, these agents should only be used under exceptional circumstances. Until more data are collected, the selective COX-2 inhibitors should not be used outside clinical trials.

Renal dysfunction and oligohydramnios. NSAIDs can cause transient renal dysfunction in adults (including pregnant women), newborns, preterm infants, and fetuses. The mechanism may be an alteration in prostaglandin-mediated tubular function as renal blood flow does not appear to change. Because these agents freely cross the placenta, they can decrease fetal urine output and result in oligohydramnios. Given shortly before delivery, they can cause a continuous decrease in renal function in the newborn, although this is usually transient. As with other complications, renal effects have been reported primarily with ibuprofen and indomethacin, and not with acetaminophen. Transient decreases in amniotic fluid have also been observed after 48 hours of celecoxib use.¹¹

Gastrointestinal complications. GI complications, including intestinal perforation, are among the most common side effects of NSAIDs in adults. Several studies have reported an increased incidence of necrotizing enterocolitis as well as isolated ileal perforation in preterm infants born after antenatal exposure to indomethacin.¹³ In animals and preterm infants, these agents decrease mesenteric blood flow, block autoregulation of terminal ileum oxygen consumption, and increase the risk of bowel necrosis after temporary ischemia. Particularly with indomethacin exposure, preterm infants—who may suffer temporary hypoxic insults during labor, delivery, and the early perinatal period—seem to have an increased risk of complications following such hypoxic insults (e.g., necrotizing enterocolitis).

Opioid analgesics

Although there are a variety of narcotic preparations available, they all share pharmacological properties and they have similar effects on the fetus. All narcotics readily cross the placental barrier.

In mice and hamsters, narcotics can cause CNS abnormalities and other major malformations when given at doses eight to 29 times greater than those used in humans. These teratogenic effects are reduced or eliminated when narcotic antagonists are administered. The malformations observed in the offspring of mice are believed to be caused by hypoxia and the subsequent hypoglycemia induced by the opioids. In contrast, epidemiological studies in humans have not shown an association between narcotics in early pregnancy and structural birth defects in the fetus.^14,15

A primary concern with narcotic use in pregnancy is the potential for CNS depression and withdrawal symptoms among newborns after in utero exposure. When opioid analgesics are administered shortly before birth, CNS depression may occur, resulting in decreased respiratory efforts and delayed neurobehavioral adjustments. If respiratory depression does take place, it is usually mild and transient. Chronic intake of opioids, however, can lead to drug dependence in the mother and her infant.

While all agents in this class have the potential for inducing drug dependence when used for prolonged periods, this effect appears to be most pronounced with oxycodone and less so with codeine. Withdrawal symptoms such as tremor, jitteriness, diarrhea, and poor feeding have been observed in neonates after maternal treatment with codeine-containing preparations late in pregnancy.¹⁶ Although data are more limited on other agents, such withdrawal symptoms can occur with any opioid preparation.

Parenteral analgesics during labor. Narcotics are widely used to relieve pain during childbirth in the US, being administered to 40% to 50% of laboring women.¹⁷ As regional analgesia has gained acceptance, popularity, and greater accessibility nationwide, the use of parenteral analgesia has decreased over the last 20 years.

The analgesic effect of parenteral opioids used in labor is limited, and benefits are the result of heavy sedation rather than true analgesia. As a result, patients who receive intrapartum opioids for analgesic relief are at an increased risk of aspiration and respiratory depression. Despite their extensive use, there are no adequate studies that clearly establish the superiority of one agent over another.¹⁸ A list of the most commonly used agents and their pharmacological characteristics is shown in Table 3.

TABLE 3
Commonly used narcotics for intrapartum analgesia

As all narcotics readily cross the placenta, the fetus and neonate may be affected. Real-time ultrasound has shown that giving an opioid to a woman in labor can decrease fetal respirations and gross body movements, and intrapartum fetal heart monitoring has proven that these drugs decrease beat-to-beat variability.¹⁹ In the neonate, respiratory depression and abnormal neurobehavioral adaptation have been reported after maternal use of narcotics during labor. The degree of neonatal depression depends on the dose of the drug, route, time of administration before delivery, and the acid-base status of the newborn. As opioids are basic drugs, in cases of fetal acidosis the proportion of ionized drug will increase and more drug will be "trapped" in the fetus.

Meperidine is probably the most commonly used opioid for intrapartum pain management in the US, largely because of its accessibility and familiarity rather than because the agent has any real therapeutic advantages. Although the peak analgesic effect after a single dose of meperidine is 40 to 50 minutes, the frequency and degree of neonatal depression is greatest 2 to 4 hours after administration, probably because of the time required for drug transfer from mother to fetus. Fentanyl, because of its rapid onset of action (almost immediately with a peak of action at 3 to 5 minutes after IV administration) and short duration (30 to 60 minutes), has gained popularity in obstetrics. It is best to avoid fentanyl whenever the expected time-to-delivery is 1 hour or less, as this is the period of greatest risk of neonatal depression.

Do analgesics pose a danger to breastfeeding mothers?

There's a great deal of evidence supporting the value of successful breastfeeding—for infants and mothers. In evaluating the impact of maternal analgesics on breastfeeding, the clinician must weigh these benefits against the risk of exposing the infant to the drug as it appears in breast milk. Unfortunately, most of the information available is based on single-dose or short-term studies, and for many drugs only a single or a few case reports have been published. Still, keeping these limitations in mind, some recommendations can be made regarding the use of analgesics during lactation (Table 4).

TABLE 4
Using analgesics during lactation

Analgesics, including NSAIDs and narcotics, are routinely used in the postpartum period by the majority of women. With the exception of aspirin, all NSAIDs are considered safe for nursing women. Aspirin is excreted into breast milk in low concentrations with peak levels at 3 hours postadministration. However, because aspirin is eliminated more slowly from milk than plasma, the milk-to-plasma ratio increases by tenfold 12 hours after ingestion.²⁰ The resulting accumulation of aspirin by nursing infants may result in toxic effects, even when repeated exposures are small.²¹ The WHO Working Group on Human Lactation considers aspirin unsafe for nursing women, whereas the American Academy of Pediatrics lists aspirin among drugs that have been associated with significant effects on some nursing infants and should be used cautiously by lactating women.^22,23

Opioid analgesics are transferred into the breast milk but are found at much lower concentrations than in maternal plasma. When used at standard adult doses, most narcotic preparations are compatible with breastfeeding. A possible exception is meperidine, which may accumulate in suckling infants. Although not well studied, the WHO Working Group on Human Lactation stated that no recommendations could be made on repeated use of meperidine during lactation, although a single dose is probably safe.

Conclusion

As we mentioned earlier, analgesics are among the most commonly used drugs in pregnancy. Despite their popularity, there is relatively little information about their safety in pregnancy. Various NSAIDs and narcotics may adversely affect the fetus but these effects are to a large degree dependent on the fetus' gestational age. Physicians should have a clear understanding of the relative safety of these agents before recommending their use.

REFERENCES

1. Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol. 2002;100:465-473.

2. Nielsen GL, Sorensen HT, Larsen H, et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ. 2001;322:266-270.

3. Klein KL, Scott WJ, Wilson JG. Aspirin-induced teratogenesis: a unique pattern of cell death and subsequent polydactyly in the rat. J Exp Zool. 1981;216:107-112.

4. Werler MM, Sheehan JE, Mitchell AA. Maternal medication use and risks of gastroschisis and small intestinal atresia. Am J Epidemiol. 2002;155:26-31.

5. Martinez-Frias ML, Rodriguez-Pinilla E, Prieto L. Prenatal exposure to salicylates and gastroschisis: a case-control study. Teratology. 1997;56:241-243.

6. Stuart MJ, Gross SJ, Elrad H, et al. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med. 1982;307:909-912.

7. Rumack CM, Guggenheim MA, Rumack BH, et al. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol. 1981;58(suppl):52S-56S.

8. Schoenfeld A, Bar Y, Merlob P, et al. NSAIDs: maternal and fetal considerations. Am J Reprod Immunol. 1992;28:141-147.

9. Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;338:701-705.

10. Hallak M, Reiter AA, Ayres NA, et al. Indomethacin for preterm labor: fetal toxicity in a dizygotic twin gestation. Obstet Gynecol. 1991;78(5 Pt 2):911-913.

11. Stika CS, Gross GA, Leguizamon G, et al. A prospective randomized safety trial of celecoxib for treatment of preterm labor. Am J Obstet Gynecol. 2002;187:653-660.

12. Takahashi Y, Roman C, Chemtob S, et al. Cyclo-oxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo. Am J Physiol Regul Integr Comp Physiol. 2000;278:R1496-505.

13. Norton ME, Merrill J, Cooper BA, et al. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med. 1993;329:1602-1607.

14. Heinonen OP, Shapiro S, Sloane D. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Sciences Group; 1977:287-295.

15. Shaw GM, Todoroff K, Velie EM, et al. Maternal illness, including fever, and medication use as risk factors for neural tube defects. Teratology. 1998;57:1-7.

16. Khan K, Chang J. Neonatal abstinence syndrome due to codeine. Arch Dis Child Fetal Neonatal Ed. 1997;76:F59-F60.

17. Marmor TR, Krol DM. Labor pain management in the United States: understanding patterns and the issue of choice. Am J Obstet Gynecol. 2002;186(5 suppl Nature):S173-S180.

18. Bricker L, Lavender T. Parenteral opioids for labor pain relief: a systematic review. Am J Obstet Gynecol. 2002;186(5 suppl Nature):S94-S109.

19. Zimmer EZ, Divon MY, Vadasz A. Influence of meperidine on fetal movements and heart rate beat-to-beat variability in the active phase of labor. Am J Perinatol. 1988;5:197-200.

20. Findlay JW, DeAngelis RL, Kearney MF, et al. Analgesic drugs in breast milk and plasma. Clin Pharmacol Ther. 1981;29:625-633.

21. McNamara PJ, Burgio D, Yoo SD. Pharmacokinetics of acetaminophen, antipyrine, and salicylic acid in the lactating and nursing rabbit, with model predictions of milk to serum concentration ratios and neonatal dose. Toxicol Appl Pharmacol. 1991;109:149-160.

22. Bennett PN, The WHO Working Group, eds. Drugs and Human Lactation. Amsterdam, NY: Elsevier; 1988:325-326.

23. The American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108:776-789.

Dr. Norton is Assistant Professor and Dr. Vargas is Adjunct Assistant Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco.

Key points

• Functional impairments, limitations in fetal growth, and subsequent cognitive and behavioral problems are examples included in a broader, more current definition of teratogenicity.

• Studies have implicated several NSAIDs in fetal gastroschisis. The association is strongest for aspirin.

• Because NSAIDs inhibit cyclooxygenase, they can impair platelet function and cause bleeding complications in the fetus, newborn, or pregnant woman.

• Several NSAIDs cause in utero constriction of the ductus arteriosus. The constriction tends to increase with advancing gestational age, and chronic fetal ductal constriction can lead to persistent pulmonary hypertension in the newborn.

• Epidemiological studies in humans have not shown an association between narcotics in early pregnancy and structural birth defects in the fetus.

• Avoid fentanyl whenever the expected time-to-delivery is 1 hour or less, as this is the period of greatest risk of neonatal depression.

 

Mary Norton. When a pregnant patient needs analgesics. Contemporary Ob/Gyn Dec. 1, 2003;48:37-51.