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Nonsteroidal Anti-Inflammatory Drugs During Pregnancy and the Initiation of Lactation

Bloor, Melanie, BMBCh, MA, FRCA; Paech, Michael, MBBS, DRCOG, FRCA, FANZCA, FFPMANZCA, DM, FRANZCOG

doi: 10.1213/ANE.0b013e31828a4b54
Obstetric Anesthesiology: Review Article
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Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, which are available as “over-the counter” medications in most countries, are widely used by both pregnant and lactating women. They are popular non-opioid analgesics for the treatment of pain after vaginal and operative delivery. In addition, NSAIDs are used for tocolysis in premature labor, and low-dose aspirin has a role in the prevention of preeclampsia and recurrent miscarriage in antiphospholipid syndrome. NSAIDs and aspirin may affect fertility and increase the risk of early pregnancy loss. In the second trimester their use is considered reasonably safe, but has been associated with fetal cryptorchism. In the third trimester, NSAIDs and aspirin are usually avoided because of significant fetal risks such as renal injury, oligohydramnios, constriction of the ductus arteriosus (with potential for persistent pulmonary hypertension in the newborn), necrotizing enterocolitis, and intracranial hemorrhage. Maternal administration or ingestion of most NSAIDs results in low infant exposure via breastmilk, such that both cyclooxygenase-1 and cyclooxygenase-2 inhibitors are generally considered safe, and preferable to aspirin, when breastfeeding.

Published ahead of print April 4, 2013

From the Department of Anaesthesia and Pain Medicine, King Edward Memorial Hospital for Women, Subiaco, Western Australia.

Accepted for publication January 16, 2013.

Published ahead of print April 4, 2013

Funding: Self-funded.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Michael Paech, MBBS, DRCOG, FRCA, FANZCA, FFPMANZCA, DM, FRANZCOG, King Edward Memorial Hospital for Women, Department of Anaesthesia and Pain Medicine, King Edward Memorial Hospital for Women, 374 Bagot Rd, Subiaco, WA 6008, Australia. Address e-mail to Michael.Paech@health.wa.gov.au.

Analgesics are one of the most frequently used classes of drugs during pregnancy.1 Consequently nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, which are available as over-the counter medications in most countries, and which have antipyretic and anti-inflammatory actions, are widely used by the general public, including women of childbearing age, pregnant, and lactating women. Information regarding the safety of medications in pregnancy is conveyed in the United States by the Food and Drug Administration (FDA) in the form of use-in-pregnancy ratings (Table 1). The NSAIDs are rated category B, low-dose aspirin category C, but doses >150 mg/d are category D. In Australia, the Australian Drug Evaluation Committee classifies both NSAIDs and aspirin as category C (Table 2). The FDA advises women to discontinue NSAIDs and aspirin during the last 3 months of pregnancy.a Some publications have recommended cessation later in the third trimester, such as 6 to 8 weeks before delivery or by gestational week 32.2–4

Table 1

Table 1

Table 2

Table 2

NSAIDs are readily available analgesics that are likely taken by many women in the postpartum period. Nonselective NSAIDs are listed as compatible with breastfeeding by the American Academy of Pediatrics,5 and the cyclooxygenase (COX)-2 selective NSAIDs are considered to be probably compatible with lactation.6 In contrast, it is advised that aspirin be used with caution4,6 or avoided when breastfeeding.7 Both NSAIDs and aspirin are believed to exert their effect primarily through inhibition of COX enzymes.

The antinociceptive site of action is both peripheral and central,8,9 and there is naloxone-reversible synergy between ketorolac and morphine in animal models.10 At similar plasma morphine concentrations, respiratory depression is less marked when ketoprofen is coadministered11 but it is not known whether this translates to clinical benefit, especially in the obstetric population that is at low risk of severe opioid-induced respiratory depression. In the complex clinical environment, meta-analysis suggests NSAIDs are effective against postchildbirth perineal pain12 and abdominal postoperative pain; and when coadministered with opioids, they produce opioid dose-sparing effects that can lead to fewer opioid-related side effects.13–16 However, the effects of NSAIDs vary with both the operative procedure and the concurrent analgesic methods. Many studies report no clinically important benefits from the use or addition of an NSAID. Their side effect profile also should be considered; decisions about their prescription should be made on an individual patient basis.

In this review, the evidence supporting the safety and effectiveness of NSAIDs and aspirin during pregnancy and the postpartum period, during lactation initiation, is evaluated. The review covers the drugs’ effects on fertility, on the fetus during early pregnancy and the second and third trimesters, and on the neonate or breastfed infant. Where appropriate, conclusions drawn about use of NSAIDS during pregnancy and the early postpartum period indicate the level of evidence supporting them.b

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PREPREGNANCY AND VERY EARLY PREGNANCY

Fertility

NSAIDs and aspirin act via inhibition of COX-1 and COX-2 enzymes.8 Animal studies that use both gene knockout and pharmacological inhibition of these enzymes suggest they play a crucial role in ovulation, fertilization, implantation, and placental decidualization.17–19 A detrimental effect of NSAIDs on fertility has been demonstrated in male mice,20 and human case series suggest an association between NSAID use and reduced female fertility.21,22 Consequently, it is recommended that women planning pregnancy should avoid or reduce the dose of aspirin, NSAIDs, or COX-2 inhibitors.6,22

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In Vitro Fertilization

Because of its antiplatelet and anti-inflammatory actions, it has been postulated that low-dose aspirin may improve outcomes after in vitro fertilization procedures.23 A number of small randomized trials have been conducted with conflicting results.23 A meta-analysis including 9 trials involving 1449 women found no significant difference in pregnancy rate or live birth rate associated with low-dose aspirin therapy compared with placebo.24 The authors concluded that further randomized trials involving larger numbers and specific patient groups are required. The use of NSAID analgesia for oocyte retrieval during in vitro fertilization procedures is also controversial. No significant effect on pregnancy or implantation rates has been found in a number of small randomized trials.25–27 However, reduced pain immediately after the implantation procedure was noted in 1 study in which diclofenac was compared with placebo.26 Larger randomized controlled trials are required before NSAID use can be recommended in association with oocyte retrieval.

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THE FIRST TRIMESTER

Spontaneous Abortion

NSAIDs are readily available over-the-counter medication. The prevalence of use within the interval from preconception through the first trimester is reported to range from 2.9% to 18%.1,28,29 NSAIDs such as diclofenac and naproxen readily cross the placenta as early as the first trimester.30,31 Case-control and cohort studies have shown an increased risk of spontaneous abortion with NSAID use during early pregnancy (Table 3).32–34 However, the higher rate of spontaneous abortion does not appear to be solely a consequence of therapy for uterine cramping pain, because similar results were seen when this indication for use was excluded.33 Also, acetaminophen use was not associated with an increased risk of abortion (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.8–1.8).33 Aspirin was associated with similar adverse outcomes, but the association was weaker because of the relatively small number of aspirin users.33

Table 3

Table 3

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Birth Defects

Cohort and case-control studies investigating the risk of congenital birth defects associated with NSAID ingestion in early pregnancy report conflicting findings (Table 4). One nested case-control study found an association with nonspecific congenital defects, but assessed only 93 cases.35 In contrast, 4 prospective cohort studies32,39–41 found no such association, although individual trials may have been underpowered. A positive association with selected congenital defects, such as cardiac anomalies36 or gastroschisis37 has been reported, but a study that specifically assessed the risk of ventricular septal defect did not find an association.38

Table 4

Table 4

The relationship between aspirin and birth defects is also controversial. Rats administered very high doses resulting in 5 times the therapeutic concentration range demonstrate more malformations than control rats, including central nervous system, skeletal, and vascular defects,42 and similar findings are noted in mice, rabbits, monkeys, and dogs.42 Retrospective human case-control studies report an increased incidence of congenital malformations,43,44 such as cleft lip,45 but are predisposed to significant bias.42 Large case-control studies report no association with cardiac defects (Table 5).46,47 A large prospective study that monitored 50,282 mother–child pairs, of whom 32,164 had been exposed to aspirin,48 found no evidence of a teratogenic effect. Follow-up of > 4000 children involved in the collaborative low-dose aspirin study in pregnancy (CLASP) trial of maternal low-dose aspirin to prevent preeclampsia reported no relationship between aspirin and the risk of congenital abnormalities or developmental delay.49

Table 5

Table 5

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Low-Dose Aspirin for Preeclampsia Prophylaxis

Preeclampsia is a relatively common disorder that affects 2% to 5% of pregnancies. The etiology of preeclampsia is still not fully understood but involves inadequate invasion of the uterine spiral arteries by the trophoblastic layer, a process that begins at 8 weeks gestation and is mostly complete by 16 to 20 weeks. An imbalance between the vasodilatory properties of prostacyclin and the vasoconstrictive action of thromboxane has been postulated as the mechanism behind this characteristic disease pattern.50 Treatment with low-dose aspirin (50–150 mg/d) to redress this imbalance has been investigated, but the outcomes of randomized controlled trials conflict. A meta-analysis of studies involving 11,348 women, published in 2010, analyzed subgroups according to gestational age at which low-dose aspirin treatment was commenced.51 Low-dose aspirin begun before 16 weeks gestation was associated with a significant risk reduction in the incidence of preeclampsia (relative risk [RR], 0.47; 95% CI, 0.34–0.65; number-needed-to-treat [NNT], 9), but if commenced after 16 weeks gestation it was not. The incidence of severe preeclampsia, intrauterine growth restriction, or preterm birth was also significantly decreased among those who began low-dose aspirin before 16 weeks. However, all the studies that included women at high risk for preeclampsia were small, and the positive findings may have been overestimated. Large randomized controlled trials adjusted by gestational age remain necessary to address this question.

A subsequent meta-analysis52 divided women (n = 28,327) into subgroups of low versus high risk of preeclampsia. A significant reduction in the incidence of preeclampsia was found among high-risk women treated with low-dose aspirin (RR, 0.79; 95% CI, 0.65–0.97; NNT, 19), but not among the low-risk group (RR, 0.86; 95% CI, 0.64–1.1; NNT, 200). There was no reduction in the risk of intrauterine growth restriction or neonatal death. Thus, there appears to be a significant, but relatively small, reduction in the incidence of preeclampsia when low-dose aspirin is given to select women at risk, although those most likely to benefit need further definition. It is reassuring to note that all studies found either no increase or a minimal increase in adverse events, such as maternal or neonatal bleeding, from treatment with low-dose aspirin.

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Therapeutic Low-Dose Aspirin for Recurrent Abortion Due to Antiphospholipid Syndrome

Low-dose aspirin in combination with low-dose heparin is recommended for treatment of recurrent spontaneous abortion in women with antiphospholipid antibodies.c A meta-analysis, of women with antiphospholipid antibodies who had a prior miscarriage, examined all treatments used to maintain pregnancy and found that unfractionated heparin with aspirin was the only treatment combination to significantly reduce pregnancy loss.53 Three trials investigating aspirin alone found no reduction in pregnancy loss (RR, 1.05; 95% CI, 0.66–1.68), but 2 trials including 140 patients found that unfractionated heparin plus low-dose aspirin, compared with low-dose aspirin alone, reduced risk (RR, 0.46; 95% CI, 0.29–0.71).

The authors of the meta-analysis suggested performing a large randomized control trial to explore the potential differences between unfractionated heparin and low molecular weight heparin. Two small pilot trials have since been published, both reporting no significant difference in outcome between unfractionated or low molecular weight heparin combined with low-dose aspirin.54,55

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THE SECOND TRIMESTER

Therapeutic NSAID Tocolysis for Premature Labor

Prostaglandins play an important role in the onset and maintenance of labor by enhancing the formation of myometrial gap junctions and increasing intracellular calcium. The expression of COX-1 increases dramatically in the decidua, myometrium, and fetal membranes during labor. Prostaglandin inhibitors such as indomethacin have a potent inhibitory effect on uterine contractions,56 and indomethacin has been used since the 1970s as a tocolytic to delay and treat premature delivery. Meta-analysis confirms that, compared with placebo and other tocolytics such as β-sympathomimetic drugs or magnesium sulphate, indomethacin reduces the risk of preterm birth (before 37 weeks) and causes fewer maternal side effects.57,58 However, as with other tocolytic drugs, no clear improvement in neonatal morbidity or mortality has been demonstrated.57 Furthermore, administration in the second trimester is associated with congenital cryptorchism, and short-term administration of indomethacin in the third trimester increases the incidence of premature closure of the fetal ductus arteriosus compared with placebo (OR, 15.04; 95% CI, 3.29–68.68).58 NSAID-induced constriction of the ductus arteriosus, leading to potential neonatal pulmonary hypertension, can be demonstrated after 48 hours administration from as early as 27 weeks.59 Other adverse effects of NSAIDs in later pregnancy include oligohydramnios caused by reduced fetal urine output, necrotizing enterocolitis, and intracranial hemorrhage.60 Although short-term administration of an NSAID is infrequently associated with fetal ductal constriction, many practitioners consider these drugs unsuitable for use after 28 to 32 weeks gestation.4

COX-2 inhibitors such as rofecoxib, sulindac, ketorolac, and nimesulide are also effective tocolytic drugs,57,58,60 and it was hoped that they might have fewer adverse effects than indomethacin.61 However, the same problems, including oligohydramnios and ductal constriction, remain after exposure to the COX-2 specific NSAIDs. A randomized controlled study comparing nimesulide with sulindac or indomethacin found a similar incidence of ductal constriction in all groups.61 The Royal College of Obstetricians and Gynaecologists note that COX-2 inhibitors are better tolerated than other tocolytics for preterm birth. However, due to poor effectiveness before 32 weeks gestation and increased neonatal morbidity beyond 28 weeks compared with alternative tocolytic drugs such as calcium channel blockers or oxytocin receptor antagonists, they are not recommended as first-line treatment.d However, the American College of Obstetricians and Gynecologists Practice Bulletin on management of preterm labor supports NSAIDs for short-term (up to 48 hours) prolongation of pregnancy, to allow administration of antenatal steroids.62

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Cryptorchism

Although generally considered to be safe in the second trimester of pregnancy, there is low-level evidence from a recent investigation of a possible harmful effect of NSAIDs during this period. A prospective birth cohort study performed in Denmark asked 491 women to complete a questionnaire about their exposure to mild analgesics during pregnancy and demonstrated a dose-dependent association between the use of acetaminophen, aspirin, or ibuprofen and congenital cryptorchism.63 The association was more marked after second trimester use (OR, 2.20; 95% CI, 1.09–4.45) or if >1 drug was used (OR, 7.72; 95% CI, 2.09–28.6). Another questionnaire among 1463 women in Finland reported no harmful association, but the results were probably affected by both underreporting and the lower incidence of congenital cryptorchism in that country. The postulated causal mechanism is the antiandrogenic effects of prostaglandin inhibition.

Congenital cryptorchism is the best-described risk factor for poor semen quality and testicular germ cell cancer;64 so in theory, intrauterine exposure to mild analgesics might also be a risk factor for the development of male reproductive disorders.

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Fetal Renal Injury

Fetal renal dysfunction induced by NSAIDs is thought to result largely from a reversible reduction in renal blood flow and hence glomerular filtration rate, but may also be due to structural changes in the kidney resulting from antenatal exposure to NSAIDs.d,65,66 Histological examination reveals typical nephrotoxicity, with abnormal glomeruli and tubules; various degrees of ischemic injury and fibrosis in the medullary area; cortical necrosis; focal tubular and glomerular microcysts in developing nephrons; and loss of differentiation between proximal and distal tubules.67 This pathology may reflect a defect in nephrogenesis as a result of the inhibition of prostaglandin release. The COX-2 enzyme is expressed prominently by the developing fetal kidney, first appearing in midgestation and increasing in prominence toward term.68 Nephrogenesis begins from the fifth gestational week and is usually complete by 36 weeks.68 The importance of COX-2 during this phase of development is demonstrated by the fact that COX-2 null mice are born with small kidneys containing fewer nephrons, dilated atrophic tubules, and interstitial fibrosis.69,70

The renal effects of in utero exposure to NSAIDs (both selective and nonselective) vary in severity from transient fetal oligohydramnios to severe and lethal neonatal renal failure.68,71–74 Preterm infants exposed to indomethacin in utero exhibit abnormal renal function when glomerular filtration rate is assessed by inulin clearance, the “gold standard” for its measurement.66 The incidence of renal dysfunction associated with NSAID exposure in utero varies from 1.5% to 20%,75,76 increasing as exposure occurs closer to delivery. A case-control study in premature infants admitted to neonatal intensive care units investigated risk factors for neonatal renal dysfunction and identified maternal consumption of NSAIDs during pregnancy as the main independent risk factor (OR, 7.38; 95% CI, 3.26–16.7).76

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THE THIRD TRIMESTER

Fetal Adverse Effects

NSAIDs are generally of low molecular weight and cross the placenta freely.30,31 Consequently, administration in the third trimester, especially beyond 32 weeks, may cause similar adverse fetal effects to those in the second trimester. Retrospective matched cohort studies of infants born at <31 weeks gestation have also noted an increased incidence of neonatal periventricular hemorrhage, patent ductus arteriosus, renal impairment, or necrotizing enterocolitis, especially if indomethacin was administered to the mother within 48 hours of delivery.77,78 This increased incidence of patent ductus arteriosus after indomethacin appears somewhat counterintuitive because indomethacin initially causes constriction of the fetal ductus. This in utero constriction usually resolves within 24 hours of drug cessation, but is thought to cause ischemic damage to the inner muscle wall.77,78 Subsequently, therefore, the ductus is less responsive to both the normal increase in oxygen tension at delivery and to further doses of indomethacin in the neonatal period.77 A case-control study based on maternal interview that included 103 infants with persistent pulmonary hypertension of the newborn (PPHN) and 298 control infants, demonstrated an association between maternal consumption of NSAIDs or aspirin during pregnancy and PPHN (adjusted OR for aspirin, 4.9; 95% CI, 1.6–15.3 and adjusted OR for NSAIDs, 6.2; 95% CI, 1.8–21.8).79 Severe PPHN can be fatal, and the neonatal mortality rate in the case-control study was 18%. Because of these serious adverse effects, most consensus guidelines recommend that NSAIDs be avoided in the third trimester, particularly after 32 weeks80 or more conservatively, after 28 weeks.e

High-dose aspirin (325–650 mg) taken during the week before delivery increases not only the incidence of minor neonatal bleeding episodes5 but also that of serious neonatal bleeding after premature delivery.81 An observational study of 108 infants of birth weight ≤1500 g, delivered up to and including 34 weeks gestation, found a higher incidence of intracranial hemorrhage among aspirin-exposed newborns compared with nonaspirin-exposed infants (71% vs 45%).81 Hence, high-dose aspirin should be avoided during pregnancy, particularly if there is an increased risk of premature delivery. In contrast, maternal administration of low-dose aspirin inhibits maternal platelet COX enzymes but not those of the newborn,82 so use of low-dose aspirin during pregnancy is not associated with fetal or neonatal toxicity.5

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Maternal Adverse Effects

Case reports suggest deterioration of preeclampsia-related hypertension after exposure to indomethacin.83,84 The mechanism is postulated to be inhibition of prostaglandin synthesis in the renal vasculature85 and interference with the action of antihypertensive medications.85 On this basis, it has been recommended that all NSAIDs should be avoided in women with preeclampsia, as well as patients with aspirin-sensitive asthma or preexisting renal impairment.

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Labor Analgesia

Only 1 study has evaluated the analgesic properties of NSAIDs to treat uterine contraction pain during labor. A single dose of IM ketorolac 50 mg had poor effectiveness, similar to that of meperidine 50 to 100 mg, although the latter caused more maternal sedation and fetal depression.86 Furthermore, there are theoretical objections to NSAID administration during labor, because uterine endothelial prostaglandin F production and prostaglandin receptor activation are important initiators of intracellular calcium increase, actin–myosin interaction, and myometrial contraction.87 This tocolytic action raises concern about uterine atony and subsequent postpartum hemorrhage. Consequently, there appears to be no role for NSAIDs in this setting.

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POSTPARTUM

Breastfeeding

The NSAIDs are acidic drugs (e.g., ketorolac pKa 3.5 and indomethacin 4.5) with low lipid solubility and high protein binding (>90%), features that mitigate against substantial transfer into breastmilk, which is slightly acidic (mean pH 7.1–7.2) compared with plasma. The latter characteristic also favors drug transfer of the nonionized form back from the milk to more alkaline maternal plasma (reverse “ion-trapping”) and thus milk to plasma ratios of NSAIDs are generally <1. Such ratios, however, are not informative about the exposure of the infant to drug transferred in breastmilk. If the estimated absolute infant dose of a drug is established (by measurement of breastmilk concentration and estimation of volume of milk ingested), the relative infant dose expressed as a percentage of the maternal dose can be calculated. For some drugs, it may be possible to compare this level of dose exposure in the breastfed infant with the exposure of an infant as a result of therapeutic pediatric dosing. High protein binding and limited gastrointestinal absorption reduce systemic infant exposure to drug from ingested breastmilk. Other considerations that may affect infant exposure include the drug’s pharmacokinetics, its duration of administration (usually short term in the postpartum period), the changes in breastmilk composition and volume that occur in the first few days of lactation, and the neonatal oral bioavailability. If a drug has no significant toxic effects and the value of the relative infant dose is <10%, the drug is arbitrarily considered unlikely to be harmful to a postterm breastfed infant, despite the possible immaturity of neonatal metabolic pathways.88

There are several theoretical concerns related to the use of NSAIDs when breastfeeding. Some NSAIDs have antiplatelet effects, so there is a potential effect on neonatal platelet function. Umbilical cord blood from women given ketorolac for labor analgesia shows placental passage of the drug89,90 leading to inhibition of the arachidonic acid and collagen responses, but not the primary adenosine triphosphate platelet response.90 This finding suggests that NSAIDs exhibiting both COX-1 and COX-2 inhibition should not be taken by women who are breastfeeding neonates and infants who have thrombocytopenia or platelet dysfunction. The COX-2–specific inhibitors may be suitable because they show no or less platelet inhibition in adults.91 This class of NSAIDs shows similar analgesic effectiveness and opioid dose-sparing to traditional NSAIDs in non-obstetric settings,92 but after cesarean delivery, studies conflict as to the effectiveness of parecoxib and celecoxib.

Aspirin persists in maternal milk for up to 24 hours and neonatal metabolism is slow.93 Even after a single dose, once lactation is fully established, the infant is exposed to 9% to 21% of the maternal dose.94,95 Toxic effects on breastfed infants exposed to larger doses of salicylates (2–4 g/d) have been known since the 19th century, but there is only 1 case report attributing infant toxicity from metabolic acidosis to a high serum salicylate.96 The mother was taking high-dose aspirin (650 mg 4 hourly), but maternal concentrations were not assayed and it is thought to be very unlikely that the measured infant concentration could have resulted from breastfeeding alone. Adverse effects of aspirin on neonatal platelet function are a theoretical risk that has not been studied. The American Academy of Pediatrics classifies aspirin under drugs that “have been associated with significant effects on some nursing infants and should be given to nursing mothers with caution.”5 Because of the theoretical risk of the Reye syndrome, the British National Formulary states that it should be avoided when breastfeeding.7 Expert opinion is that drugs such as ibuprofen are preferable.97

Indomethacin has limited lipid solubility, high plasma protein binding, and is highly ionized at normal plasma pH, resulting in a median milk to plasma ratio of 0.37. Infant plasma concentrations are usually below the level of quantification (20 µg/L), and the relative infant dose is <1%.98 This level of exposure is equivalent to <10% of the therapeutic dose used in infants to manage patent ductus arteriosus. A case report suggesting indomethacin-induced seizures in a 7-day-old infant whose mother was taking 200 mg/d99 has been criticized because objective evidence of exposure was not confirmed. Indomethacin is considered “probably compatible”7 or “usually compatible”5 with short-term use when breastfeeding.

Maternal ingestion of ibuprofen 400 mg 6 hourly is detectable in breastmilk at a lower limit of quantification of 2.5 ng/mL,100 and the maternal weight-adjusted relative infant dose is <1%, even after repeat maternal dosing (400 mg 6 times over the first 2 postoperative days and twice daily for 3 weeks).100–102 Furthermore, ibuprofen is approved as a therapeutic drug for children, so it is classified as compatible or usually compatible with breastfeeding.5,6 A drug of similar class, flurbiprofen, has been evaluated after both single and repeat dose and transfer into milk is very low, with recovery of <0.1% of the maternal dose in breastmilk.103 Exposure to ketoprofen is likewise very low (relative infant dose <0.5%),104 as is that to fenoprofen.105

Diclofenac is of similar class to indomethacin, has a short 1-hour adult half-life, and results in a relative infant dose of 1.2%.106 Naproxen concentrations in breastmilk peak approximately 4 hours after a maternal dose of 250 to 375 mg, but <0.3% of the maternal dose is excreted in the infant’s urine.107 The product information of tenoxicam states that it appears in breastmilk in low concentration. Piroxicam excretion into breastmilk is very low (milk concentration approximately 1% of the maternal plasma concentration),108 but the drug has a long half-life. Tolmetin has low lipid solubility and very high protein binding, so breastmilk transfer is very low and the estimated relative infant dose only 0.4%.109 Flufenamic acid is highly protein bound and shows very low transfer into breastmilk.110 All these NSAIDs are classified as suitable for early postpartum use (Table 6).

Table 6

Table 6

Ketorolac tromethamine has a molecular weight of 376 Da, pKa 3.54, and is 99% plasma protein bound. A dose of 10 mg 4 times a day, for 2 to 6 days after delivery, results in milk to plasma ratios of 0.016 to 0.027. Milk concentrations are below the lower limit of quantification in some women, and relative infant dose (0.18%) is very low.111

Despite this reassuring information, and a recommendation to the contrary within the American Academy of Pediatrics Policy Statement on the transfer of drugs and other chemicals into human milk,5 the United States FDA-approved product information has a “black box” warning stating that ketorolac is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. Similar statements appear in the United Kingdom regulatory material; in Australia, the drug is not recommended.

Among the COX-2–specific inhibitors, celecoxib is excreted into breastmilk but is largely eliminated from both plasma and milk by 12 hours from last exposure, and plasma concentrations in the infant may decrease below the limit of detection within 4 hours. A maternal dose of 100 mg twice daily has been estimated to produce a maximum infant dose of 40 µg/kg/d; measured median absolute infant doses after a maternal dose of 200 mg were 10 to 13 µg/kg/d.112–114 Thus, the relative infant dose is only 0.2% to 0.3% of the weight-adjusted maternal dose and 0.2% to 0.6% of the off-label dose of celecoxib (typically 2–6 mg/kg/d) used in children to treat pain and inflammation.115

Concentrations of the prodrug parecoxib in early human milk lie below the limit of quantification in most women,116 and the transfer of its active metabolite valdecoxib is consistent with its molecular weight of 314 Da, lipid solubility, and 8-hour elimination half-life. However, the combined relative infant dose of parecoxib and valdecoxib is very low (0.63%), and in the apparent absence of any detrimental infant effect after exposure to a single 40-mg dose of parecoxib on the third or fourth day after cesarean delivery, it is unlikely the exposed infant will be harmed.116 There is no information about repeat dosing or use later in the puerperium, when breastmilk is mature and production maximal.

In summary, short-term maternal administration of most NSAIDs, apart from aspirin in doses above 150 mg/d, is considered to be of low risk to the breastfed infant (Table 6).

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Postpartum Pain

Many NSAIDs have proven effective against postpartum pain caused by episiotomy or other perineal trauma,117–119 uterine involution,120,121 cesarean delivery, or incidental causes (e.g., migraine or rheumatoid arthritis). After rectal NSAID suppositories, perineal pain is reduced for 48 hours, and less additional analgesia is required.122 Ibuprofen 400 mg 6 hourly appears as effective as acetaminophen and codeine, but shows a better side effect profile, for pain from perineal injury.123 Oral celecoxib 200 mg 12 hourly may be a better choice than oral diclofenac 100 mg 12 hourly in the first 24 hours after perineal repair, based on a randomized trial that found less initial rest pain and fewer upper gastrointestinal symptoms.124 Ketorolac is more effective than aspirin 650 mg for postpartum uterine pain.125 A meta-analysis of 9 trials investigating postlaparotomy pain in non-obstetric patients indicated that analgesia was better and side effects reduced with NSAIDs compared with acetaminophen (paracetamol) and codeine.126

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Post–Cesarean Delivery Pain

As a primary analgesic method after cesarean delivery, an NSAID-based regimen has the benefit of low cost and a superior side effect profile to some systemic opioid methods (e.g., IM meperidine or oral codeine)127–129 or oral tramadol regimens,130 but the analgesia is frequently inadequate.131,132 In contrast, as adjuncts within a multimodal analgesic regimen, NSAIDs are frequently of benefit. The addition of an NSAID improves IV tramadol or opioid analgesia and/or reduces opioid dose requirements after epidural,133 general,134–136 or spinal anesthesia.137–142 There may be a benefit from combining an NSAID with acetaminophen,143,144 although this appears to depend on what concurrent analgesic method is used. As adjuncts to a primary method of systemic opioid, such as IV morphine patient-controlled analgesia, ketorolac, parecoxib, celecoxib, or ibuprofen show similar analgesic effectiveness or opioid dose-sparing effects.145–147 IV diclofenac can augment analgesia achieved with continuous bupivacaine wound infusion.148

When neuraxial opioid techniques are the primary method of postoperative analgesia, the benefits of NSAIDs are much less consistent among both non-obstetric and obstetric surgical populations. Three studies have reported improved analgesia from low-dose epidural morphine with the addition of either diclofenac or ketorolac.131,149,150 Rectal NSAIDs prolonged the time until request for additional analgesia after spinal morphine.151,152 In contrast, after spinal morphine 100 µg, neither IV ketorolac153 nor oral valdecoxib154 had beneficial effects, and celecoxib 300 mg did not improve analgesia.155 Although some studies have found a small dose-sparing effect, pain relief is not improved by combining diclofenac with patient-controlled epidural local anesthetic and opioid.156 Neither IV ketorolac, nor parecoxib followed by oral celecoxib, improved meperidine patient-controlled epidural analgesia or reduced opioid consumption (M. Paech, unpublished data).157

Failure to demonstrate improved analgesia when an NSAID is used with a neuraxial opioid technique likely reflects the high quality of analgesia achieved with the primary method. Subsequently however, as postoperative pain wanes, there may be a role for NSAIDs. Twenty-four hours after spinal morphine, regular oral naproxen reduced incisional pain, cramping pain, and worst pain compared with placebo and modestly reduced rescue opioid requirements, although the incidence of inadequate pain control was not reduced.158

An opioid dose-sparing effect is of no clinical benefit unless the lower opioid dose translates to a better patient outcome because of fewer opioid-induced side effects. One small single-blinded randomized trial found that the intraoperative, postdelivery administration of NSAID (flurbiprofen) was more effective in producing transient improvement in emetic symptoms compared with metoclopramide or droperidol,159 but the finding has not been replicated, and an etiology for this effect is unclear.

There is no information about the incidence of adverse effects in women after short-term postpartum administration of NSAIDs; in particular, safety data with respect to events such as acute gastric ulceration, acute renal impairment, or exacerbation of hypertension are lacking. A 1991 case series160 describes 3 women with the rare complication of necrotizing fasciitis of their abdominal wall after cesarean delivery, all of whom were receiving an NSAID. The authors postulated that there might be a possible causal relationship because NSAIDs impair chemotaxis, phagocytosis, and granulocyte bactericidal activity,161 but there have been no similar reports in the past 20 years.

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NOVEL ROUTES OF NSAID DELIVERY AND RESEARCH DIRECTIONS

The inflammatory response in the wound, which includes the release of substance P and various cytokines, is modified by the direct application of local anesthetic.162 A novel approach to peripheral inhibition of inducible COX expression in immune cells and fibroblasts at peripheral sites of injury, to reduce the production of sensitizing prostaglandins, is the wound infusion or infiltration of NSAID.163,164 A 48-hour infusion of diclofenac 300 mg, via a multiholed catheter, superficial to the fascia within a Pfannenstiel incision, resulted in similar analgesia to an infusion of ropivacaine, supplemented by IV diclofenac, and superior pain control and opioid dose-sparing to systemic diclofenac alone.164 Although diclofenac wound infusion did not reduce punctate hyperalgesia around the wound (compared with a ropivacaine infusion or IV diclofenac),164 systemic diclofenac and tramadol combined are more effective than either drug alone in preventing wound sensitization.138 Whether this has benefits in preventing persistent pain has not been investigated.

Experimental work suggests that targeting spinal COX-2, to reduce central prostaglandin production and endogenous cannabinoid breakdown, might be useful in reducing wound hyperalgesia and acute visceral pain from the uterine cervix.165 The potential to treat postoperative pain with intrathecal COX-1 inhibitors has been confirmed in animal models,166 but the first human trial, using spinal ketorolac, produced negative results.167 Nevertheless, this area of investigation is likely to continue.

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CONCLUSIONS

There is experimental and animal evidence (level 5) that NSAID use during preconception reduces fertility and evidence from case-control studies (level 3b) that consumption of these drugs in early pregnancy is associated with increased rates of spontaneous abortion. The second trimester use of NSAIDs appears relatively safe, although recent level 2b evidence has identified an association with infant cryptorchism. Second and, particularly, third trimester NSAID use may be associated with neonatal renal impairment in premature infants. Use of low-dose aspirin from early pregnancy by women at high risk for preeclampsia appears to reduce the incidence and severity of preeclampsia and growth restriction without causing harm, but because of fetal and neonatal bleeding risks it has been recommended that higher doses of aspirin (>150 mg/d) during pregnancy be avoided (level 4). Considerable caution with regard to third trimester use of NSAIDs is recommended. These drugs should preferably be avoided because of a large and consistent body of level 2b evidence indicating an increased risk of adverse effects, including PPHN and renal injury.

It appears systemic NSAIDs are of no value (level 1b) and potentially harmful if administered during labor analgesia, but level 1a evidence supports their effectiveness for postpartum analgesia after perineal injury. Depending on the primary analgesic method used after cesarean delivery and the timing of administration in the postoperative period, NSAIDs have the potential to reduce pain intensity, opioid requirements (and hence either maternal opioid-related side effects or neonatal exposure through breastmilk), or both (level 1a). However, NSAIDs can worsen hypertension and cause renal dysfunction; so they are best avoided in women with preeclampsia or renal disease (level 4).

Maternal use of NSAIDs during early lactation appears safe for healthy term neonates, given that the relative infant doses of all NSAIDs studied to date have been low and below the limit considered to be acceptable for drugs with a low risk of toxicity. Avoidance of high-dose aspirin when breastfeeding has been recommended (level 4), but low-dose aspirin may be warranted if the individual risk–benefit assessment appears favorable (level 5).

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DISCLOSURES

Name: Melanie Bloor, BMBCh, MA, FRCA.

Contribution: This author helped write the manuscript.

Attestation: Melanie Bloor approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Michael Paech, MBBS, DRCOG, FRCA, FANZCA, FFPMANZCA, DM, FRANZCOG.

Contribution: This author helped write the manuscript.

Attestation: Michael Paech approved the final manuscript.

Conflicts of Interest: Michael Paech received research funding from Pfizer. Professor Paech recently held an investigator-initiated project grant from Pfizer Australia.

This manuscript was handled by: Cynthia A. Wong, MD.

a US Food and Drug Administration. For consumers. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118567.htm Accessed January 13, 2013.
Cited Here...

b Centre for evidence based medicine. Levels of evidence (March 2009). Available at: http://www.cebm.net/index.aspx?o=1025 Accessed January 13, 2013.
Cited Here...

c Royal College of Obstetricians and Gynaecologists. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Available at: http://www.rcog.org.uk/files/rcog-corp/GTG17recurrentmiscarriage.pdf Accessed January 13, 2013.
Cited Here...

d Royal College of Obstetricians and Gynaecologists. Tocolysis for women in preterm labour. Available at: http://www.rcog.org.uk/files/rcog-corp/GTG1b26072011.pdf. Accessed January 13, 2013.
Cited Here...

e US Food and Drug Administration. Drugs. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm125225.htm. Accessed January 13, 2013.
Cited Here...

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