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Antirheumatic drugs in pregnancy and lactation P E T E R M. B R O O K S C H R I S T O P H E R J. N E E D S
Some of the rheumatic diseases, such as rheumatoid arthritis, have their peak age of onset in women during the child bearing years. With improvements in treatment of more serious rheumatic diseases, such as systemic lupus erythematosus, pregnancy is becoming a viable option and there is a need to appreciate the impact of antirheumatic medication on the mother and the fetus or neonate during pregnancy and lactation. The use of antirheumatic drugs during pregnancy and the puerperium has been extensively reviewed (Needs and Brooks, 1985a, 1985b; Brooks and Needs, 1989). Although pregnancy itself might modify the activity of inflammatory rheumatic diseases, there are still patients who need to take slow-acting antirheumatic drugs or non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy and lactation. Some of these women will have been taking these drugs before becoming pregnant and the issue of how long a person should be removed from these treatments before attempting to conceive also needs to be addressed. Most women have a particular and proper aversion to taking any drug during pregnancy, especially during the first 12 weeks, and appropriate counselling needs to be provided. Although it is important that drug therapy be kept to a minimum during pregnancy, as well as while breast feeding, it is important that the rheumatic disease itself is not allowed to become active, as this might significantly compromise the mother's ability to care for the child once it is delivered. Since there is a dearth of clinical experience with antirheumatic medications during pregnancy and lactation, recommendations regarding their use are often based on theoretical grounds. Teratogenicity studies carried out in animals are not infallible and significant interspecies variation in response might lead to false assumptions of human safety (Stern, 1981). Other factors need to be considered, such as the long lead time from in utero exposure to drug before side-effects are noted, as observed with diethyl stilboestrol exposure being associated with the occurrence of vaginal adenocarcinoma up to 20 years later (Herbst et al, 1971). When considering the use of any medication during pregnancy and lactation a number of issues need to be considered. During pregnancy, there is not only the question of teratogenicity early in gestation but also the potential for alterations in maternal and fetal physiology produced by the Bailli&e's Clinical Rheumatology--
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drug. This is often relevant during the last trimester and, in particular, during delivery. During breast feeding it is important to ascertain whether the parent drug or its metabolites (particularly if they are active) are present in breast milk and whether the infant will be able to absorb sufficient quantities to produce an effect. If inactive metabolites are present in significant quantities, then it is important to know whether the infant will be able to release the active drug from the metabolite and what adverse reactions might be expected to occur in the baby. PHYSIOLOGICAL CONSIDERATIONS OF PREGNANCY The major physiological changes occurring during pregnancy are outlined in Table 1. Maternal pharmacokinetics might be significantly influenced by these changes but much of the information regarding pharmacokinetics in pregnancy is derived from studies based on small numbers of maternal blood samples and good data have been difficult to obtain in this area. During pregnancy, hormonal changes might affect gastric and small intestinal motility and alter the rate of absorption of drugs taken by mouth. Acid production from the stomach is reduced and there is an increase in mucus formation as part of normal pregnancy (Gryboski and Spiro, 1958). Although gastric emptying time is reduced during pregnancy (Davison et al, 1970), this is unlikely to have a significant affect on antirheumatic drugs. However, many women might also take antacids or iron supplements during pregnancy and these can certainly influence the absorption of NSAIDs (Day et al, 1984) or D-penicillamine (Osman et al, 1983). The maternal blood volume increases by up to 45% during pregnancy, with most of this increase occurring during the second trimester (Pritchard, 1965). There are also increases in both plasma volume and in the number of red cells, which contribute to a reduction of serum albumin concentration by about 25 % towards the end of the third trimester (Mendenhall, 1970). From a pharmacokinetic point of view, this will lead to a reduction in the binding capacity of a given volume of plasma and an increase in the apparent volume of distribution of a drug (Levy, 1975). Although this might be considered important for highly protein-bound drugs such as NSAIDs, because the action of a drug is primarily determined by the free concentration and this does not alter significantly unless metabolic or excretory pathways are also impaired, protein binding changes have little clinical relevance. In a study of Maternal physiological changes duringpregnancy.
Table 1.
Delayed gastricemptying Reduced gastricacid production Increased blood volume Reduced serum albumin Enhanced hepaticmetabolism Cholestasis Increased renal blood flow
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salicylate pharmacokinetics during pregnancy, Levy (1975) demonstrated increased protein binding of salicylate (84.4%) in neonatal plasma compared with maternal plasma (78%), suggesting that the fetus might be exposed to higher concentrations of salicylate. During pregnancy, a number of metabolic pathways in the liver are enhanced and this has the potential to alter kinetics of drugs metabolized by this organ (Christiansen et al, 1977). Since serum cholinesterase activity decreases during pregnancy (Pritchard, 1955), there is the potential for alteration of methylprednisolone and aspirin metabolism. Cholestasis might occur as a consequence of pregnancy, and drugs excreted in the bile, such as indomethacin, sulphasalazine and sulindac, might be retained. During early pregnancy there is increase in renal blood flow and, since creatinine clearance increases as well, it might be expected that those medications primarily excreted by the kidney would be cleared more rapidly in pregnant patients. Although this is a theoretical problem, there is little data to support it in practice (Krauer and Krauer, 1983). Although the drugs are given to the mother, the fetus will also receive the drug through the maternofetal circulation. Fetal exposure to the drug will depend on the rate of uptake of the drug by the mother and on maternal metabolism and excretion, as well as transfer across to the placenta. The drug distribution in the mother and the fetus, as well as the rate of elimination of the drug by the fetus itself, needs to be considered (Levy, 1975). Changes in maternal pharmacokinetics during pregnancy must also take into account placental transfer and possible metabolism by the fetus, drug distribution, metabolism and elimination, in addition to the normal factors which influence pharmacokinetics. There are many pharmacokinetic models devised to study and predict fetal exposure and these have been reviewed by Krauer and Krauer (1983).
ANALGESIC AGENTS Paracetamol is the most commonly prescribed pure analgesic agent and crosses the placenta relatively easily (Levy et al, 1975). There have been a number of relatively large studies of maternal and child exposure which do not suggest that paracetamol is associated with fetal malformations (Heinonen et al, 1977; Aselton et al, 1985). There is no evidence that codeine is associated with fetal malformations (Heinonen et al, 1977) but if the mother is exposed to significant amounts late in pregnancy, there can be some drug withdrawal symptoms occurring in the neonate (Mangurten and Benawra, 1980). Although anecdotal case reports have linked the ingestion of propoxyphene with fetal malformations (Barrow and Souder, 1971; Golden et al, 1982), the Collaborative Perinatal Project (Heinonen et al, 1977) failed to demonstrate any clear link with propoxyphene ingestion, although neonatal withdrawal syndromes have again been reported (Tyson, 1974). Although codeine is soluble in lipids and might concentrate in breast milk, it is considered by the American Academy of Pediatrics to be compatible
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with breast feeding. Similarly, paracetamol is excreted in small amounts in breast milk but is a safe analgesic to use for nursing mothers (Bitzen et al, 1981). NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Since prostaglandins play a major role in fetal development, it is important to appreciate the impact that cyclo-oxygenase inhibitors might have on fetal physiology. Prostaglandin E2 produces relaxation of systemic and pulmonary vessels, as well as the ductus arteriosus, in some animals and in man (Cassin et al, 1975). NSAIDs, including salicylates, indomethacin and naproxen, have been used therapeutically to close a patent ductus arteriosus (Sharp et al, 1974, 1975). The circulation within other organs might be influenced by locally produced prostaglandins and, again, are subject to the influence of NSAIDs. Aspirin has been shown to increase pulmonary artery pressure without any change in aortic pressure and to potentiate hypoxia-induced renal vasospasm (Rudolph, 1981). The slow phase of pulmonary vascular dilatation which occurs during ventilation is inhibited by indomethacin (Leffler et al, 1978) and fetal lambs given indomethacin on a chronic basis have been shown to have increased amounts of pulmonary arterial wall smooth muscle, presumably the result of sustained elevation in pulmonary artery pressure (Levin et al, 1979). This increase in smooth muscle within pulmonary arterial walls has also been described in the offspring of mothers taking other NSAIDs (Levin et al, 1978). These fetal effects are a major reason for restricting NSAID use, particularly during the third trimester of pregnancy. Salicylates
Up to 65% of women have been reported as taking aspirin or salicylatecontaining compound analgesics at some stage during their pregnancy (Hill, 1973; Corby, 1978). Whether aspirin use during pregnancy is associated with fetal abnormalities is still a matter for conjecture. Animal studies using at least five times the normal human aspirin dose have demonstrated a variety of skeletal craniovertebral abnormalities in rats, mice and dogs (Warkany and Takacs, 1959; Larsson and Eriksson, 1966; Robertson et al, 1978). Although several retrospective studies in humans indicate that mothers of malformed infants take more aspirin during pregnancy than control mothers (Nelson and Forfan, 1971; Saxen, 1975; Crombie et al, 1976), more recent prospective studies have failed to demonstrate any increased incidence of fetal malformations with maternal aspirin ingestion during pregnancy (Buckfield, 1973; Turner and Collins, 1975; Sloane et al, 1976). On the strength of these studies, there would seem little reason to restrict aspirin use during pregnancy on the basis of potential teratogenicity. Rats exposed to aspirin in utero have been shown to have certain learning difficulties (Butcher et al, 1972), but whether this occurs in man is not known. Turner and Collins have shown that chronic aspirin ingestion during
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pregnancy is associated with a higher incidence of stillbirths and a lower mean birth weight, even after correction for gestational age and maternal smoking. However, Sloane et al (1976) were unable to demonstrate any changes in birth weight patterns associated with salicylate use, and it has been suggested that other factors such as the ingestion of pure analgesic agents (for example, caffeine, phenacetin and paracetamol) might be operating to reduce infant birth weight (Collins, 1981). Maternal aspirin ingestion in the week prior to delivery is associated with the increased risk of intracranial haemorrhage in premature infants (Rumack et al, 1981). Lewis and Shulman (1973) have demonstrated that regular aspirin ingestion in patients with rheumatic diseases increases the period of gestation, prolongs labour and increases blood loss at delivery. These effects of salicylates are produced by inhibition of prostaglandin production necessary for uterine contraction and for platelet aggregation. The effect of aspirin on birth weight might also be due to other factors such as cigarette smoking, alcohol and caffeine abuse. There is, however, little doubt that chronic aspirin use might prolong gestation, increase the length of labour and increase the risk of pre- and postpartum haemorrhage, as well as predisposing premature infants to intracranial haemorrhage. On present data there is little evidence to associate aspirin or salicylate ingestion with teratogenic effects or an increased risk of stillbirth. As with other NSAIDs, there is the theoretical concern that primary pulmonary hypertension may be associated with its use. Following ingestion of between 450 and 650 mg aspirin, up to 21% of the maternal dose is available in breast milk over a 24-h period (Berlin et al, 1980; Findlay et al, 1981). Levy (1978) has demonstrated that infants have the ability to cleave salicyl phenolic glucuronide and absorb the free salicylic acid. Peak salicylate concentrations are found in breast milk some 2 h after peak maternal serum concentrations (Findlay et al, 1981). No studies have been reported in lactation during chronic high dose salicylate therapy but, from the known dose-dependent kinetics of salicylate, concentrations can be predicted to be higher than in the milk of those mothers taking single doses. Indomethacin and sulindac
Placental transfer of indomethacin occurs rapidly, with similar concentrations in maternal and fetal plasma. Although there are two anecdotal reports of fetal malformations in mothers taking indomethacin (Buckfield, 1973; DiBattista et al, 1975), these were quite unrelated malformations and any influence of indomethacin must be considered tenuous. Indomethacin has been used to treat premature labour by suppressing prostaglandin production. Zuckerman et al (1974) reported that five of 12 infants whose mothers had been treated with indomethaein for premature labour died within 48 h of birth from respiratory distress. On the other hand, Wiquist et al (1975) failed to show any increase in fetal mortality when indomethacin was used in a similar fashion. It is important to appreciate that the respiratory failure might be a reflection of the prematurity itself, rather than the result of possible indomethacin-induced pulmonary hypertension from duct closure in
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utero. However, several recent reports have confirmed the association between pulmonary hypertension and maternal indomethacin ingestion (Manchester et al, 1976), and histological studies have demonstrated increased amounts of smooth muscle in the pulmonary arterial wall of some of these infants. On present evidence it can be said that indomethacin does induce premature closure of the ductus arteriosus and that this might give rise to pulmonary hypertension in susceptible neonates. The enterohepatic recycling of indomethacin and its metabolites makes its use unwise in lactation. In fact, a grand real seizure has been reported in a child being breast fed by a mother ingesting regular indomethacin (EegOlofsson et al, 1978). Sulindac has a long half-life and active metabolites which might be excreted in breast milk. It is therefore not appropriate to prescribe this agent for nursing mothers (Kwan et al, 1978). Teratogenicity studies in rats and mice using high doses of sulindac have failed to demonstrate any problems. There are no reports in the literature linking sulindac with fetal malformations in human beings but, together with other prostaglandin synthetase inhibitors, it might infuence labour and induce closure of a patent ductus arteriosus.
Diflunisal Diflunisal has been shown to be teratogenic in animal studies using significantly higher doses than those recommended for humans (Van Winzum and Verhaest, 1979). Fetal abnormalities have not been reported with diflunisal use in humans. Diflunisal has similar effects to other NSAIDs on parturition and closure of a patent ductus arteriosus. Since diflunisal has a long half-life, it is not as appropriate to use during lactation as NSAIDs with a shorter half-life.
Phenylbutazone Phenylbutazone should now be restricted to the treatment of severe seronegative inflammatory rheumatic diseases and, even then, only when they fail to respond to indomethacin. Since ingestion of phenylbutazone has been associated with significant haematological side-effects (O'Brien and Bagby, 1985), its use in pregnancy or lactation cannot be recommended.
Diclofenac Midorikawa et al (1972) reported minor fetal abnormalities occurring in rats and mice with doses considerably in excess of those found in humans. Recent follow-up studies on mice, rats and rabbits, however, have failed to show any clear evidence of mutagenicity with diclofenac (H. Rothing and P. Graepel, personal communication). There have been no reports of fetal abnormalities in man following ingestion of this drug. Soiufi et al (1982) have demonstrated minor amounts of radioactivity in breast milk after radiolabelled diclofenac administration to lactating rats. The majority of the radioactivity was due to unchanged drug. Diclofenac
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sodium has not been detected in human milk following either single doses of 50 mg or after 1 week of treatment with 100 mg daily. As only a small amount of diclofenac is present in breast milk and the drug has a short half-life of 2 h, with minimal glucuronide formation, it is suitable for use by lactating mothers. It should be remembered, however, that some of the metabolites do have longer half-lives and might be present in breast milk, though again in small quantities. Propionic acid derivatives There is no evidence that ibuprofen, naproxen, fenoprofen or ketoprofen are teratogenic in animals or man. They might, however, delay parturition and have been associated with persistent pulmonary hypertension in preterm infants. A patient who was taking naproxen to suppress labour gave birth to triplets at 30 weeks, all of whom had severe hypoxaemia (Wilkinson et al, 1979). The ductus arteriosus remained closed in these infants and high concentrations of naproxen (60 ~g/ml) were found in neonatal plasma (Wilkinson et al, 1979). Hyponatraemia and fluid retention have also been reported in a neonate following ingestion of 5 g naproxen by the mother 8 h prior to delivery. The infant recovered completely and subsequent development was unimpaired (Alun-Jones and Williams, 1986). On the basis of these reports, care should be taken in using these drugs to suppress labour. Ibuprofen, fenoprofen, flurbiprofen, ketoprofen, naproxen and fenbufen have all been found in small quantities in human breast milk. In a study of 12 patients ingesting 1600 mg ibuprofen over a 24-h period, ibuprofen was not detected in breast milk during the dosing interval (Townsend et al, 1984). This would suggest that, at a maternal dose of 1.6g ibuprofen daily, a nursing infant will receive less than 1 mg ibuprofen per day. Following ingestion of 250 mg naproxen, small amounts of the drug were found in the breast milk, but less than 0.26% of the maternal dose was recovered from the infant, suggesting that the extent of naproxen ingestion from breast milk of mothers on chronic therapy is limited and unlikely to cause significant problems in the infant (Jamali and Stevens, 1983). Fenoprofen and ketoprofen both have short plasma half-lives and limited data on breast milk concentrations of these drugs suggest that they are extremely low (Rubin, 1984). Although they are converted to glucuronide metabolites, they are also acceptable NSAIDs for nursing mothers. Oxicams Along with other NSAIDs, the oxicams have been shown to delay parturition in animals (Wiseman, 1985). Piroxicam and tenoxicam have not been shown to have any teratogenic effects in animals and there are no reports of fetal abnormalities in man. A recent study of piroxicam administration during lactation has shown that the drug appears in breast milk at about 1-3% of maternal plasma concentrations (Ostensen 1983; Ostensen et al, 1988).
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A N T I M A L A R I A L DRUGS
There is good evidence that the antimalarial drugs cross the placenta and accumulate in the fetal tissues, such as the eye (Ullberg et al, 1970). Antimalarial drugs have been shown to induce chromosomal damage in vitro (Neill et al, 1973) but this has not been shown in vivo. Administration of chloroquine phosphate during the first trimester of pregnancy has been associated with sensory neural hearing loss in an infant (Hart and Naunton, 1964). Parke (1988) has recently reviewed pregnancy outcomes in systemic lupus erythematosus (SLE) patients treated with antimalarial drugs. In this survey, six normal babies resulted from 14 pregnancies in eight women with SLE. The high fetal wastage seemed to be related to disease activity rather than to treatment, and there would seem to be no reason for ceasing antimalarial drug therapy during pregnancy in rheumatoid arthritis or SLE if the disease process is controlled. Both hydroxychloroquine and chloroquine are found in small amounts in human milk (Merland and Creste, 1954; Soares et al, 1959). Plasma concentrations achieved in breast-fed infants are not, however, adequate to protect them from malarial infection (Pinotti, 1959). In a study of the secretion of hydroxychloroquine in human breast milk, Nation et al (1984) have shown an M/P (milk:plasma concentration) ratio of 5.5 for hydroxychloroquine and predicted that the infant would be exposed to about 2% of the maternal dose per day. In developing countries, many women continue to feed their infant while taking malarial prophylaxis and adverse reactions are not reported. However, some caution should be taken in patients with chronic rheumatic diseases as considerably higher doses of hydroxychloroquine or chloroquine are taken. GOLD COMPOUNDS Malformations of the central nervous system and the skeleton have been reported in rabbits and rats treated with gold thiomalate (Szabo et al, 1978). Fetal tissues of mothers on gold treatment contain small amounts of the metal (Rocker and Henderson, 1976; Richards, 1977). Gold certainly crosses the placenta, and Cohen et al (1981) have described a normal infant with plasma concentration of gold in the therapeutic range at delivery. Auranofin has also been shown to cross the placenta in both rats and rabbits (Szabo et al, 1978), although no adverse reactions in mothers or infants have been described in 13 rheumatoid arthritis patients continuing to take auranofin treatment throughout pregnancy (Ostensen and Husby, 1985). On the evidence available, there would seem to be no reason for withdrawing gold therapy during pregnancy if it is controlling disease, although an attempt might be made to reduce the dose and frequency of administration. Although trace amounts of aurothioglucose have been detected in breast milk (Blau, 1973; r et al, 1986), it cannot be absorbed by the suckling infant. Auranofin has been demonstrated in breast milk in animals but there are no data available in humans.
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D-PENICILLAMINE Many patients with Wilson's disease and cystinuria have given birth to normal infants, despite large doses of D-penicillamine throughout the pregnancy (Walshe, 1977; Gregory and Mansell, 1983). Endres (1981) has described two infants with active tissue defects similar to Ehlers-Danlos syndrome in association with D-penicillamine and there is at least one report of this condition occurring in an infant of a patient with rheumatoid arthritis similarly treated (Solomon et al, 1977). No adverse effects were reported in mother or offspring in 19 patients treated with D-penicillamine (Lyle, 1978) but a review by Rosa (1986) described five cases of cutis laxa in offspring of mothers treated with b-penicillamine. On this data, Rosa suggests that D-penicillamine should be continued in patients with Wilson's disease as the benefits of treatment outweigh the risks to the fetus. He does, however, suggest a discontinuation of D-penicillamine during pregnancy in conditions where safer alternatives are available. This view is shared by Lyle, who suggests the drug dose be reduced, and ceased if possible, during the pregnancy. No data is available on excretion of D-penicillamine in breast milk. SULPHASALAZINE Although sulphasalazine reduces spermatogenesis it does not alter fertility in females. Sulphasalazine and its metabolites readily cross the placenta and are found in cord blood (Jarnerot et al, 1981). Although Newman and Correy (1983) have described varying congenital defects in three children of two mothers treated with sulphasalazine, there is overwhelming data from mothers with inflammatory bowel disease treated with sulphasalazine during pregnancy who demonstrate no increased incidence of fetal malformations (Mogadam et al, 1981; Vender and Spiro, 1982). Sulphasalazine and sulphapyridine are found in breast milk following a single dose (Kahn and Truelove, 1979) but neither of these compounds are absorbed by the neonate in sufficient quantities to displace bilirubin or cause other problems (Esbjorner et al, 1986). CORTICOSTEROIDS Cleft palate formation has been described in a variety of animals following administration of corticosteroids (Fainstatt, I954; Schlesinger and Mark, 1964). However, it should be remembered that animals show a marked variation in teratogenic responses to corticosteroids (Tuchmann-Duplessis, 1975) and the mouse is particularly prone to developing cleft palate (Sidhu, 1987). Despite the fact that corticosteroids have been given to many thousands of pregnant women for a variety of conditions, only occasional adverse reactions have been reported in offspring. Cleft palate has been reported in association with the administration of large doses of cortico-
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steroids during the first trimester (Bongiovanni and McPadden, 1960). Popert (1962) reported ten patients with a variety of rheumatic diseases treated with corticosteroids during pregnancy and concluded that the drugs were not associated with an increase in maternal or fetal abnormalities in 20 pregnancy outcomes. Although Warrell and Taylor (1968) reported poor pregnancy outcomes in patients taking corticosteroids when compared with controls, Yackel et al (1966) were unable to confirm this. Grigor et al (1977) have shown that corticosteroids produce fetal immaturity when they are used in pregnant women with systemic lupus erythematosus. From the above data it would seem that, though there is a slightly increased risk of cleft palate and interuterine fetal growth retardation in association with high doses of corticosteroids during the first trimester, the risks are small in comparison to the risks of the underlying disease. After a single dose of 5 mg prednisolone, less than 0.23% of the administered dose was found in breast milk (McKenzie et al, 1975). There is no reason why corticosteroids should be withdrawn during breast feeding. CYTOTOXIC AGENTS There is clear evidence that chlorambucil, cyclophosphamide and methotrexate are teratogenic and mutagenic in humans when used during the first trimester of pregnancy (Nicholson, 1968; Barker, 1983). However, normal pregnancies do result from patients taking these drugs. For example, Sokal and Lessman (1966) have described 36 normal children resulting from 50 pregnancies in women exposed to these drugs. Fetal exposure during the first trimester might also lead to bone marrow depression, infection and haemorrhage (Hill and Stern, 1979). There are now an increasing number of normal pregnancy outcomes in women with SLE or renal transplants treated with azathioprine or prednisolone throughout the pregnancy (Hayslett and Lynn, 1980; Fine et al, 1981). However, long-term effects of immunosuppression on the offspring of mothers treated with these drugs during pregnancy have not been established and there is the possibility of chromosome damage and the increased risk of carcinogenesis. From a practical point of view, cytotoxic drugs should be ceased sometime before conception is contemplated, though the optimal timing of pregnancy after these drugs have been discontinued is not yet known. Cyclophosphamide is contraindicated during lactation since large quantities are excreted in human breast milk (Wiernik and Duncan, 1971). Although only small amounts of methotrexate (Johns et al, 1972) and azathioprine (Anderson, 1977) are detected in breast milk, these compounds might accumulate in fetal tissues; their use during lactation should be reduced to a minimum. SUMMARY
The natural inclination of patients with rheumatic diseases wishing to become pregnant or to breast feed will be to take as few medications as
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possible. The guidelines outlined above can be used to balance the risk of drug effect on the fetus or neonate with the risk of inducing a flare in disease activity by stopping the drug. Although there are situations where no information on drug behaviour during pregnancy or lactation exists, some guidelines can be developed from a knowledge of the drug's inherent metabolism. In the majority of the rheumatic diseases, disease activity can be reduced to a minimum using the smallest possible dose of drugs known to be safe in pregnancy and lactation, thus providing minimum risk to mother, fetus and neonate.
Acknowledgements Supported by a grant from the Arthritis Foundation of Australia,
REFERENCES Alun-Jones E & Williams J (1986) Hyponatremia and fluid retention in the neonate associated with maternal naproxen overdosage. Journal of Toxicology and Clinical Toxicology 24: 257-260. Anderson PO (1977) Drugs and breast feeding--a review. Drug Intelligence and Clinical Pharmacology 11: 208. Aselton P, Jick H, Milunsky A et al (1985) First trimester drug use and congenital disorders. Obstetrics and Gynaecology 65: 451-455. Barker GH (1983) Cytotoxic drugs in pregnancy. In Lewis P (ed.) Clinical Pharmacology in Obstetrics, pp 144-145. Bristol: Wright. Barrow MV & Souder DE (1971) Propoxyphene and congenital malformations. Journal of the American Medical Association 217: 1551-1552. Berlin CM, Pascuzzi MJ & Yaffe SJ (1980) Excretion of salicylate in human milk. Clinical Pharmacology and Therapeutics 27: 245. Bitzen PO, Gustafsson B, Jostell KG et al (1981) Excretion of paracetamol in human breast milk. European Journal of Clinical Pharmacology 20: 123-125. Blau SP (1973) Metabolism of gold during lactation. Arthritis and Rheumatism 16: 777-778. Bongiovanni AM & McPadden AJ (1960) Steroids during pregnancy and possible foetal consequences. Fertility and Sterility 2: 181-186. Brooks PM & Needs CJ (1989) The use of antirheumatic medication during pregnancy and in the puerperium. Rheumatic Disease Clinics of North America 15: 789-805. Buckfield P (1973) Major congenital faults in new born infants: a pilot study in New Zealand. New Zealand Medical Journal 78: 195-204. Butcher RE, Vorhees CV & Kimmel CA (1972) Learning impairment from maternal salicylate treatment in rats. Nature 236: 211. Cassin S, Tyler TL & Wallis R (1975) The effects of prostaglandin E on fetal pulmonary vascular resistance. Proceedings of the Societyfor Experimental Biology and Medicine 148: 584. Christiansen J, Mygind K, Munck O et al (1977) Plasma levels of anti-epileptic drugs in pregnancy. Epilepsia 18: 295. Cohen DL, Orzel J & Taylor A (1981) Infants of mothers receiving gold therapy. Arthritis and Rheumatism 24: 104-105. Collins E (1981) Maternal and fetal effects of acetaminophen and salicylates in pregnancy. Obstetrics and Gynecology 58 (supplement): 57-62. Corby DR (1978) Aspirin in pregnancy: maternal and fetal effects. Pediatrics 62 (supplement): 930. Crombie DL, Pinsent K & Slater BC (1976) Teratogenic drugs--R.C.G.P, survey. British Medical Journal 4: 523.
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Davison JM, Davison MC & Hay DM (1970) Gastric emptying time in late pregnancy and labour. Journal of Obstetrics and Gynaecology 77: 37-41. Day RO, Graham GG, Champion GD et al (1984) Antirheumatic drug interactions. Clinics in Rheumatic Diseases 10: 251-275. DiBattista C, Laudiei L & Tamborino G (1975) Focamelia ed agenesia del pene in neonato: possible rudi teratogeno di un farmeaco assunto dalla madre in gravidanza. Minerva Pediatrica 27: 675-679. Eeg-Olofsson O, Malmros I, Elwin CE et al (1978) Convulsions in a breast-fed infant after maternal indomethacin. Lancet ii: 215. Endres W (1981) D-Penicillamine in pregnancy--to ban or not to ban. Klinische Wochenschrift 59: 535-537. Esbjorner E, Jarnerot G & Wranne L (1986) Sulphasalazine and sulphapyridine levels in children to mothers treated with sulphasalazine during pregnancy and lactation. Acta Paediatrica Scandinavica 76: 137-142. Fainstatt T (1954) Cortisone-induced congenital cleft palate in rabbits. Endocrinology 55: 502-508. Findlay JW et al (1981) Analgesic drugs in breast milk and plasma. ClinicalPharmacology and Therapeutics 29: 625-633. Fine LG et al (1981) Systemic lupus erythematosus and pregnancy. Annals oflnternal Medicine 94: 667-677. Golden NL, King KC & Sokol RJ (1982) Propoxyphene and acetaminophen: possible effects on the fetus. Clinical Pediatrics 21: 752-754. Gregory MC & Mansell MA (1983) Pregnancy and cystinuria. Lancet ii: 1158-1160. Grigor RR, Shervington PC, Hughes GRV et al (1977) Outcome of pregnancy in systemic lupus erythematosus. Proceedings of the Royal Society of Medicine 70: 99-100. Gryboski WA & Spiro HM (1958) The effect on pregnancy of gastric excretion. New England Journal of Medicine 255: 1131-1137. Hart CN & Naunton RF (1964) The ototoxicity of chloroquine phosphate. Archives of Otolaryngology and Head and Neck Surgery 80: 40%412. Hayslett JP & Lynn RI (1980) Effect of pregnancy in patients with lupus nephropathy. Kidney International 18: 207-220. Heinonen OP, Sloane D & Shapiro S (1977) Birth Defects in Pregnancy, pp 286-295. Littleton, MA: Publishing Science Group. Herbst AL, Ulfelder H & Poskanzer DC (1971) Adenocarcinoma of the vagina: association of maternal stilboestrol therapy with tumor appearance in young women. New England Journal of Medicine 284: 878-880. Hill RM (1973) Drugs ingested by pregnant women. Clinical Pharmacology and Therapeutics 14: 654-659. Hill RM & Stern L (1979) Drugs in pregnancy: effects on the fetus and the new born. Drugs 17: 183-197. Jamali F & Stevens DRS (1983) Naproxen excretion in milk and its uptake by the infant. Drug Intelligence and Clinical Pharmacy 17: 910--911. Jarnerot G, Into-Malmberg MB & Esbjorner E (1981) Placental transfer of sulphasalazine and sulphapyridine and some of its metabolites. Scandinavian Journal of Gastroenterology 16: 693-697. Johns DG, Rutherford LD, Keighton PC et al (1972) Secretion of methotrexate into human milk. American Journal of Obstetrics and Gynecology 112: 978-980. Kahn A K A & Truelove SC (1979) Placental and mammary transfer of sulphasalazine. British Medical Journal 2: 1553. Krauer B & Krauer F (1983) Drug kinetics in pregnancy. In Gilbaldi M & Prescott L (eds) Handbook of Clinical Pharmacokinetics, pp 1-17. Sydney: Adis Press. Kwan KC, Duggan DE, Van Arman E G et al (1978) Sulindac: chemistry pharmacology and pharmacokinetics. European Journal of Rheumatology and Inflammation 1: 9-11. Larsson KS & Eriksson M (1966) Salicylate-induced fetal death and malformations in two mouse strains. Acta Paediatrica Scandinavica 55: 569-572. Leffier CW, Tyler TL & Cassin S (1978) Effect of indomethacin on pulmonary vasculature response to ventilation of fetal goats. American Journal of Physiology 234: 346-351. Levin DL et al (1978) Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors. Journal of Pediatrics 92: 478-483.
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Levin DL et al (1979) Haemodynamic pulmonary vasculature and myocardial abnormalities secondary to pharmacologic constriction of fetal ductus arteriosus: a possible mechanism for persistent pulmonary hypertension and transient tricuspid insufficiency in the new born infant. Circulation 60: 360-364. Levy G (1975) Salicylate pharmacokinetics in the human neonate. In Morselli PL, Garattini F, Sereni F (eds) Basic and Therapeutic Aspects of Perinatal Pharmacology, pp 319-330. New York: Raven Press. Levy G (1978) Clinical pharmacokinetics of aspirin. Pediatrics 62: 867. Levy G, Garretson LK & Soda DM (1975) Evidence of placental transfer of acetaminophen. Pediatrics 55: 895. Lewis RB & Shulman JD (1973) Influence of acetylsalicylic acid, an inhibitor of prostaglandin synthesis, on the duration of human gestation and labour. Lancet i: 1159-1161. Lyle WH (1978) Penicillamine in pregnancy. Lancet i: 606-607. McKenzie SA, Selley JA & Agnew JE (1975) Secretion of prednisone into breast milk. Archives of Disease in Childhood 50: 894-896. Manchester D, Margolis HS & Sheldon RE (1976) Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. American Journal of Obstetrics and Gynecology 126: 467469. Mangurten HH & Benawra R (1980) Neonatal codeine withdrawal in infants of non-addicted mothers. Pediatrics 65: 159-160. Mendenhall HW (1970) Serum protein concentrations in pregnancy. 1. Concentration in maternal serum. American Journal of Obstetrics and Gynecology 106: 388. Merland R & Creste M (1954) Study of the elimination and estimation of Nivaquin in human milk. Bulletin of Tropical Diseases 49: 363. Midorikawa O, Kyo J, Adachi T et al (1972) Teratological studies of CGP45840 in mice and rats. Clinical Report Journal 6: 41-49. Mogadam M, Dobbins WO, Korelitz BIet al (1981) Pregnancy in inflammatory bowel disease: effects of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 80: 72-76. Nation RL, Hacket LP, Dusci LJ et al (1984) Excretion of hydroxychloroquine in human milk. British Journal of Clinical Pharmacology 17: 368-369. Needs CJ & Brooks PM (1985a) Anti-rheumatic medication during lactation. British Journal of Rheumatology 24: 291-297. Needs CJ & Brooks PM (1985b) Antirheumatic medication in pregnancy. British Journal of Rheumato/ogy 24: 282-290. Neill WA et al (1973) Action of chloroquine phosphate in rheumatoid arthritis. II. Chromosome damaging effect. Annals of the Rheumatic Diseases 32: 547-550. Nelson NM & Forfan JO (1971) Association between drug administration during pregnancy and congenital abnormalities of the fetus. British Medical Journal 1: 523. Newman NM & Correy JF (1983) Possible teratogenicity of sulphasatazine. Medical Journal of Australia 1: 528-529. Nicholson HO (1968) Cytotoxic drugs in pregnancy. British Journal of Obstetrics and Gynaecology 75: 301, O'Brien WM & Bagby GF (1985) Rare adverse reactions to non-steroidal anti-inflammatory drugs. Journal of Rheumatology 12: 347-353. Osman MA, Patel RB, Schuna A, Sundstrom WR & Welling PG (1983) Reduction of oral penicillamine absorption by food, antacid and ferrous sulphate. Clinical Pharmacology and Therapeutics 33: 465-470. gOstensen M (1983) Piroxicamin human breast milk. EuropeanJournalofClinicalPharmacology 25: 829-830. Ostensen M & Husby G (1985) Antirheumatic drug treatment during pregnancy and lactation. Scandinavian Journal of Rheumatology 14: 1-7. Ostensen M, Skavdal K, Myklebust G e t al (1986) Excretion of gold in human breast milk. European Journal of Clinical Pharmacology 31: 261. fOstensen M, Matheson I & Laufen H (1988) Piroxicam in breast milk after long term treatment. European Journal of Clinical Pharmacology 35: 567-569. Parke AL (1988) Anti-malarial drugs. Systemic lupus erythematosus and pregnancy. Journal of Rheumatology 15: 607-610. Pinotti M (1959) General considerations of the plan of campaign against malaria in Brazilian Amazonia with chloroquine-salt technique. Review of Parasitology 20: 345.
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Popert AJ (1962) Pregnancy and adrenocortical hormones, some aspects of their interactions in rheumatic disease. British Medical Journal 1: 967. Pritchard JA (1955) Plasma cholinesterase activity in normal pregnancy and in eclamptogenic toxemias. American Journal of Obstetrics and Gynecology 70" 1083. Pritchard JA (1965) Changes in the blood volume during pregnancy and delivery. Anesthesiology 26: 293. Richards AJ (1977) Transfer of gold from mother to foetus. Lancet i: 99. Robertson RT, Allen HL & Bokelman DL (1978) Aspirin: teratogenic evaluation in the dog. Teratology 20" 313-318. Rocker I & Henderson MJH (1976) Transfer of gold from mother to foetus. Lancet ii: 1246. Rosa FW (1986) Teratogen update: penicillamine. TeratoIogy 33: 127-131. Rubin A et al (1984) A profile of the physiological disposition and gastrointestinal effects of fenoprofen in man. Current Medical Research and Opinion 2: 529-544. Rudolph AM (1981) The effects of non-steroidal anti-inflammatory drugs on fetal circulation and pulmonary function. Obstetrics and Gynecology 58 (supplement): 63-67. Rumack CM, Guggenheim MA & Rumack BH (1981) Neonatal intracranial haemorrhage and maternal use of aspirin. Obstetrics and Gynecology 52 (supplement): 52-56. Saxen I (1975) Association between oral clefts and drugs taken during pregnancy. International Journal of Epidemiology 4: 37-46. Schlesinger M & Mark R (1964) Corticosteroid-induced cleft palate. Science 143: 965. Sharp GL, Thalme B & Larsson KS (1974) Studies on the closure of the ductus arteriosus. XI. Ductal closure in utero by a prostaglandin synthetase inhibitor. Prostaglandins 8: 363365. Sharp GL, Larsson KS & Thalme B (1975) Studies on the closure of the ductus arteriosus. XII. In vitro effect of indomethacin and sodium salicylate in rats and rabbits. Prostaglandins9: 585-587. Sidhu RK (1987) Corticosteroids in pregnancy. In Hawkins CF (ed.) Drugs and Pregnancy, 2nd edn, pp 166--179. Edinburgh: Churchill Livingstone. Sloane D, Heinonen O, Kaufman DW et al (1987) Aspirin and congenital malformations. Lancet i: 1373. Soares R, Paulini E & Pereina JP (1959) Concentration and elimination of chloroquin by the placental circulation and milk in patients receiving chloroquin salt. Bulletin of Tropical Diseases 56: 412. Soiufi A et al (1982) Recent findings concerning clinically relevant pharmacokinetics of diclofenac sodium. In Kass E (ed.) Voltarin--New Findings, pp 19-30. Vienna: Hans Huber. Sokal JE & Lessman EM (1966) Effects of cancer chemotherapeutic agents on the human fetus. Journal of the American Medical Association 172: 1765-1771. Solomon L, Abrams G, Dinner M e t al (1977) Neonatal abnormalities associated with D-penicillamine treatment during pregnancy. New England Journal of Medicine 296: 54-55. Stern L (1981) In vivo assessment of the teratogenic potential of drugs in humans. Obstetrics and Gynecology 58 (supplement): 3-8. Szabo KT, Difebb ME & Phelan DG (1978) The effects of gold-containing compounds on pregnant rabbits and their fetuses. Veterinary Pathology 15: 95-98. Townsend RJ et al (1984) Excretion of ibuprofen in breast milk. American Journal of Obstetrics and Gynecology 149: 184-185. Tuchmann-Duplessis H (1975) Drug Effects on the Foetus. A Survey of the Mechanisms and Effects of Drugs on Embryogenesis and Foetogenesis, pp 219-221. New York: Adis Press. Turner G & Collins E (1975) Fetal effects of regular salicylate ingestion in pregnancy. Lancet ii" 338--340. Tyson HK (1974) Neonatal withdrawal symptoms associated with maternal use of propoxyphene hydrochloride (Darvon). Journal of Pediatrics 85: 684-685. UUberg S, Lindquist NJ & Sjostrand SE (1970) Accumulation of chorioretinotoxic drugs in the fetal eye. Nature 227: 1257-1258. van Winzum C & Verhaest L (1979) Diflunisal. Clinics in Rheumatic Diseases 5: 707-731. Vender RJ & Spiro HW (1982) Inflammatory bowel disease and pregnancy. Journal of Clinical Gastroenterology 4: 231-249. Walshe JM (1977) Pregnancy in Wilson's disease. QuarterlyJournal of Medicine N-$46: 73-83.
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Warkany J & Takacs E (1959) Experimental production of congenital malformations in rats by salicylate poisoning. American Journal of Pathology 35: 315-319. Warrell DW & Taylor R (1968) Outcome for the fetus of mothers receiving prednisone during pregnancy. Lancet i: 117-118. Wiernik PH & Duncan JH (1971) Cyclophosphamide in human milk. Lancet i: 912. Wilkinson AR, Aynsley-Green A & Mitchell MD (1979) Persistent pulmonary hypertension and abnormal prostaglandin E levels in preterm infants after maternal treatment with naproxen. Archives of Disease in Childhood 54: 942-945. Wiquist N, Lundstrom V & Green K (1975) Premature labour and indomethacin. Prostaglandins 10: 515-526. Wiseman EH (1985) Piroxicam and related oxicams. In Rainsford KD (ed.) Anti-inflammatory andAnti-rheumatic Drugs, vol. 2, pp 218-219. Boca Raton, FL: CRC Press. Yackel DB, Kempers RD & McConahey WM (1966) Adrenocorticosteroid therapy in pregnancy. American Journal of Obstetrics and Gynecology 96" 985-989. Zuckerman H, Reiss V & Rubinstein I (1974) Inhibition of human premature labour by indomethacin. Obstetrics and Gynecology 44: 787-789.
Antirheumatic drugs in pregnancy and lactation P E T E R M. B R O O K S C H R I S T O P H E R J. N E E D S
Some of the rheumatic diseases, such as rheumatoid arthritis, have their peak age of onset in women during the child bearing years. With improvements in treatment of more serious rheumatic diseases, such as systemic lupus erythematosus, pregnancy is becoming a viable option and there is a need to appreciate the impact of antirheumatic medication on the mother and the fetus or neonate during pregnancy and lactation. The use of antirheumatic drugs during pregnancy and the puerperium has been extensively reviewed (Needs and Brooks, 1985a, 1985b; Brooks and Needs, 1989). Although pregnancy itself might modify the activity of inflammatory rheumatic diseases, there are still patients who need to take slow-acting antirheumatic drugs or non-steroidal anti-inflammatory drugs (NSAIDs) during pregnancy and lactation. Some of these women will have been taking these drugs before becoming pregnant and the issue of how long a person should be removed from these treatments before attempting to conceive also needs to be addressed. Most women have a particular and proper aversion to taking any drug during pregnancy, especially during the first 12 weeks, and appropriate counselling needs to be provided. Although it is important that drug therapy be kept to a minimum during pregnancy, as well as while breast feeding, it is important that the rheumatic disease itself is not allowed to become active, as this might significantly compromise the mother's ability to care for the child once it is delivered. Since there is a dearth of clinical experience with antirheumatic medications during pregnancy and lactation, recommendations regarding their use are often based on theoretical grounds. Teratogenicity studies carried out in animals are not infallible and significant interspecies variation in response might lead to false assumptions of human safety (Stern, 1981). Other factors need to be considered, such as the long lead time from in utero exposure to drug before side-effects are noted, as observed with diethyl stilboestrol exposure being associated with the occurrence of vaginal adenocarcinoma up to 20 years later (Herbst et al, 1971). When considering the use of any medication during pregnancy and lactation a number of issues need to be considered. During pregnancy, there is not only the question of teratogenicity early in gestation but also the potential for alterations in maternal and fetal physiology produced by the Bailli&e's Clinical Rheumatology--
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drug. This is often relevant during the last trimester and, in particular, during delivery. During breast feeding it is important to ascertain whether the parent drug or its metabolites (particularly if they are active) are present in breast milk and whether the infant will be able to absorb sufficient quantities to produce an effect. If inactive metabolites are present in significant quantities, then it is important to know whether the infant will be able to release the active drug from the metabolite and what adverse reactions might be expected to occur in the baby. PHYSIOLOGICAL CONSIDERATIONS OF PREGNANCY The major physiological changes occurring during pregnancy are outlined in Table 1. Maternal pharmacokinetics might be significantly influenced by these changes but much of the information regarding pharmacokinetics in pregnancy is derived from studies based on small numbers of maternal blood samples and good data have been difficult to obtain in this area. During pregnancy, hormonal changes might affect gastric and small intestinal motility and alter the rate of absorption of drugs taken by mouth. Acid production from the stomach is reduced and there is an increase in mucus formation as part of normal pregnancy (Gryboski and Spiro, 1958). Although gastric emptying time is reduced during pregnancy (Davison et al, 1970), this is unlikely to have a significant affect on antirheumatic drugs. However, many women might also take antacids or iron supplements during pregnancy and these can certainly influence the absorption of NSAIDs (Day et al, 1984) or D-penicillamine (Osman et al, 1983). The maternal blood volume increases by up to 45% during pregnancy, with most of this increase occurring during the second trimester (Pritchard, 1965). There are also increases in both plasma volume and in the number of red cells, which contribute to a reduction of serum albumin concentration by about 25 % towards the end of the third trimester (Mendenhall, 1970). From a pharmacokinetic point of view, this will lead to a reduction in the binding capacity of a given volume of plasma and an increase in the apparent volume of distribution of a drug (Levy, 1975). Although this might be considered important for highly protein-bound drugs such as NSAIDs, because the action of a drug is primarily determined by the free concentration and this does not alter significantly unless metabolic or excretory pathways are also impaired, protein binding changes have little clinical relevance. In a study of Maternal physiological changes duringpregnancy.
Table 1.
Delayed gastricemptying Reduced gastricacid production Increased blood volume Reduced serum albumin Enhanced hepaticmetabolism Cholestasis Increased renal blood flow
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salicylate pharmacokinetics during pregnancy, Levy (1975) demonstrated increased protein binding of salicylate (84.4%) in neonatal plasma compared with maternal plasma (78%), suggesting that the fetus might be exposed to higher concentrations of salicylate. During pregnancy, a number of metabolic pathways in the liver are enhanced and this has the potential to alter kinetics of drugs metabolized by this organ (Christiansen et al, 1977). Since serum cholinesterase activity decreases during pregnancy (Pritchard, 1955), there is the potential for alteration of methylprednisolone and aspirin metabolism. Cholestasis might occur as a consequence of pregnancy, and drugs excreted in the bile, such as indomethacin, sulphasalazine and sulindac, might be retained. During early pregnancy there is increase in renal blood flow and, since creatinine clearance increases as well, it might be expected that those medications primarily excreted by the kidney would be cleared more rapidly in pregnant patients. Although this is a theoretical problem, there is little data to support it in practice (Krauer and Krauer, 1983). Although the drugs are given to the mother, the fetus will also receive the drug through the maternofetal circulation. Fetal exposure to the drug will depend on the rate of uptake of the drug by the mother and on maternal metabolism and excretion, as well as transfer across to the placenta. The drug distribution in the mother and the fetus, as well as the rate of elimination of the drug by the fetus itself, needs to be considered (Levy, 1975). Changes in maternal pharmacokinetics during pregnancy must also take into account placental transfer and possible metabolism by the fetus, drug distribution, metabolism and elimination, in addition to the normal factors which influence pharmacokinetics. There are many pharmacokinetic models devised to study and predict fetal exposure and these have been reviewed by Krauer and Krauer (1983).
ANALGESIC AGENTS Paracetamol is the most commonly prescribed pure analgesic agent and crosses the placenta relatively easily (Levy et al, 1975). There have been a number of relatively large studies of maternal and child exposure which do not suggest that paracetamol is associated with fetal malformations (Heinonen et al, 1977; Aselton et al, 1985). There is no evidence that codeine is associated with fetal malformations (Heinonen et al, 1977) but if the mother is exposed to significant amounts late in pregnancy, there can be some drug withdrawal symptoms occurring in the neonate (Mangurten and Benawra, 1980). Although anecdotal case reports have linked the ingestion of propoxyphene with fetal malformations (Barrow and Souder, 1971; Golden et al, 1982), the Collaborative Perinatal Project (Heinonen et al, 1977) failed to demonstrate any clear link with propoxyphene ingestion, although neonatal withdrawal syndromes have again been reported (Tyson, 1974). Although codeine is soluble in lipids and might concentrate in breast milk, it is considered by the American Academy of Pediatrics to be compatible
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with breast feeding. Similarly, paracetamol is excreted in small amounts in breast milk but is a safe analgesic to use for nursing mothers (Bitzen et al, 1981). NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
Since prostaglandins play a major role in fetal development, it is important to appreciate the impact that cyclo-oxygenase inhibitors might have on fetal physiology. Prostaglandin E2 produces relaxation of systemic and pulmonary vessels, as well as the ductus arteriosus, in some animals and in man (Cassin et al, 1975). NSAIDs, including salicylates, indomethacin and naproxen, have been used therapeutically to close a patent ductus arteriosus (Sharp et al, 1974, 1975). The circulation within other organs might be influenced by locally produced prostaglandins and, again, are subject to the influence of NSAIDs. Aspirin has been shown to increase pulmonary artery pressure without any change in aortic pressure and to potentiate hypoxia-induced renal vasospasm (Rudolph, 1981). The slow phase of pulmonary vascular dilatation which occurs during ventilation is inhibited by indomethacin (Leffler et al, 1978) and fetal lambs given indomethacin on a chronic basis have been shown to have increased amounts of pulmonary arterial wall smooth muscle, presumably the result of sustained elevation in pulmonary artery pressure (Levin et al, 1979). This increase in smooth muscle within pulmonary arterial walls has also been described in the offspring of mothers taking other NSAIDs (Levin et al, 1978). These fetal effects are a major reason for restricting NSAID use, particularly during the third trimester of pregnancy. Salicylates
Up to 65% of women have been reported as taking aspirin or salicylatecontaining compound analgesics at some stage during their pregnancy (Hill, 1973; Corby, 1978). Whether aspirin use during pregnancy is associated with fetal abnormalities is still a matter for conjecture. Animal studies using at least five times the normal human aspirin dose have demonstrated a variety of skeletal craniovertebral abnormalities in rats, mice and dogs (Warkany and Takacs, 1959; Larsson and Eriksson, 1966; Robertson et al, 1978). Although several retrospective studies in humans indicate that mothers of malformed infants take more aspirin during pregnancy than control mothers (Nelson and Forfan, 1971; Saxen, 1975; Crombie et al, 1976), more recent prospective studies have failed to demonstrate any increased incidence of fetal malformations with maternal aspirin ingestion during pregnancy (Buckfield, 1973; Turner and Collins, 1975; Sloane et al, 1976). On the strength of these studies, there would seem little reason to restrict aspirin use during pregnancy on the basis of potential teratogenicity. Rats exposed to aspirin in utero have been shown to have certain learning difficulties (Butcher et al, 1972), but whether this occurs in man is not known. Turner and Collins have shown that chronic aspirin ingestion during
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pregnancy is associated with a higher incidence of stillbirths and a lower mean birth weight, even after correction for gestational age and maternal smoking. However, Sloane et al (1976) were unable to demonstrate any changes in birth weight patterns associated with salicylate use, and it has been suggested that other factors such as the ingestion of pure analgesic agents (for example, caffeine, phenacetin and paracetamol) might be operating to reduce infant birth weight (Collins, 1981). Maternal aspirin ingestion in the week prior to delivery is associated with the increased risk of intracranial haemorrhage in premature infants (Rumack et al, 1981). Lewis and Shulman (1973) have demonstrated that regular aspirin ingestion in patients with rheumatic diseases increases the period of gestation, prolongs labour and increases blood loss at delivery. These effects of salicylates are produced by inhibition of prostaglandin production necessary for uterine contraction and for platelet aggregation. The effect of aspirin on birth weight might also be due to other factors such as cigarette smoking, alcohol and caffeine abuse. There is, however, little doubt that chronic aspirin use might prolong gestation, increase the length of labour and increase the risk of pre- and postpartum haemorrhage, as well as predisposing premature infants to intracranial haemorrhage. On present data there is little evidence to associate aspirin or salicylate ingestion with teratogenic effects or an increased risk of stillbirth. As with other NSAIDs, there is the theoretical concern that primary pulmonary hypertension may be associated with its use. Following ingestion of between 450 and 650 mg aspirin, up to 21% of the maternal dose is available in breast milk over a 24-h period (Berlin et al, 1980; Findlay et al, 1981). Levy (1978) has demonstrated that infants have the ability to cleave salicyl phenolic glucuronide and absorb the free salicylic acid. Peak salicylate concentrations are found in breast milk some 2 h after peak maternal serum concentrations (Findlay et al, 1981). No studies have been reported in lactation during chronic high dose salicylate therapy but, from the known dose-dependent kinetics of salicylate, concentrations can be predicted to be higher than in the milk of those mothers taking single doses. Indomethacin and sulindac
Placental transfer of indomethacin occurs rapidly, with similar concentrations in maternal and fetal plasma. Although there are two anecdotal reports of fetal malformations in mothers taking indomethacin (Buckfield, 1973; DiBattista et al, 1975), these were quite unrelated malformations and any influence of indomethacin must be considered tenuous. Indomethacin has been used to treat premature labour by suppressing prostaglandin production. Zuckerman et al (1974) reported that five of 12 infants whose mothers had been treated with indomethaein for premature labour died within 48 h of birth from respiratory distress. On the other hand, Wiquist et al (1975) failed to show any increase in fetal mortality when indomethacin was used in a similar fashion. It is important to appreciate that the respiratory failure might be a reflection of the prematurity itself, rather than the result of possible indomethacin-induced pulmonary hypertension from duct closure in
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utero. However, several recent reports have confirmed the association between pulmonary hypertension and maternal indomethacin ingestion (Manchester et al, 1976), and histological studies have demonstrated increased amounts of smooth muscle in the pulmonary arterial wall of some of these infants. On present evidence it can be said that indomethacin does induce premature closure of the ductus arteriosus and that this might give rise to pulmonary hypertension in susceptible neonates. The enterohepatic recycling of indomethacin and its metabolites makes its use unwise in lactation. In fact, a grand real seizure has been reported in a child being breast fed by a mother ingesting regular indomethacin (EegOlofsson et al, 1978). Sulindac has a long half-life and active metabolites which might be excreted in breast milk. It is therefore not appropriate to prescribe this agent for nursing mothers (Kwan et al, 1978). Teratogenicity studies in rats and mice using high doses of sulindac have failed to demonstrate any problems. There are no reports in the literature linking sulindac with fetal malformations in human beings but, together with other prostaglandin synthetase inhibitors, it might infuence labour and induce closure of a patent ductus arteriosus.
Diflunisal Diflunisal has been shown to be teratogenic in animal studies using significantly higher doses than those recommended for humans (Van Winzum and Verhaest, 1979). Fetal abnormalities have not been reported with diflunisal use in humans. Diflunisal has similar effects to other NSAIDs on parturition and closure of a patent ductus arteriosus. Since diflunisal has a long half-life, it is not as appropriate to use during lactation as NSAIDs with a shorter half-life.
Phenylbutazone Phenylbutazone should now be restricted to the treatment of severe seronegative inflammatory rheumatic diseases and, even then, only when they fail to respond to indomethacin. Since ingestion of phenylbutazone has been associated with significant haematological side-effects (O'Brien and Bagby, 1985), its use in pregnancy or lactation cannot be recommended.
Diclofenac Midorikawa et al (1972) reported minor fetal abnormalities occurring in rats and mice with doses considerably in excess of those found in humans. Recent follow-up studies on mice, rats and rabbits, however, have failed to show any clear evidence of mutagenicity with diclofenac (H. Rothing and P. Graepel, personal communication). There have been no reports of fetal abnormalities in man following ingestion of this drug. Soiufi et al (1982) have demonstrated minor amounts of radioactivity in breast milk after radiolabelled diclofenac administration to lactating rats. The majority of the radioactivity was due to unchanged drug. Diclofenac
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sodium has not been detected in human milk following either single doses of 50 mg or after 1 week of treatment with 100 mg daily. As only a small amount of diclofenac is present in breast milk and the drug has a short half-life of 2 h, with minimal glucuronide formation, it is suitable for use by lactating mothers. It should be remembered, however, that some of the metabolites do have longer half-lives and might be present in breast milk, though again in small quantities. Propionic acid derivatives There is no evidence that ibuprofen, naproxen, fenoprofen or ketoprofen are teratogenic in animals or man. They might, however, delay parturition and have been associated with persistent pulmonary hypertension in preterm infants. A patient who was taking naproxen to suppress labour gave birth to triplets at 30 weeks, all of whom had severe hypoxaemia (Wilkinson et al, 1979). The ductus arteriosus remained closed in these infants and high concentrations of naproxen (60 ~g/ml) were found in neonatal plasma (Wilkinson et al, 1979). Hyponatraemia and fluid retention have also been reported in a neonate following ingestion of 5 g naproxen by the mother 8 h prior to delivery. The infant recovered completely and subsequent development was unimpaired (Alun-Jones and Williams, 1986). On the basis of these reports, care should be taken in using these drugs to suppress labour. Ibuprofen, fenoprofen, flurbiprofen, ketoprofen, naproxen and fenbufen have all been found in small quantities in human breast milk. In a study of 12 patients ingesting 1600 mg ibuprofen over a 24-h period, ibuprofen was not detected in breast milk during the dosing interval (Townsend et al, 1984). This would suggest that, at a maternal dose of 1.6g ibuprofen daily, a nursing infant will receive less than 1 mg ibuprofen per day. Following ingestion of 250 mg naproxen, small amounts of the drug were found in the breast milk, but less than 0.26% of the maternal dose was recovered from the infant, suggesting that the extent of naproxen ingestion from breast milk of mothers on chronic therapy is limited and unlikely to cause significant problems in the infant (Jamali and Stevens, 1983). Fenoprofen and ketoprofen both have short plasma half-lives and limited data on breast milk concentrations of these drugs suggest that they are extremely low (Rubin, 1984). Although they are converted to glucuronide metabolites, they are also acceptable NSAIDs for nursing mothers. Oxicams Along with other NSAIDs, the oxicams have been shown to delay parturition in animals (Wiseman, 1985). Piroxicam and tenoxicam have not been shown to have any teratogenic effects in animals and there are no reports of fetal abnormalities in man. A recent study of piroxicam administration during lactation has shown that the drug appears in breast milk at about 1-3% of maternal plasma concentrations (Ostensen 1983; Ostensen et al, 1988).
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There is good evidence that the antimalarial drugs cross the placenta and accumulate in the fetal tissues, such as the eye (Ullberg et al, 1970). Antimalarial drugs have been shown to induce chromosomal damage in vitro (Neill et al, 1973) but this has not been shown in vivo. Administration of chloroquine phosphate during the first trimester of pregnancy has been associated with sensory neural hearing loss in an infant (Hart and Naunton, 1964). Parke (1988) has recently reviewed pregnancy outcomes in systemic lupus erythematosus (SLE) patients treated with antimalarial drugs. In this survey, six normal babies resulted from 14 pregnancies in eight women with SLE. The high fetal wastage seemed to be related to disease activity rather than to treatment, and there would seem to be no reason for ceasing antimalarial drug therapy during pregnancy in rheumatoid arthritis or SLE if the disease process is controlled. Both hydroxychloroquine and chloroquine are found in small amounts in human milk (Merland and Creste, 1954; Soares et al, 1959). Plasma concentrations achieved in breast-fed infants are not, however, adequate to protect them from malarial infection (Pinotti, 1959). In a study of the secretion of hydroxychloroquine in human breast milk, Nation et al (1984) have shown an M/P (milk:plasma concentration) ratio of 5.5 for hydroxychloroquine and predicted that the infant would be exposed to about 2% of the maternal dose per day. In developing countries, many women continue to feed their infant while taking malarial prophylaxis and adverse reactions are not reported. However, some caution should be taken in patients with chronic rheumatic diseases as considerably higher doses of hydroxychloroquine or chloroquine are taken. GOLD COMPOUNDS Malformations of the central nervous system and the skeleton have been reported in rabbits and rats treated with gold thiomalate (Szabo et al, 1978). Fetal tissues of mothers on gold treatment contain small amounts of the metal (Rocker and Henderson, 1976; Richards, 1977). Gold certainly crosses the placenta, and Cohen et al (1981) have described a normal infant with plasma concentration of gold in the therapeutic range at delivery. Auranofin has also been shown to cross the placenta in both rats and rabbits (Szabo et al, 1978), although no adverse reactions in mothers or infants have been described in 13 rheumatoid arthritis patients continuing to take auranofin treatment throughout pregnancy (Ostensen and Husby, 1985). On the evidence available, there would seem to be no reason for withdrawing gold therapy during pregnancy if it is controlling disease, although an attempt might be made to reduce the dose and frequency of administration. Although trace amounts of aurothioglucose have been detected in breast milk (Blau, 1973; r et al, 1986), it cannot be absorbed by the suckling infant. Auranofin has been demonstrated in breast milk in animals but there are no data available in humans.
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D-PENICILLAMINE Many patients with Wilson's disease and cystinuria have given birth to normal infants, despite large doses of D-penicillamine throughout the pregnancy (Walshe, 1977; Gregory and Mansell, 1983). Endres (1981) has described two infants with active tissue defects similar to Ehlers-Danlos syndrome in association with D-penicillamine and there is at least one report of this condition occurring in an infant of a patient with rheumatoid arthritis similarly treated (Solomon et al, 1977). No adverse effects were reported in mother or offspring in 19 patients treated with D-penicillamine (Lyle, 1978) but a review by Rosa (1986) described five cases of cutis laxa in offspring of mothers treated with b-penicillamine. On this data, Rosa suggests that D-penicillamine should be continued in patients with Wilson's disease as the benefits of treatment outweigh the risks to the fetus. He does, however, suggest a discontinuation of D-penicillamine during pregnancy in conditions where safer alternatives are available. This view is shared by Lyle, who suggests the drug dose be reduced, and ceased if possible, during the pregnancy. No data is available on excretion of D-penicillamine in breast milk. SULPHASALAZINE Although sulphasalazine reduces spermatogenesis it does not alter fertility in females. Sulphasalazine and its metabolites readily cross the placenta and are found in cord blood (Jarnerot et al, 1981). Although Newman and Correy (1983) have described varying congenital defects in three children of two mothers treated with sulphasalazine, there is overwhelming data from mothers with inflammatory bowel disease treated with sulphasalazine during pregnancy who demonstrate no increased incidence of fetal malformations (Mogadam et al, 1981; Vender and Spiro, 1982). Sulphasalazine and sulphapyridine are found in breast milk following a single dose (Kahn and Truelove, 1979) but neither of these compounds are absorbed by the neonate in sufficient quantities to displace bilirubin or cause other problems (Esbjorner et al, 1986). CORTICOSTEROIDS Cleft palate formation has been described in a variety of animals following administration of corticosteroids (Fainstatt, I954; Schlesinger and Mark, 1964). However, it should be remembered that animals show a marked variation in teratogenic responses to corticosteroids (Tuchmann-Duplessis, 1975) and the mouse is particularly prone to developing cleft palate (Sidhu, 1987). Despite the fact that corticosteroids have been given to many thousands of pregnant women for a variety of conditions, only occasional adverse reactions have been reported in offspring. Cleft palate has been reported in association with the administration of large doses of cortico-
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steroids during the first trimester (Bongiovanni and McPadden, 1960). Popert (1962) reported ten patients with a variety of rheumatic diseases treated with corticosteroids during pregnancy and concluded that the drugs were not associated with an increase in maternal or fetal abnormalities in 20 pregnancy outcomes. Although Warrell and Taylor (1968) reported poor pregnancy outcomes in patients taking corticosteroids when compared with controls, Yackel et al (1966) were unable to confirm this. Grigor et al (1977) have shown that corticosteroids produce fetal immaturity when they are used in pregnant women with systemic lupus erythematosus. From the above data it would seem that, though there is a slightly increased risk of cleft palate and interuterine fetal growth retardation in association with high doses of corticosteroids during the first trimester, the risks are small in comparison to the risks of the underlying disease. After a single dose of 5 mg prednisolone, less than 0.23% of the administered dose was found in breast milk (McKenzie et al, 1975). There is no reason why corticosteroids should be withdrawn during breast feeding. CYTOTOXIC AGENTS There is clear evidence that chlorambucil, cyclophosphamide and methotrexate are teratogenic and mutagenic in humans when used during the first trimester of pregnancy (Nicholson, 1968; Barker, 1983). However, normal pregnancies do result from patients taking these drugs. For example, Sokal and Lessman (1966) have described 36 normal children resulting from 50 pregnancies in women exposed to these drugs. Fetal exposure during the first trimester might also lead to bone marrow depression, infection and haemorrhage (Hill and Stern, 1979). There are now an increasing number of normal pregnancy outcomes in women with SLE or renal transplants treated with azathioprine or prednisolone throughout the pregnancy (Hayslett and Lynn, 1980; Fine et al, 1981). However, long-term effects of immunosuppression on the offspring of mothers treated with these drugs during pregnancy have not been established and there is the possibility of chromosome damage and the increased risk of carcinogenesis. From a practical point of view, cytotoxic drugs should be ceased sometime before conception is contemplated, though the optimal timing of pregnancy after these drugs have been discontinued is not yet known. Cyclophosphamide is contraindicated during lactation since large quantities are excreted in human breast milk (Wiernik and Duncan, 1971). Although only small amounts of methotrexate (Johns et al, 1972) and azathioprine (Anderson, 1977) are detected in breast milk, these compounds might accumulate in fetal tissues; their use during lactation should be reduced to a minimum. SUMMARY
The natural inclination of patients with rheumatic diseases wishing to become pregnant or to breast feed will be to take as few medications as
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possible. The guidelines outlined above can be used to balance the risk of drug effect on the fetus or neonate with the risk of inducing a flare in disease activity by stopping the drug. Although there are situations where no information on drug behaviour during pregnancy or lactation exists, some guidelines can be developed from a knowledge of the drug's inherent metabolism. In the majority of the rheumatic diseases, disease activity can be reduced to a minimum using the smallest possible dose of drugs known to be safe in pregnancy and lactation, thus providing minimum risk to mother, fetus and neonate.
Acknowledgements Supported by a grant from the Arthritis Foundation of Australia,
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