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Home , Choanal atresia, Diethylstilbestrol, Drugs in pregnancy, Gray baby syndrome, Griseofulvin, Pregnancy category

23 Drugs to avoid preconceptionally

Vivek Nama and Hassan Shehata

Pharmacologic agents are unnecessary for Though not widely practiced, unfortunately, normal ; however, some women drug regimens prescribed for chronic illness- plan pregnancy with medical conditions that es are best altered preconceptionally. In all require continuing or episodic treatment (e.g. probability, at least 10% of birth defects can asthma, epilepsy and ). More- be attributed to maternal drug exposure in over, during the reproductive years and during pregnancy5. pregnancy, new medical problems may devel- op, and old ones can worsen (e.g. migraine ), to the extent of warranting phar- COUNSELING FOR THE macologic therapy. In addition, many women EXPECTANT MOTHER consume prescribed and/or over-the-counter The expectant mother should be counseled (OTC) during pregnancy1,2. A as to whether to continue or initiate a new comparison of therapeutic drug usage in preg- in an open, supportive and infor- nancy across Europe documented that 64% mative manner. Most conditions that require of women used at least one drug during their medication involve drug exposures at low lev- pregnancy3, while, in France, pregnant women els of relative and absolute risks. The goals of were prescribed an average of five drugs dur- preconception medical management include: ing the first trimester2. In the UK about one- identifying patterns of medication and sup- third of women take pharmacological agents at plement use prior to conception; counseling least once in pregnancy, whereas only 6% take women with chronic conditions about the 4 these agents in the first trimester . Whereas it potential impact of the condition and its vari- is plausible to collect data regarding the usage ous treatments on maternal and fetal health; of medications in the preconception period, establishing effective treatment for chronic it would not be wrong to imagine that such conditions before conception; and counsel- usage is higher than the rates that have been ing women to avoid the use of non-essential documented in pregnancy. medications and OTC medications. Table 1 Preconceptional counseling on the use of describes simple strategies for prescribing medications is of importance, as the con- medication preconception and during preg- sumption of medications is on the rise, new nancy. Factors that affect the action(s) of the products are being marketed directly to the drug should be understood, including the FDA consumer and more prescription medications risk stratification of drug usage in pregnancy have been granted non-prescription status by before prescribing (Table 2) and counseling an the US and Drug Administration (FDA). expectant mother.

321 PRECONCEPTIONAL MEDICINE

Table 1 Useful strategies for prescribing medications in pregnancy and preconception

Avoid multiple medications if possible and choose those that are ‘safe’ (anticonvulsants, antihyperten- sives) and in the smallest dose possible Determine what is the best method to monitor therapy (asthma: peak flow meters; hypertension: por- table blood pressure monitors; : glucometers) The healthiest mother is most likely to deliver the healthiest infant Focus on the underlying disorder, not on the drug alone, to explain any additional risk to the (hy- pertension and fetal growth restriction, seizures and childhood seizures, systemic lupus and fetal growth restriction) Only a few drugs are clearly linked with specific birth defects (, , , , diethystilbestrol, cis retinoic acid, valproic acid, ) Experience with first trimester exposure for any drug is often too limited in humans to be considered ‘safe’

Table 2 US FDA definitions

Category Description A Controlled studies in women fail to show a risk to the fetus in the first trimester, and the possibility of fetal harm appears remote B Animal studies do not indicate a risk to the fetus and there are no controlled human studies, or animal studies do show an on the fetus but well controlled studies in pregnant women have failed to demonstrate a risk to the fetus C Studies have shown the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women D Positive evidence of human fetal risk exists, but benefits in certain (for example, life-threaten- ing or serious for which safer drugs cannot be used or are ineffective) may make use of the drug acceptable despite its risks X Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit

FACTORS AFFECTING THE EFFECT OF during the trial are excluded from such stud- DRUGS DURING PRECONCEPTION ies. Thus, at a drug’s first marketing, except for products developed to treat conditions Safety information data specific to pregnancy such as oxytocics and/ or cervical ripening agents, human data on the The safety and efficacy of drugs at a given dos- proper dosage and frequency of administration age regimen is established by phase 3 clinical during pregnancy seldom exist. All medica- trials, involving numerous and typical repre- tions approved by the FDA must undergo ani- sentatives from the target patient population. mal studies to determine possible teratogenic Pregnant women and those who fall pregnant effects. Doses (per body weight or surface

322 Drugs to avoid preconceptionally area) are often much higher than typically ovum period (fertilization to implantation). In used to determine possible detrimental repro- contrast, the embryonic period (implantation ductive harm. Although such studies may be to 8th week of gestation) involves organogen- helpful, especially if findings indicate no addi- esis and encompasses the most critical time tional risk, their results do not reliably predict with respect to structural malformations. the human response. Whereas specific harmful effects relate to the timing and duration of drug exposure during this relatively brief but critical time of devel- of opment, information in humans is minimal or inconsistent regarding long-term effects, such The physiological changes during pregnancy as learning or behavior problems (functional exert a marked impact on drug pharmacoki- teratogenesis) that may result from chronic netics and hence established therapeutic rang- prenatal exposure to given medications. es might be inappropriate. Pharmacokinetic This chapter provides a quick reference changes during pregnancy include a higher guide for drug use in pregnancy. The drugs volume of distribution, lower maximum plas- listed here are in groups according to how they ma concentration, lower steady serum state appear in the WHO 11th Model List of Essen- concentration, shorter plasma half-life and tial Drugs. A quick reference guide of drugs higher clearance rate. As the essen- contraindicated in pregnancy (category X) is tially acts as a lipid barrier between the mater- listed in Table 3. nal and fetal circulations and drugs cross it by passive diffusion, transfer of drugs to the fetus is unavoidable. In this regard, low molecular ANESTHETICS weight, lipid soluble and unionized drugs cross the placenta more readily than polar drugs. General anesthetics

Intravenous anesthetics induce anesthesia Human teratogenesis rapidly; common examples are thiopentone and propofol, though the latter has not been Teratogenesis is defined as structural or func- used during the first and second trimesters tional dysgenesis of the fetal organs. Typical in humans. Reproduction studies in rats and manifestations include congenital malfor- rabbits at doses six times the recommended mations with varying severity, intrauterine human induction dose revealed no evidence of growth restriction (IUGR), carcinogenesis impaired or fetal harm. and fetal death. Lack of understanding of the Commonly used inhalation anesthetics full and exact mechanisms of teratogenicity include halothane and nitric oxide. Halo- makes it difficult to predict, on pharmacologi- thane can induce , and because cal grounds, that a given drug will produce of its property of relaxing the smooth uter- congenital malformations. Confirmation of ine muscle it increases the risk of postpar- pregnancy and accurate gestational dating are tum hemorrhage. The Collaborative Perinatal critical in determining susceptibilities, and ‘all Project6 showed no embryonic or fetal effects or none’ effect (spontaneous or not) associated with use of nitric oxide. Use during is believed to result from exposure during the ­delivery, however, leads to neonatal

323 PRECONCEPTIONAL MEDICINE and fetal accumulation of nitric oxide, which ANALGESICS, ANTIPYRETICS, NON- increases over time. Therefore it is safer to STEROIDAL ANTI-INFLAMMATORY keep the induction to delivery time as short DRUGS, DRUGS USED TO TREAT GOUT as possible. AND -MODIFYING AGENTS USED IN RHEUMATIC DISORDERS

Neuromuscular blocking agents Non- analgesics, antipyretics and non-steroidal anti-inflammatory drugs These agents are used as adjuncts to anesthet- ics in order to provide muscle relaxation. Based and non-steroidal anti-inflammatory on , they are divided into drugs (NSAIDs) do not produce structural depolarizing and non-depolarizing agents. defects. Salicylates (in analgesic doses) and Succinylcholine is the only depolarizing agent NSAIDs may increase the risk of neonatal commonly used. The Collaborative Perinatal hemorrhage by inhibition of platelet function. Project6 recorded 50,282 mother-child pairs, NSAIDs may also lead to oligohydramnios 26 of whom had first trimester exposure to by their effect on the fetal . The use of succinylcholine. No congenital malformations NSAIDs in the last trimester causes prema- were observed in any of the newborns. ture closure of the ductus arteriosus leading

Table 3 Examples of contraindicated drugs and their known adverse effects on the developing human fetus

Drugs First-trimester fetal effects Second- and third-trimester fetal effects Quinolones Toxic to developing cartilage NSAIDs Cardiac, gastroschisis, , premature ductal closure Methotrexate Miscarriage, cranial anomalies IUGR Immunosuppressants Embryopathy Effect on growth I-131 Fetal development, CNS development Chemotherapeutics Abortion, anomalies Hypoplastic , IUGR Antabuse Congenital malformations ACE inhibitors Cardiac/CNS malformations Oligohydramnios, IUGR, renal failure Retin-A derivatives CNS, cardiac, facial anomalies , mental retardation Otoxicity None known None known Staining of teeth Limb reduction (gastrointestinal/ cardiac/renal defects) Warfarin Skeletal defects CNS defects Microhemorrhages IUGR, intrauterine growth retardation; ACE, angiotensin converting enzyme; CNS, central nervous system

324 Drugs to avoid preconceptionally to neonatal primary hypertension. Both pre- result in an increased frequency of trisomy 21 mature closure of the ductus and the oligohy- in the offspring by causing chromosomal non- dramnios are reversible. If used during preg- dysjunction. If used around conception, fetal nancy, NSAIDs should be discontinued at least karyotyping is recommended. In a couple plan- 6–8 weeks before delivery. ning a pregnancy ingestion by either parent should be discontinued 3 months before conception7. Opioid analgesics

In a surveillance study of Michigan Medicaid Disease-modifying agents of recipients, 375 (4.9%) major birth defects rheumatic disorders were noted (325 expected)7. Specific data were available for six defect categories, including Sulfasalazine (observed/expected) 74/76 cardiovascular defects, 14/13 oral clefts, 4/4 spina bifida, Sulfasalazine and its , , 25/22 polydactyly, 15/13 limb reduction readily cross the placenta to the fetal circula- defects and 14/18 . Only with the tion. No increase in human congenital defects total number of defects is there a suggestion or newborn has been observed from of an association between and con- its use in pregnancy. Milk concentrations are genital defects, but other reasons, including roughly 40–60% of maternal serum levels. maternal disease, concurrent drug use and Bloody in an exclusively breastfed chance may be involved. In an investigation infant was attributed to the mother’s sul- of 1427 malformed newborns compared with fasalazine therapy (3 g/day). Cautious use 3001 controls, first trimester use of narcotic of sulfasalazine is recommended in nursing analgesics (codeine most commonly) is associ- women because of significant adverse effects ated with inguinal hernias, cardiac and circula- in some nursing infants. tory defects, cleft lip and palate, dislocated hip and other musculoskeletal defects. These data serve as a possible warning that indiscriminate use of codeine may present a risk to the fetus. Use of codeine during labor produces neona- Various abnormalities ranging from karyo- tal respiratory depression to the same degree typing abnormalities to multiple structural as other narcotic analgesics. Neonatal codeine anomalies have been described with the use of withdrawal has also been reported8. cyclophosphamide in the first trimester. Use of cyclophosphamide in the second and third Drugs used to treat gout trimesters does not place the fetus at risk for congenital defects. Except in a few individual Colchicine is used to treat the pain of acute cases, long-term studies of growth and men- gouty arthritis attacks and as prophylaxis tal development in offspring exposed to cyclo- for recurrent gout attacks. It is also used in phosphamide during the second trimester, the f­amilial Mediterranean fever, Behcet’s disease period of neuroblast multiplication, have not and amyloidosis. It is embryocidal in mice been conducted. Cyclophosphamide is con- and rabbits, but the risk of teratogenesis in traindicated during because of humans is unknown. It is possible that colchi- a reported case of and because cine given around the time of conception may of the potential adverse effects of immune

325 PRECONCEPTIONAL MEDICINE suppression, fetal growth retardation and possible, and special care should be taken to carcinogenesis. keep doses as low as possible and compatible with seizure prophylaxis. To lower the risk of hemorrhagic disease of the newborn, vitamin ANTICONVULSANTS/ANTIEPILEPTICS K (10–20 mg orally) should be prescribed for all epileptic women on enzyme-inducing drugs Phenytoin, primidone, phenobarbitone, carba- in the last 4 weeks of pregnancy. mazepine and sodium all cross the The traditional anticonvulsants, such as phe- placenta and are teratogenic. The major abnor- nytoin, carbamazepine and valproic acid, are malities produced by anticonvulsants are neu- considered safe for use during breastfeeding; ral tube, orofacial and congenital defects. however, observation for adverse effects such Neural tube defects are mainly caused by sodi- as drowsiness is recommended for women um valproate (1–2%) and carbamazepine (0.5– receiving high doses. The use of phenobarbi- 1%). Orofacial defects are mainly from phenyt- tal with breastfeeding is controversial because oin, which also produces the fetal hydantoin of its slow elimination by the infant. Data are syndrome. The syndrome includes prenatal sparse regarding the long-term effects of new- and postnatal growth restriction, motor or er antiepileptic drugs on cognition and behav- mental deficiency, short nose with broad nasal ior when used in pregnancy and . bridge, microcephaly, hypertelorism, strabis- mus, epicanthus, wide fontanelles, low-set or abnormally formed ears, limb deformities, nail ANTI-INFECTIVE DRUGS and distal phalange hypoplasia, hypospadias, hernia, webbed neck, low hairline, impaired Antihelminthics: intestinal antifilarials, neurodevelopment and low performance antischistosomals and antitrematode drugs scores on tests of intelligence. Phenytoin and sodium valproate also produce heart defects. Mebendazole Primidone produces abnormalities similar to those produced by phenytoin. The risk for any single drug is about 6–7% Mebendazole is a broad spectrum antihelmin- (i.e. two to three times the background lev- thic agent effective in the treatment of ascaria- el). The risk increases with multiple drugs. sis, enterobiasis, trichuriasis and hookworm Patients on two or more anticonvulsants carry disease. It is embryotoxic and teratogenic in a risk of 15%, and for those taking a combina- rats, and is therefore not recommended for use tion of valproate, carbamazepine and phenyto- during pregnancy. in the risk is as high as 50%. The risk of neural tube defects may be decreased with consump- tion of preconceptional and first trimester folic acid at a dose of 5 mg/day, i.e., more than 10 times the recommended dose of 400 μg/ The observation of limb reduction defects at day for normal pregnant woman. Because the all doses in one animal study, potential for newer anticonvulsant drugs such as vigaba- higher plasma concentrations of the metabo- trin, lamotrogine, and gabapentin lite if consumed with a fatty meal, and limited are often prescribed in combination with oth- human pregnancy data all suggest that use of er anticonvulsants, it is difficult to ascertain albendazole during pregnancy is not recom- the teratogenic risk of these agents in isola- mended. Data on the safety of albendazole in tion. Monotherapy should be used wherever breastfeeding are lacking.

326 Drugs to avoid preconceptionally

Praziquantel an increased risk of fetal malformations or musculoskeletal problems. Long-term follow- is not a teratogen in animals, but up is required to exclude subtle cartilage and there are few human data. Recent data indi- bone damage. cate that the agent may be mutagenic and carcinogenic in humans, especially in devel- oping countries where infections of trema- todes and cestodes are frequent and multiple treatment courses may often need to be pre- Except for eighth cranial nerve damage, no scribed. Because of this potential toxicity, the reports of congenital defects caused by strep- use of praziquantel during pregnancy should tomycin have been found. The Collaborative 6 be reserved for those cases in which the para- Perinatal Project monitored 50,282 mother- site is causing clinical illness or public health child pairs, 135 of whom had first trimester problems. exposure to streptomycin. For use any time during pregnancy, 355 exposures were record- ed. In neither group was evidence found to Antibacterials: betalactam drugs, suggest a relationship to large categories of major or minor malformations or to individ- other antibacterials, antileprosy ual defects. have drugs, antituberculosis drugs, no detectable teratogenic risk for structural drugs and antiviral drugs defects. The study also concluded that the risk (antiherpes and antiretroviral) of deafness after in utero aminoglycoside expo- sure was small. Streptomycin is compatible Tetracycline with breastfeeding. Tetracycline is contraindicated during preg- nancy. This broad spectrum crosses the placenta, chelates and is deposited in the developing teeth and of the fetus. Chloramphenicol should be avoided in late The effects on bone are minimal, but discolor- pregnancy and during labor because of the ation of the teeth and enamel hypoplasia can potential for the ‘gray baby syndrome’ in occur from the end of the first trimester. Stain- newborns. The syndrome usually starts 2–9 ing of the permanent teeth is most likely when days after therapy is begun and causes vom- are administered after 24 weeks’ iting, suck refusal, rapid irregular respiration, gestation. abdominal distension followed by flaccidity, an ashen gray color and . About 40% of affected neonates die of circulatory collapse on or about the 5th day. Its use in pregnancy should be confined to life-threatening condi- Quinolone treatment in developing adoles- tions, when no alternative is available. cents of several animal species is associated with acute arthropathy of the weight-bearing joints. A recent study examining the effect of intrauterine exposure to quinolones suggested that the use of ciprofloxacin during the first Nitrofurantoin may be administered in preg- trimester of pregnancy is not associated with nancy, but should be avoided near term. Low

327 PRECONCEPTIONAL MEDICINE levels of glutathione may predispose the fetus to hemolytic if it is exposed to nitrofu- rantoin shortly before birth. Ketoconazole is used in systemic mycoses, serious chronic resistant mucocutaneous can- didiasis, gastrointestinal mycoses, chronic Vancomycin resistant vaginal candidiasis and resistant der- matophyte infections of skin or fingernails. It Vancomycin is a bactericidal antibiotic with a inhibits placental microsomal and fetal ototoxic effect. It acts mainly by inhib- . Although it has been used iting cell wall synthesis and inhibiting RNA in some pregnant women without complica- synthesis in bacterial cytoplasmic membranes. tions, it should be avoided during pregnancy It should be avoided unless benefit outweighs as there is insufficient information to confirm potential risk. its safety.

Trimethoprim Antiprotozoal drugs: antiamebic and antimalarial drugs inhibits the reduction of dihy- drofolate to tetrahydrofolate and readily crosses the placenta appearing in measurable amounts in fetal blood. The use of trimeth­ Most of the published evidence now suggests oprim in pregnancy was associated with an that metronidazole does not present a signifi- approximate quadrupling of the risk of car- cant risk to the fetus. A possible small risk for diovascular defects and/or an oral cleft. Risk cleft lip with or without palate abnormalities was increased with use during the second and has been reported, but the validity and the third months after the last menstrual period clinical significance of this finding is question- but not before or after this time. It is advisable able. Metronidazole is contraindicated during to avoid trimethoprim in the first trimester the first trimester in patients with trichomo- unless benefit outweighs potential risk, and niasis or bacterial vaginosis9. The American administration, if prescribed, must always be College of Obstetricians and Gynecologists accompanied with folic acid. (ACOG) recommends that (orally or intravaginally) be used during the first tri- 9 Antifungal drugs mester for symptomatic bacterial vaginosis . The use of metronidazole for trichomoniasis or vaginosis during the second and third tri- mesters is acceptable, as either a single 2-g oral Griseofulvin is a systemic agent used to treat dose or a 7-day course of 750–1000 mg/day in fungal infections of the skin, hair and nails. divided doses. For other indications, metro- It is a known teratogen in laboratory animals nidazole can be used ­during pregnancy if no and crosses the human placenta. Griseofulvin other alternatives with established safety pro- use is contraindicated during pregnancy, and files are available. In these cases, the patient pregnancy should be avoided for 1 month after should be counseled about the potential risks treatment. Men should not try to father chil- and informed consent obtained before initiat- dren within 6 months of treatment. ing therapy.

328 Drugs to avoid preconceptionally

Chloroquine in combination with and during pregnancy. Ethambutol is A 1985 report10 summarized the results of compatible with breastfeeding. 169 infants exposed in utero to 300 mg of chlo- roquine base once weekly throughout preg- nancy. The control group consisted of 454 ADRENOCORTICAL non-exposed infants. Two study group infants had anomalies (tetralogy of Fallot and con- The adrenal cortex synthesizes two classes genital ) compared with four of steroids: the (glucocorti- in the control group. Based on these data, the coids and mineralocorticoids) having 21 car- authors concluded that chloroquine is not a bon atoms and the which have major teratogen, but a small increase in birth 19. is the main , and defects could not be excluded. The amount of is the main mineralocorticoid. chloroquine excreted into milk is not consid- are administered in multi- ered to be harmful to a nursing infant. ple formulations for disorders that share an inflammatory or immunological basis. Except in patients receiving replacement therapy for Quinine , glucocorticoids are nei- ther specific nor curative, but rather are con- Newer agents have effectively replaced qui- sidered palliative because of their anti-inflam- nine to treat malaria. Although no increased matory and immunosuppressive actions. teratogenic risk can be documented, its use is the biologically active form during pregnancy should be avoided. Quinine of . The placenta can oxidize pred- is compatible with breastfeeding. nisolone to inactive prednisone or even less active cortisone. A study of 229,101 patients exposed to prednisolone, prednisone and Antituberculous drugs methyl-prednisolone during the first trimes- ter failed to show any association between Rifampicin these agents and congenital defects17. When prednisolone was used throughout the preg- No controlled studies have linked the use of nancy, cataracts in the newborn occurred in rifampicin with congenital defects. Several rare instances. At maternal doses of 20 mg, the reviews11–13 have evaluated the available agents infant would be exposed to minimal amounts for treatment of during preg- of . At higher doses, however, mothers nancy. All concluded that rifampicin was not are advised to wait at least 4 hours after a dose a proven teratogen and recommended use of before nursing their infants. the drug with isoniazid and ethambutol if nec- Betamethasone use for therapy of pre- essary. The American Academy of Pediatrics14 term labor is associated with decreases in ­considers rifampicin to be compatible with ­respiratory distress syndrome, periventricular breastfeeding. leukomalacia and intraventricular hemorrhage in preterm infants. However, this drug can precipitate myasthenic crisis in patients with Ethambutol myasthenia gravis, induce hyperglycemia and rarely a hypertensive crisis. Single courses of No congenital defects are linked to ethambu- betamethasone have no effects on the fetus, tol. The literature13,15,16 supports the safety of but multiple courses have been associated

329 PRECONCEPTIONAL MEDICINE with lower birth weights and reduced head as childhood has been noted. The circumference at birth18–20. Follow-up studies information on breastfeeding while taking aza- have not shown any differences in cognitive thioprine is without consensus. Despite little and pscychosocial development when com- or no drug being found in milk, most pared with controls21–23. Hydrocortisone and rheumatologists advise avoidance of azathio- its inactive precursor cortisone present small prine if possible, or counsel against breast- risks to the human fetus. These corticoste- feeding because of theoretical risks of immune roids produce dose-related teratogenic and suppression of the neonate. toxic effects in genetically susceptible experi- mental animals, which consist of cleft palate, cataracts, spontaneous abortion, IUGR and Cyclosporine polycystic kidney disease. Although extensive data24,25 support no Based on relatively small numbers, the use of adverse effects in the vast majority of human cyclosporine during pregnancy apparently does , adverse outcomes have been not pose a major risk to the fetus. No pattern observed and may have been caused by cor- of defects has emerged in the few newborns ticosteroids. Moreover, the decrease in birth with anomalies. Skeletal defects, other than a weight and a small increase in the incidence single case of osseous malformation, have not of cleft lip with or without cleft palate are sup- been observed. The disease process per se for ported by large epidemiologic studies. Because which cyclosporine is indicated makes these benefits of corticosteroids far outweigh fetal pregnancies high risk and subject to numer- risks, these agents should not be withheld if ous potential problems, of which the most the mother’s condition necessitates their use. common is growth retardation, and this is The mother, however, should be informed of probably more closely related to the mother’s the risks, so she can actively participate in the disease rather than to her drug therapy. None- decision regarding whether to use these agents theless, a contribution from cyclosporine and during her pregnancy. corticosteroids cannot be excluded. Cyclospo- rine is contraindicated during breastfeeding due to its potential for immune suppression IMMUNOSUPPRESSIVE DRUGS and neutropenia, unknown effect on growth, and possible association with carcinogenesis.

Azathioprine is a 6-mercaptopurine deriva- CYTOTOXIC DRUGS tive which acts as a ‘steroid-sparing’ agent, suppressing cell-mediated hypersensitiv- These drugs exert their effects mainly on rap­ ity and altering production. Use of idly dividing cells, and hence are most dan- azathioprine in pregnant patients with renal gerous at the stage of organogenesis. The transplant, systemic lupus erythematosus and alkylating agents cyclophosphamide and inflammatory bowel disease is extensive. Cur- chlorambucil, and the folic acid antagonist rent evidence indicates that maternal use of methotrexate all are teratogenic and all are azathioprine is not associated with an increased contraindicated in pregnancy. The risk of con- risk of impaired fetal immunity, growth retar- genital abnormalities in cyclophosphamide- dation and prematurity. In children followed exposed children ranges between 16 and for up to 20 years, no increase in congenital 22%, but its use may be contemplated later abnormalities or subsequent problems such in pregnancy if the mother’s disease is life

330 Drugs to avoid preconceptionally threatening. Methotrexate should be discon- developmental delay. -exposed tinued at least 3 months prior to conception older children had well developed social com- and folic acid (5 mg) supplementation given petence, favorable global IQ scores but exhib- preconceptionally10. ited problems with reading comprehension, written language and arithmetic, a picture reminiscent of the non-verbal learning dis- CARDIOVASCULAR DRUGS ability syndrome28. In another report, normal psychomotor development was observed in Antiangina drugs two patients with full-scale IQ score, and ver- bal and performance IQ scores within normal Nitroglycerin range. However, these data need validation by larger studies. In conclusion, drug therapy of The use of nitroglycerin during pregnancy cardiovascular rhythm disorders should be does not appear to present a risk to the fetus. avoided during the first trimester of pregnancy However, the number of women treated dur- if possible, and drugs with the longest record ing pregnancy is limited, especially during the of safety should be used as first-line therapy. first trimester. With the smaller doses report- Conservative therapies should be used when appropriate. ed, transient decreases in the mother’s blood pressure may occur, but these do not appear to be sufficient to jeopardize placental perfu- Digoxin sion. Nitroglycerin appears to be a safe, effec- tive, rapid-onset, short-acting tocolytic agent. Of 229,101 completed pregnancies studied The use of transdermal nitroglycerin patches between 1985 and 1992, 34 newborns were is also effective when longer periods of tocoly- exposed to digoxin during the first trimester17. sis are required. One (2.9%) major was observed (one expected), an oral cleft. Although the number of exposures is small, these data are Antiarrhythmic drugs supportive of previous experience for a lack of association between the drug and con- Amiodarone genital defects. Digoxin is compatible with breastfeeding. Amiodarone is an iodine-rich antiarrhythmic drug with proven benefit in the treatment of patients with ventricular and atrial arrhyth- ANTIHYPERTENSIVE DRUGS mias. It can reach the fetus by transplacental passage and induce fetal hypothyroidism. It Beta-adrenergic antagonists inhibits the conversion of thyroxine to triiodo- thyronine in most tissues. It may also inhibit Beta-adrenergic antagonists have fewer side- thyroid synthesis and , caus- effects than most antihypertensives, but their ing hypothyroidism in 5–25% of patients26. safety in pregnancy is not so well established. Transplacental exposure to amiodarone may Some studies found no adverse effects on the be associated with neurotoxicty. When com- outcome of pregnancy, while others described pared with controls, amiodarone-exposed a variety of fetal and neonatal complications29. toddlers showed expressive language skills The major concern is that if these drugs are relatively poorer than their verbal skills27. One used before 28 weeks’ gestation, they may amiodarone-exposed toddler exhibited global increase the risk of IUGR. Later complications

331 PRECONCEPTIONAL MEDICINE include , , hypoglyce- disorders, but causal relationships cannot be mia and respiratory distress. However, many inferred from these data without independent studies suggest that they are safe antihyper- confirmation. Bendroflumethiazide, chlorthal- tensives for use in the third trimester. If treat- idone, chlorothiazide and hydrochlorothiazide ment of hypertension is required before 28 are compatible with breastfeeding weeks, methyldopa should be the first drug of is a competitive antagonist of choice. aldosterone at receptor sites in the distal renal tubules, causing a moderate and water diuresis with reduced loss of potassium and Angiotensin converting enzyme inhibitors hydrogen. Spironolactone also exhibits antian- drogenic effects, probably through competitive This group of drugs are orally active inhibitors inhibition at the level of , dihy- of angiotensin converting enzyme, which is drotestosterone and recep- responsible for conversion of inactive angio- tors. These properties underlie its successful tensin I to the potent pressor peptide angioten- use in the treatment of idiopathic . sin II. These drugs have been associated with These antiandrogenic effects were observed in prolonged renal failure and hypotension in the spironolocatone-exposed male animal newborn30, decreased skull ossification, hypo- born with anomalies of external genitalia31. calvaria and renal tubular dysgenesis. In addi- Its use in pregnancy is contraindicated, and if tion, there are several case reports of IUGR, diuretics are necessary another agent is prefer- oligohydramnios, patent ductus arteriosus and able. It is also used for the treatment of hyper- neonatal hypotension. The use of these drugs aldosteronism, where amiloride or potassium in the first trimester is not thought to produce supplements may be alternatives in pregnancy. structural malformations, so it is acceptable to cease treatment early in pregnancy and not necessarily preconception. ANTITHROMBOTIC DRUGS

Warfarin Loop diuretics (furosemide) Warfarin is a form of coumarin with vitamin K There is an association between use of furo- antagonist action. Its use in pregnancy is asso- semide in the first trimester and hypospadias. ciated with a high incidence of fetal loss, con- Furosemide is considered safe in breastfeed- genital malformations and physical disability. ing. Its use is not recommended in the treat- Exposure to the drug between the 6th and 9th ment of pre-eclampsia due to intravascular weeks of gestation is associated with defective volume depletion. ossification of bone resulting in nasal hypo- plasia and chondrodysplasia punctata. On a molecular level, vitamin K inhibitors may alter Thiazide diuretics calcium binding for several , affecting bone ossification and causing the characteris- Use of thiazides and related diuretics in the tic bony abnormalities of the ‘fetal warfarin’ first trimester does not indicate that these syndrome. The syndrome constitutes skeletal agents are teratogenic. However, the Collabor- defects (nasal hypoplasia and stippled epiphy- ative Perinatal Project6 found an increased risk ses), limb hypoplasia (particularly distal dig- of defects when diuretics were used during the its), low birth weight (<10th centile), hear- first trimester in women with cardiovascular ing loss and ophthalmic anomalies. The use of

332 Drugs to avoid preconceptionally warfarin in the second and third trimester is early pregnancy does not appear to present a associated with serious complications, mainly significant fetal risk. The outcomes reported central nervous system abnormalities thought are within those expected in a non-exposed to be due to brain microhemorrhages. The population. However, because the interrup- defects include dorsal midline dysplasia (agen- tion of -lowering therapy during esis of corpus callosum and Dandy-Walker pregnancy should have no apparent effect on malformations) or ventral midline dysplasia the long-term treatment of hyperlipidemia, (optic atrophy), mental retardation, delayed should not be used during preg- development, seizures and microcephaly. The nancy. Women taking this agent before con- risk of teratogenicity with warfarin led to the ception should ideally stop the therapy before recommendation that be substituted becoming pregnant and certainly on recogni- for the treatment and prophylaxis of venous tion of pregnancy. Accidental use of the drug thromboembolism. However, heparin is not during gestation, though, apparently has no as effective as warfarin in preventing arte- known consequences for the fetus. Because of rial thromboembolism in women with artifi- the potential for adverse effects in the nurs- cial heart valves or mitral disease with arte- ing infant, the drug should not be used during rial fibrillation. In these situations, the risk of may exceed the risks of warfarin lactation. use, and warfarin therefore may be indicated. It should, however, be used with great caution and close monitoring of both the mother and AND OTHER ENDOCRINE fetus. DRUGS AND CONTRACEPTIVES

Androgens Heparin Heparin is the of choice from the fetal perspective, as it does not cross the Danazol is a testosterone derivative and a weak placenta. Two major side-effects that can occur , used for the treatment of endo- with heparin treatment are heparin-induced metriosis, menstrual disturbances, immune and osteoporosis. Two thrombocytopenic purpura, classic hemo- types of thrombocytopenia occur with heparin philia, Christmas disease and α1 antitrypsin treatment. Non-immune heparin-associated deficiency. Reports suggest virilization of the thrombocytopenia is associated with a mild external genitalia of fetuses exposed reduction in platelet counts and occurs 2–5 to the drug during pregnancy producing fused days after heparin . Immune throm- labia and clitoral hypertrophy32. It should be bocytopenia, on the other hand, occurs due avoided in pregnancy. to IgG antiplatelet , occurring 3–4 weeks after therapy and increasing the risk of formation. Hormonal contraceptives

LIPID-LOWERING AGENTS Because oral contraceptives are primarily com- bination products, it is difficult to separate Simvastatin entirely the fetal effects of the contained pro- gestogens and . Except for the modi- Based on the animal data and limited human fied development of sexual organs, no firm evi- experience, exposure to simvastatin during dence has appeared that establishes a causal

333 PRECONCEPTIONAL MEDICINE relationship between oral contraceptives and and mortality in developing countries where various congenital anomalies. The acronym the proper use of is problematic, as VACTERL (vertebral, anal, cardiac, tracheal, insulin is still the treatment of choice for this esophageal, renal or radial, and limb) was disease. Moreover, insulin, unlike metformin, used initially to describe fetal malformations does not cross the placenta and, thus, elimi- produced by oral contraceptives or the related nates the additional concern that the drug hormonal pregnancy test preparations (no lon- therapy itself is adversely affecting the fetus. ger available in the US). The Population Coun- Carefully prescribed insulin therapy provides cil33 estimates that, even if the study findings better control of the mother’s blood glucose, for VACTERL malformations are accurate, thereby preventing fetal and neonatal compli- such abnormalities occur in only 0.07% of cations. High maternal glucose levels, as may pregnancies exposed to oral contraceptives. occur in un- or poorly treated diabetes mel- Some later reviewers34 have concluded that the litus, are closely associated with a number of risk to the fetus for non-genital malformations maternal and fetal adverse effects, including after in utero exposure to these agents is small, fetal structural anomalies if the hyperglyce- if indeed it exists at all. mia occurs early in gestation. To prevent this, In contrast, the effect of estrogens and some most experts, including ACOG, recommend synthetic on the development of that insulin be used for types I and II diabe- the sexual organs is well established. Mascu- tes occurring during pregnancy and, if diet linization of the female infant has been asso- therapy alone is not successful, for gestational ciated with norethindrone, norethynodrel, diabetes. hydroxyprogesterone, medroxyprogesterone and . The incidence of mas- culinization of female infants exposed to syn- THYROID HORMONE AND thetic progestogens is approximately 0.3%. OTHER ANTITHYROID DRUGS Pseudohermaphroditism in the male infant is not a problem, because of the low doses of Propylthiouracil employed in oral contraceptives. Of 229,101 completed pregnancies between 1985 and 1992, 35 newborns were exposed Progestogens to propylthiouracil (PTU) during the first tri- mester17. One (2.9%) major birth defect was Although many of the progestagens used as observed (one expected), a case of hypospa- contraceptive agents, such as dias (none expected). A 1992 study reported and , are 19-nortestosterone the retrospective evaluation of hyperthy- derivatives and have mild androgenic proper- roid pregnancy outcomes treated with either ties with a potential to produce virilization of a PTU (n = 99) or methimazole (n = 36)36. ­female fetus35, they are unlikely to do so owing Three (3.0%) defects were observed in those to the small amounts present. exposed to PTU (ventricular septal defect, pul- monary stenosis, patent ductus arteriosus in a term infant), whereas one newborn (2.8%) INSULIN AND OTHER had a defect (inguinal hernia) in the methima- ANTIDIABETIC AGENTS zole group. No scalp defects were observed. In comparison with other antithyroid drugs, Metformin may be beneficial for decreasing the PTU is considered the drug of choice for incidence of fetal and/or newborn morbidity the medical treatment of hyperthyroidism

334 Drugs to avoid preconceptionally during pregnancy, and is compatible with initial information regarding the teratogenic breastfeeding37. risk of lithium treatment was derived from biased retrospective reports, more recent epi- demiological data indicate that the teratogenic Methimazole and carbimazole risk of first trimester lithium exposure is lower than previously suggested. The clinical man- A specific pattern of rare congenital malforma- agement of women with bipolar disorder who tions secondary to exposure to methimazole have childbearing potential should be modi- during the first 7 weeks of gestation is report- fied using this revised risk estimate. If lithium ed that consists of some or all of the following: is used for prophylaxis, it is advisable to dis- scalp or patchy hair defects; choanal atresia; continue it during the first trimester, unless esophageal atresia with tracheoesophageal its withdrawal would jeopardize the woman or fistula; minor facial anomalies; hypoplastic or her pregnancy. During pregnancy, the small- absent nipples; and psychomotor delay. These est dose possible for acceptable therapeutic defects may indicate a phenotype for methim- effects should be used. Frequent small dosages embryopathy. Because of the possible avoid larger fluctuations in maternal plasma association with aplasia cutis and other mal- concentrations, and each dosage should not formations, and the passage of methimazole exceed 300 mg with even spacing throughout into breast milk, PTU is the drug of choice for the 24-hour period. Plasma levels should be the medical treatment of hyperthyroidism dur- monitored every 3–7 days. ing pregnancy. Both methimazole and carbim- azole are compatible with breastfeeding. Drugs used in depressive disorders

PSYCHOTHERAPEUTIC DRUGS Tricyclic antidepressants and

Antipsychotic drugs Tricyclic antidepressants and fluoxetine are the first-line choices in the management of depres- Lithium sion. Tricyclic antidepressants have a long his- tory of use without increasing teratogenic risk Lithium carbonate may be administered to in pregnant women. Fluoxetine has been stud- pregnant women for treatment of the manic ied in prospective trials without evidence for phase in manic–depressive psychosis (bipolar a higher incidence of malformations or other disorder). The precise mechanism of action is teratogenicity. Doses of tricyclic antidepres- unknown, but it is thought to be due to altered sants may need to be higher in pregnancy transport or inhibition of adenyl cyclase, due to increased hepatic . Where influencing nerve excitation, synaptic trans- appropriate, to avoid withdrawal symptoms in mission and neuronal metabolism in the CNS. the neonate, antidepressants should be slowly Lithium is associated with an increased inci- withdrawn or reduced to the minimum dose dence of ­fetal abnormalities. Since the 1960s prior to delivery. an international Register of Lithium Babies has collected information about lithium-exposed children in the first trimester of pregnancy38. Drugs used in generalized It is estimated that 7.8% of lithium-exposed and sleep disorders embryos develop abnormalities. Early data showed that the cardiovascular system is the are contraindicated in the most affected, with Ebstein anomaly affecting first trimester. Diazepam and its metabolite, one-third of lithium-exposed embryos. While desmethyl diazepam, freely cross the placenta

335 PRECONCEPTIONAL MEDICINE and accumulate in the fetal circulation with exposure to theophylline or aminophylline. newborn levels about 1–3 times greater than No evidence was found for an association with maternal serum levels. Transfer across the pla- malformations. Theophylline withdrawal in a centa occurs as early as 6 weeks’ gestation, newborn exposed throughout gestation has suggesting that diazepam accumulates in the been reported. Apneic spells developed at fetal circulation and tissues during organogen- 28 hours after delivery and became progres- esis. In 1427 malformed newborns compared sively worse over the next 4 days40. Therapy to 3001 controls, first trimester use of tran- with theophylline resolved the spells. Except quilizers (diazepam most common) was asso- for the precaution that theophylline may cause ciated with inguinal hernia, cardiac defects and irritability in the nursing infant, the American pyloric stenosis39. Second trimester exposure Academy of Pediatrics14 considers the drug to was associated with hemangiomas and cardiac be compatible with breastfeeding. and circulatory defects. The effects of benzodiazepines, including diazepam, on the human embryo and fetus are RADIOACTIVE IODINE controversial. However, the risk appears to be low, if indeed diazepam and the other agents Radioactive iodine therapy is contraindicated do cause birth defects. Continuous use during in pregnancy since the uptake by fetal thyroid gestation results in and results in thyroid ablation and hypothyroid- a dose-related syndrome is apparent if diaz- ism. Pregnancy should be avoided for at least epam is used close to delivery. Consequently, 4 months after treatment with radioactive if the maternal condition requires the use of iodine therapy and investigations using 131I in diazepam during pregnancy, the lowest pos- view of the theoretical risk of chromosomal sible dose should be prescribed. Abrupt dis- damage and genetic abnormalities. continuation of benzodiazepines should be avoided, as severe maternal withdrawal symp- toms (physical and psychological) may occur. VITAMINS Fetal withdrawal, such as that observed with narcotics, has not been reported, but should be considered. Retinoids Use during labor is considered safe as long as the dose does not exceed more than 30–40 mg Acitretin and and the drug is not used over a long period of time. Neonatal complications from ben- Acitretin and isotretinoin are synthetic vita- zodiazepines include floppy infant syndrome min A derivatives. Acitretin, a metabolite of with , lethargy, sucking difficulties etretinate, is an oral preparation used for the or withdrawal syndrome with IUGR, , treatment of severe resistant or complicated irritability, hypertonicity, diarrhea/ psoriasis and some of the congenital disorders and vigorous sucking. of keratinization. Isotretinoin reduces sebum secretion and in its oral form is used for the treatment of nodulo-cystic and conglobate DRUGS ACTING ON THE and severe antibiotic-resistant acne. Tera- RESPIRATORY TRACT togenic effects have been reported to occur in up to 25% of babies born to mothers who took Theophyllines retinoids. The embryopathy includes CNS defects (hydrocephalus, optic nerve blind- The Collaborative Perinatal Project6 monitored ness, retinal defects, micropthalmia, poste- 193 mother-child pairs with first trimester rior fossa defects, and cortical and cerebellar

336 Drugs to avoid preconceptionally defects), craniofacial defects (microtia or VACCINES IN PREGNANCY anotia, low-set ears, hypertelorism, depressed nasal bridge, microcephaly, micrognathia and Live attenuated vaccines are generally avoided agenesis or stenosis of external ear canals), in pregnancy. All killed vaccines are safe in cardiovascular defects (transposition of great pregnancy. Vaccines that give passive immuni- vessels, tetralogy of Fallot and ventricular or zation are safe in the preconception period and atrial septal defects), thymic defects (ectopia during pregnancy. A list of vaccines and their and hypoplasia or aplasia) and miscellaneous use is shown in Table 4. defects (limb reduction, decreased muscle tone, spontaneous miscarriage and behavior- al abnormalities). Isotretinoin is eliminated CONCLUSION from the body within 4 weeks of stopping treatment, but acitretin is eliminated more Current practice of prescribing in the precon- slowly and pregnancy should be avoided for 2 ceptional period is similar to that in patients years after a course of the drug. Fetal abnor- who are not planning for a pregnancy. With malities have not been associated with topical the limitations in the available data regard- retinoids, but it is advisable to avoid their use ing safety; however, the possibility of seri- in pregnancy and ensure women use adequate ous detrimental effects to the fetus, many of contraception. which may not be even identified in the fetal

Table 4 Usage of vaccines in pregnancy and preconception. (Adapted from the CDC guideline41)

Hepatitis A The safety of A vaccination during pregnancy has not been determined; however, because vaccine is produced from in- activated (hepatitis A virus), the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk for hepatitis A in pregnant women who may be at high risk for exposure to hepatitis A virus Pregnancy is not a contraindication to vaccination. Limited data indicate no apparent risk for adverse events to developing fetuses when hepatitis B vaccine is administered to pregnant women. Current vaccines contain non-infectious HBsAg and should cause no risk to the fetus. Pregnant women who are identified as being at risk for HBV infection during pregnancy (e.g. having more than one partner during the previous 6 months, been evaluated or treated for a sexually transmitted disease, recent or current injection drug use, or having had an HBsAg- positive sex partner) should be vaccinated Human papillomavirus (HPV) Quadrivalent HPV vaccine is not recommended for use in pregnancy. If a woman is found to be pregnant after initiating the vaccination se- ries, the remainder of the three-dose regimen should be delayed until after completion of the pregnancy. If a vaccine dose has been adminis- tered during pregnancy, no intervention is needed Influenza (inactivated) Vaccination with inactivated influenza vaccine is recommended for per- sons who are at increased risk for severe complications from influenza, such as women who will be pregnant during the influenza season Influenza (LAIV) Should not be used in pregnancy

continued

337 PRECONCEPTIONAL MEDICINE

Table 4 continued

MMR Measles-mumps-rubella (MMR) vaccine and its component vaccines should not be administered to women known to be pregnant. Because a risk to the fetus from administration of these live virus vaccines can- not be excluded for theoretical reasons, women should be counseled to avoid becoming pregnant for 28 days after vaccination with measles or mumps vaccines or MMR or other rubella-containing vaccines If vaccination of an unknowingly pregnant woman occurs or if she be- comes pregnant within 4 weeks after MMR vaccination, she should be counseled about the theoretical basis of concern for the fetus; however, MMR vaccination during pregnancy should not be regarded as a reason to terminate pregnancy Pneumococcal (PPV23) The safety of pneumococcal polysaccharide vaccine during the first tri- mester of pregnancy has not been evaluated, although no adverse con- sequences have been reported among newborns whose mothers were inadvertently vaccinated during pregnancy Polio (IPV) Although no adverse effects of IPV have been documented among preg- nant women or their fetuses, vaccination of pregnant women should be avoided on theoretical grounds. However, if a pregnant woman is at increased risk for infection and requires immediate protection against polio, IPV can be administered in accordance with the recommended schedules for adults Rubella Rubella-susceptible women who are not vaccinated because they state they are or may be pregnant should be counseled about the potential risk for congenital rubella syndrome and the importance of being vac- cinated as soon as they are no longer pregnant Tetanus, and Pregnancy is not a contraindication for use of Tdap. Data on safety, ­pertussis (Tdap) immunogenicity and the outcomes of pregnancy are not available for pregnant women who receive Tdap. When Tdap is administered during pregnancy, transplacental maternal antibodies might protect the infant against pertussis in early life. They also could interfere with the infant’s immune response to infant doses of TdaP, and leave the infant less well protected against pertussis Varicella The effects of the varicella virus vaccine on the fetus are unknown; therefore, pregnant women should not be vaccinated. Non-pregnant women who are vaccinated should avoid becoming pregnant for 1 month following each injection. For susceptible persons, having a preg- nant household member is not a contraindication to vaccination. If vac- cination of an unknowingly pregnant woman occurs or if she becomes pregnant within 4 weeks after varicella vaccination, she should be coun- seled about the theoretical basis of concern for the fetus; however, vari- cella vaccination during pregnancy should not be regarded as a reason to terminate pregnancy BCG Although no harmful effects to the fetus have been associated with BCG vaccine, its use is not recommended during pregnancy

continued

338 Drugs to avoid preconceptionally

Table 4 continued

Japanese encephalitis (JE) No specific information is available on the safety of JE vaccine in preg- nancy. Vaccination poses an unknown but theoretical risk to the de- veloping fetus, and the vaccine should not be routinely administered during pregnancy. Pregnant women who must travel to an area where risk of JE is high should be vaccinated when the theoretical risks of im- munization are outweighed by the risk of infection to the mother and developing fetus Rabies Because of the potential consequences of inadequately treated rabies exposure, and because there is no indication that fetal abnormalities have been associated with rabies vaccination, pregnancy is not consid- ered a contraindication to postexposure prophylaxis. If the risk of exposure to rabies is substantial, pre-exposure prophylaxis might also be indicated during pregnancy Typhoid No data have been reported on the use of any of the three typhoid vac- cines among pregnant women Yellow fever The safety of yellow fever vaccination during pregnancy has not been established, and the vaccine should be administered only if travel to an endemic area is unavoidable and if an increased risk for exposure exists. Infection of the fetus with YF17D apparently occurs at a low rate and has not been associated with congenital anomalies. If international travel requirements are the only reason to vaccinate a pregnant woman, rather than an increased risk of infection, efforts should be made to obtain a waiver letter from the traveler’s physician. Pregnant women who must travel to areas where the risk of yellow fever is high should be vaccinated and, despite the apparent safety of this vaccine, infants born to these women should be monitored closely for evidence of congenital infection and other possible adverse effects resulting from yellow fever vaccination Zoster (singles) Contraindications: Zostavax should not be administered to individu- als who are or may be pregnant. It is not known whether Zostavax can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. However, naturally occurring VZV infection is known to sometimes cause fetal harm. Therefore, Zostavax should not be administered to pregnant ; furthermore, pregnancy should be avoided for 3 months following vaccination life, emphasizes the need for change of prac- an overview of epidemiological (drug tice. In view of the above-mentioned as well as utilization) studies. Eur J Clin Pharmacol unforeseen dangers, prescribing in the precon- 1990;38:325–8 ceptional period should in the future be on the 2. Lacroix I, Damase-Michel C, Lapeyre- same grounds as prescribing for pregnancy. Mestre M, Montastruc JL. Prescription of drugs during pregnancy in France. Lancet 2000;356:1735–6 References 3. De Vigan C, De Walle HE, Cordier S, et al. Therapeutic drug use during pregnancy: 1. Bonati M, Bortolus R, Marchetti F, Rome- a comparison in four European countries. ro M, Tognoni G. Drug use in pregnancy: OECM Working Group. Occupational

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