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Drug Use During Pregnancy

Date of revision: April 2013 Orna Diav-C itrin MD Gideon Koren MD FRC PC The following is an overview of drug use during pregnancy. This information is not intended to be a comprehensive review; the reader is therefore encouraged to seek additional and confirmatory information.

Principles of Prescribing in Pregnancy

Many pregnant women are exposed to a variety of medications that may exert therapeutic, toxic or teratogenic effects on the fetus. Since the thalidomide disaster, many physicians and pregnant women tend to withhold any medication during pregnancy, although the risk of teratogenic effect from most drugs in therapeutic doses is nonexistent. Major congenital defects occur in 13% of the general population at birth.1 Of the major defects,

about 25% are of genetic origin (genetically inherited diseases, new mutations and chromosomal abnormalities) and 65% are of unknown etiology (multifactorial, polygenic, spontaneous errors of development and synergistic interactions of teratogens). Only 23% of malformations are thought to be associated with drug treatment. The remaining defects are related to other environmental exposures including infectious agents, maternal disease states, mechanical problems and irradiation.2 , 3 Optimal prescribing in pregnancy is a challenge and should provide maximal safety to the fetus as well as therapeutic benefit to the mother. To date, very few drugs are proven teratogens in humans. However, druginduced malformations are important because they are potentially preventable. Maternal physiologic changes during pregnancy may alter the pharmacokinetics of drugs. C learance rates of many drugs increase during late pregnancy due to increases in both renal and hepatic elimination (e.g., digoxin, phenytoin), while for other drugs the clearance rate decreases (e.g., theophylline). Generally, little is known about the relationship between maternal serum drug concentration and risk of teratogenicity. The importance of timing of drug exposure is better understood; the effect produced by a teratogenic agent depends upon in which developmental stage the conceptus is exposed. Several important phases in human development are recognized:3 The all or none period, the time from conception until somite formation, corresponds to the first 17 days after conception. Insults to the embryo in this phase are likely to result in death and miscarriage or intact survival. The embryo is undifferentiated, and repair and recovery are possible through multiplication of the still totipotential cells. C onsider that exposure to teratogens during the presomitic stage usually does not cause congenital malformations unless the agent persists in the body beyond this period.3 , 4

The embryonic period, from 1860 days after conception when the basic steps in organogenesis occur. This is the period of maximum sensitivity to teratogenicity since tissues are differentiating rapidly and damage becomes irreparable. Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. The pattern of anomalies produced depends on which systems are differentiating at the time of teratogenic exposure. The fetal phase , from the end of the embryonic stage to term, when growth and functional maturation of formed organs and systems occurs. Teratogen exposure in this period will affect fetal growth (e.g., intrauterine growth restriction) and the size or function of an organ, rather than cause gross structural anomalies. The term fetal toxicity is commonly used to describe such an effect. The potential effect of psychoactive agents (e.g., antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system has led to the new field of behavioural teratology. Many organ systems continue structural and functional maturation long after birth. Most of the adenocarcinomas associated with first trimester exposure to diethylstilbestrol occurred many years later. Teratogens must reach the a molecular weight greater bloodstream. Other factors solubility and the existence developing conceptus in sufficient amounts to cause their effects. Large molecules with than 1000 (e.g., heparin) do not easily cross the placenta into the embryonic-fetal influencing the rate and extent of placental transfer of drugs include polarity, lipid of a specific carrier protein (e.g., P-glycoprotein).

In an attempt to provide the practitioner with a better assessment of fetal risk, the US Food and Drug Administration (FDA) developed a classification of fetal risk in 19795 (see Glossary). These categories initially appeared logical but are not helpful in counselling individual patients. Drug manufacturers may have legal rather than scientific reasons for assigning particular designations. The classification frequently results in ambiguity and

even false alarm. For example, oral contraceptives are denoted as X (contraindicated in pregnancy), despite failure of two meta-analyses to show increased teratogenic risk. In 1994 the Teratology Society stated that the FDA ratings are inappropriate and should be replaced by narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of teratogenic risk.6 During the last few years the FDA has begun a process to change the present system.

Teratology Counselling7
Ascertain the clinical facts regarding the nature of the exposure: the length, dosage and timing during pregnancy, as well as other exposures of concern (e.g., alcohol, cigarette smoking, herbal remedies). C ollect all available current data regarding the agent and the risk of exposure. C ounselling should include background human baseline risk for major malformations, whether the fetus is at increased risk, which anomaly has been associated with the agent in question, a risk assessment, methods of prenatal detection when available, limitations in our knowledge and limitations of prenatal diagnostic capabilities. Additional considerations include the potential risk of the medical condition for which a drug is prescribed, known interactions between the disease state and the pregnancy, and preventive measures when applicable (e.g., folic acid supplementation in carbamazepine exposure). Because more than 50% of pregnancies are unplanned, teratogenic risk assessment should be started prior to pregnancy. Table 1 lists drugs with sufficient evidence to prove their teratogenic effect in humans. Use an alternative in pregnancy when possible. Table 2 lists possible teratogenic drugs with insufficient evidence as yet for teratogenicity in humans.

Drugs of Choice During Pregnancy

Table 3 presents drugs of choice during gestation for common maternal conditions.

Note: Antenatal drug/chemical risk counselling or information on safety of drug use during breastfeeding is available from the Motherisk Program, Hospital for Sick C hildren, Toronto, Ontario. Tel.: 416-813-6780; email: momrisk@sickkids.ca; Web site: www.motherisk.org. Table 1: Proven Teratogenic Drugs in Humans7 Drug Angiotensin C onverting Enzyme Inhibitors (AC EI) and Angiotensin II Antagonists Adverse Effects Adverse effects relate to hemodynamic effects of AC EI and angiotensin II antagonists on the fetus. In late pregnancy, AC EI fetopathy: intrauterine renal insufficiency, neonatal hypotension, oliguria with renal failure, hyperkalemia, complications of oligohydramnios (fetal limb contractures, lung hypoplasia and craniofacial anomalies), prematurity, intrauterine growth restriction and fetal death. 1st trimester exposure: questionable teratogenic risk of cardiovascular and C NS malformations.8 Several cohort studies and meta-analyses suggest the observed risk is associated with the underlying maternal conditions.9 , 10 , 11 , 12 , 13 , 14 A significant increase in the incidence of various fetal malformations and early miscarriages following 1st trimester exposure.15 1st trimester exposure: 1% risk of neural tube defects (10 baseline risk) and an increased risk of cardiovascular malformations. A pattern of malformations similar to the fetal hydantoin syndrome has also been associated.16 C ocaine Abruptio placenta, prematurity, fetal loss, decreased birth weight, microcephaly, limb defects, urinary tract malformations and poorer neurodevelopmental performance. Methodological problems make the findings difficult to interpret. C ocaine abuse is often associated with polydrug abuse, alcohol consumption, smoking, malnutrition and poor prenatal care. Human epidemiology indicates the risk of major malformation from cocaine is probably low, but the anomalies may be severe.17 1st trimester exposure: <1% increased risk of oral clefts.18

Antineoplastic Agents C arbamazepine

C orticosteroids (systemic)

C oumarin Anticoagulants (e.g., nicoumalone, warfarin)

1st trimester exposure (69 wk gestation): fetal warfarin syndrome (nasal hypoplasia and calcific stippling of the epiphyses). Intrauterine growth restriction and developmental delay (C NS damage), eye defects and hearing loss. Warfarin embryopathy is found in up to of the cases where a coumarin derivative was given throughout pregnancy. Associated with high rate of miscarriage. Risk of C NS damage due to hemorrhage after the 1st trimester.19 , 20

Diethylstilbestrol Vaginal clear cell adenocarcinoma in offspring exposed in utero before 18th wk (>90% of the cancers occurred after 14 y of age). High incidence of benign vaginal adenosis. Increased miscarriage rate and preterm delivery. In males exposed in utero: no signs of malignancy but genital lesions in 27% and pathologic changes in spermatozoa in 29%. The drug is not currently available in C anada.21 Ethanol Fetal alcohol spectrum disorders including fetal alcohol syndrome: growth impairment, developmental delay and dysmorphic facies. C left palate and cardiac anomalies may occur. Full expression of the syndrome occurs with chronic daily ingestion of 2 g alcohol per kg (8 drinks/day) in about of offspring and partial effects in of offspring.22 , 23 , 24 , 25 , 26 Fetal aminopterin-methotrexate syndrome: C NS defects, craniofacial anomalies, abnormal cranial ossification, abnormalities in first branchial arch derivatives, intrauterine growth restriction and mental retardation after 1st trimester exposure. Maternal dose of methotrexate needed to induce defects is probably above 10 mg/wk.27 Fetal hydantoin syndrome: craniofacial dysmorphology, anomalies and hypoplasia of distal phalanges and nails, growth restriction, mental deficiency and cardiac defects.28 Small increase in risk for cardiac teratogenesis in early gestation (1%). The risk of Ebstein's anomaly (a congenital heart defect, characterized by anterior displacement of the tricuspid valve, enlarged right chambers, often with atrial septal defect and arrhythmias) exceeds spontaneous rate of occurrence. Fetal echocardiography if exposed in 1st trimester.29 , 30 1st trimester exposure: limb defects and Moebius sequence (a congenital facial palsy with impairment of ocular abduction, as a result of dysfunction of cranial nerves VI and VII). Absolute teratogenic risk: probably low. Uterine contraction inducing activity.31 , 32 Mycophenolate mofetil Retinoids (acitretin, isotretinoin) and megadoses of Vitamin A Tetracyclines 1st trimester exposure: ear, eye and craniofacial malformations, oral clefts, cardiac, finger, urogenital, gastrointestinal, C NS and skeletal malformations.33 , 34 , 35 Systemic exposure: potent human general and behavioural teratogens. Risk of retinoic acid embryopathy: craniofacial anomalies, cardiac defects, abnormalities in thymic development and alterations in C NS development (congenital anomalies in 28% of prospectively ascertained pregnancies that resulted in births). Risk for associated miscarriage: 40%.36 , 37

Folic Acid Antagonists: aminopterin and methotrexate Hydantoins (phenytoin) Lithium

Misoprostol

Discolouration of the teeth after 17 wk gestation when deciduous teeth begin to calcify. C lose to term: crowns of permanent teeth may be stained. Oxytetracycline and doxycycline associated with a lower incidence of enamel staining.38 , 39 Malformations limited to tissues of mesodermal origin, primarily limbs (reduction defects), ears, cardiovascular system and gut musculature. C ritical period: 3450th day after the beginning of the last menstrual period. A single dose of <1 mg/kg has produced the syndrome. Embryopathy found in about 20% of pregnancies exposed in the critical period.40

Thalidomide

Valproic Acid

1st trimester exposure: neural tube defects with 12% risk of meningomyelocele, primarily lumbar or lumbosacral, cardiovascular malformations and hypospadias. Fetal valproate syndrome: craniofacial dysmorphology, cardiovascular defects, long fingers and toes, hyperconvex fingernails and cleft lip, has been delineated by some investigations. Neurobehavioural teratogen.41 , 42 , 43 , 44 , 45 , 46

Table 2: Possible Teratogenic Drugs in Humansa , 47 Drug Diazepam Adverse Effects A questionable small increase in the incidence of cleft lip and palate (small

studies). Larger studies did not confirm the association.48 Fluconazole HMG C oA Reductase Inhibitors (statins) Methimazole High-dose treatment: multiple synostosis, congenital heart defects, skeletal anomalies and recognizable dysmorphic facial features (case reports).49 A questionable increase in the risk of C NS and limb anomalies (retrospective data), not confirmed by several prospective cohort studies.50 Scalp defects such as aplasia cutis congenita suggested through case reports and an epidemiological study in which methimazole had been added to animal feeds as a weight enhancer; methimazole embryopathy (choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay).51 , 52 A questionable increase in the risk of cardiac malformations, which may be associated with the underlying psychiatric disorder.53 High-dose treatment: connective tissue disorders (cutis laxa) (case reports).54 Possible increased risk of neural tube and cardiovascular defects and oral clefts with 1st trimester exposure. Folic acid supplementation may reduce these risks.55 , 56 , 57 a. This list is not e x haustive . Table 3: Drugs of C hoice for Select C onditions During Pregnancy 7 Condition Allergy Drugs of Choice Antihistamines: chlorpheniramine, desloratadine, diphenhydramine, dimenhydrinate, loratadine Alternative Intranasal preparations of sodium cromoglycate, beclomethasone, budesonide, fluticasone; cetirizine, fexofenadine Comments

Paroxetine Penicillamine Sulfamethoxazole/trimethoprim

Anticoagulation Anxiety

Heparin and low molecular weight heparins Short-term treatment: benzodiazepines48 Long-term treatment: citalopram, fluoxetine, sertraline 58 Watch for possible transient neonatal effects when benzodiazepines or SSRIs used close to term. Short or intermediate-acting benzodiazepines (e.g., lorazepam, oxazepam) may be preferred if needed for regular use near term. For diazepam, there is a questionable small increase in the incidence of cleft lip and palate (small studies). Larger studies did not confirm the association. Systemic corticosteroids and theophylline

Asthma

Inhaled bronchodilators (ipratropium bromide, salbutamol or terbutaline ) and inhaled corticosteroids (beclomethasone, budesonide, fluticasone)

Bacterial Infections

C ephalosporins, clindamycin, Aminoglycosides erythromycin, penicillins (amikacin, gentamicin, tobramycin), azithromycin, clarithromycin,

quinolones Bipolar Disorder Lithium C arbamazepine, lamotrigine With lithium, monitor using fetal echocardiography. Avoid valproic acid when possible, especially in the first trimester (if not possible to avoid, limit dose to <6001000 mg/day). With carbamazepine and valproic acid, prescribe periconceptional folate supplementation: 5 mg po daily, ideally starting 3 months before trying to conceive and continuing at least until the end of the first trimester. Monitor using level II ultrasound for prevention of neural tube defects. Long term use of mineral oil can decrease absorption of lipid soluble vitamins A, D, E and K.

C onstipation

Bulk-forming agents (e.g., methylcellulose, psyllium hydrophilic mucilloid)

Docusate sodium, glycerin suppository, lactulose, mineral oil

C ough

Antihistamines (in the case of Dextromethorphan cough due to rhinitis or allergy), codeine (when indicated) C italopram, fluoxetine, sertraline, tricyclic antidepressants Other selective serotonin reuptake inhibitors, bupropion, venlafaxine Metformin in gestational diabetes in 3rd trimester, glyburide

Avoid high doses of codeine close to term (risk of neonatal opioid withdrawal).

Depression

Neonatal withdrawal may occur when used in 3rd trimester. There is a questionable association between paroxetine exposure in pregnancy and cardiac malformations. Important to achieve strict glycemic control before conception and during the 1st trimester.

Diabetes Mellitus

Human insulin

Diarrhea

Bulk-forming agents (e.g., methylcellulose, psyllium hydrophilic mucilloid), kaolin pectin Alginic acid compound, antacids (various combinations of aluminum, calcium, magnesium salts), omeprazole,59 ranitidine C arbamazepine, lamotrigine

Loperamide

Dyspepsia

Famotidine

Epilepsy60 , 61 , 62

Benzodiazepines (e.g., clonazepam) (see Anxiety), phenobarbital, phenytoin, valproic acid

The drug of choice for epilepsy in pregnancy should be the drug that best controls the seizures; monotherapy should be favoured. Use the lowest effective dose. Valproic acid dose should be <6001000 mg/day whenever possible. With carbamazepine and valproic acid, prescribe periconceptional folate supplementation: 5 mg po daily, ideally starting 3 months before trying to conceive and continuing at least until the end of the first trimester. Monitor using level II ultrasound for prevention of neural tube defects. Avoid full anti-inflammatory dose of NSAIDs in 3rd trimester due to the risk of

Fever and Pain

Acetaminophen

ASA, NSAIDs63

oligohydramnios and premature closure of ductus arteriosus. Hemorrhoids (3rd Topical hydrocortisone/pramoxine,64 trimester) topical lidocaine, topical zinc oxide

Herpetic Infections Hypertension67

Acyclovir, valacyclovir65 , 66 Hydralazine, methyldopa Beta-blockers, calcium channel blockers With beta-blockers, reduced birth weight and persistent beta-blockade possible in newborn. Monitor growth using serial ultrasounds in the 3rd trimester. Monitor newborn for hypoglycemia, bradycardia, hypotension and respiratory problems during the first 2448 h.

Hyperthyroidism Migraine (abortive therapy) Nausea/Vomiting Schizophrenia

Propylthiouracil Acetaminophen ASA, NSAIDs, sumatriptan68 , 69

Perform fetal ultrasound near term for goitre detection. Avoid full anti-inflammatory dose of NSAIDs in 3rd trimester due to the risk of oligohydramnios and premature closure of ductus arteriosus.

Doxylamine/pyridoxine (Diclectin) Phenothiazines

Dimenhydrinate, metoclopramide Haloperidol, risperidone Watch neonate for possible adverse effects if taken close to term. C ontinue present antipsychotic if the woman is stable and unplanned pregnancy occurs. Monitor the woman for metabolic complications (weight gain, hyperglycemia, hyperlipidemia), especially with atypical antipsychotics.

Vaginal C andidiasis

Vaginal: clotrimazole, miconazole, nystatin Topical azoles are preferred70 , 71

Fluconazole: single systemic dose of 150 mg

Abbre viations: C NS = ce ntral ne rvous syste m ; NSAID = nonste roidal anti-inflam m atory drug; SSR I = se le ctive se rotonin re uptak e inhibitor.

References
1. 2. 3. 4. 5. 6. 7. 8. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy . Littleton (MA): Publishing Sciences Group; 1977. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128-37. Brent RL, Beckman DA. Environmental teratogens. Bull NY Acad Med 1990;66(2):123-63. Adam MP. The all-or-none phenomenon revisited. Birth Defects Res A Clin Mol Teratol 2012;94(8):664-9. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk . 9th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2011. FDA classification of drugs for teratogenic risk. Teratology Society Public Affairs C ommittee. Teratology 1994;49(6):446-7. Koren G. Medication safety in pregnancy and breastfeeding. New York (NY): McGraw-Hill; 2007. C ooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester