Drugs are used in over half of all pregnancies, and prevalence of use is increasing. The most commonly used drugs include antiemetics, antacids, antihistamines, analgesics, antimicrobials, diuretics, hypnotics, tranquilizers, and social and illicit drugs. Despite this trend, firm evidence-based guidelines for drug use during pregnancy are still lacking.
Regulatory information about drug safety during pregnancy
Until recently, the FDA classified OTC and prescription drugs into 5 categories of safety for use during pregnancy (A, B, C, D, X). However, few well-controlled studies of therapeutic drugs have been done in pregnant women. Most information about drug safety during pregnancy is derived from animal studies, uncontrolled studies, and postmarketing surveillance. Consequently, the FDA classification system led to confusion and difficulty applying available information to clinical decisions. In December 2014, the FDA responded by requiring that the pregnancy categories A, B, C, D, and X be removed from the labeling of all drugs.
Instead of categories, the FDA now requires that labeling provide information about the specific drug in a consistent format (called the final rule).
The information required by the FDA has 3 subsections:
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Pregnancy: Information relevant to the use of the drug in pregnant women (eg, dosing, fetal risks) and information about whether there is a registry that collects and maintains data on how pregnant women are affected by the drug
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Lactation: Information about using the drug while breastfeeding (eg, the amount of drug in breast milk, potential effects on the breastfed child)
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Females and males of reproductive potential: Information about pregnancy testing, contraception, and infertility as it relates to the drug
The pregnancy and lactation subsections each include 3 subheadings (risk summary, clinical considerations, and data) that provide more detail.
Effects of drug use during pregnancy
During pregnancy, drugs are often required to treat certain disorders. In general, when potential benefit outweighs known risks, drugs may be considered for treatment of disorders during pregnancy.
Not all maternal drugs cross the placenta to the fetus. Drugs that cross the placenta may have a direct toxic effect or a teratogenic effect. Drugs that do not cross the placenta may still harm the fetus by
For a list of some drugs with adverse effects during pregnancy, see table Some Drugs With Adverse Effects During Pregnancy. More information on a particular drug can be obtained from the
Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers (see Drug Absorption). Whether and how quickly a drug crosses the placenta depend on the drug’s molecular weight, extent of its binding to another substance (eg, carrier protein), area available for exchange across the placental villi, and amount of drug metabolized by the placenta. Most drugs with a molecular weight of < 500 daltons readily cross the placenta and enter the fetal circulation. Substances with a high molecular weight (eg, protein-bound drugs) usually do not cross the placenta. One exception is immune globulin G, which may be used to treat disorders such as fetal alloimmune thrombocytopenia. Generally, equilibration between maternal blood and fetal tissues takes at least 30 to 60 min; however, some drugs do not reach similar concentrations in the maternal and fetal circulation.
A drug’s effect on the fetus is determined largely by fetal age at exposure, maternal factors, drug potency, and drug dosage.
Fetal age affects the type of drug effect:
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Before the 20th day after fertilization: Drugs given at this time typically have an all-or-nothing effect, killing the embryo or not affecting it at all. Teratogenesis is unlikely during this stage.
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During organogenesis (between 20 and 56 days after fertilization): Teratogenesis is most likely at this stage. Drugs reaching the embryo during this stage may result in spontaneous abortion, a sublethal gross anatomic defect (true teratogenic effect), covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or an increased risk of childhood cancer (eg, when the mother is given radioactive iodine to treat thyroid cancer); or the drugs may have no measurable effect.
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After organogenesis (in the 2nd and 3rd trimesters): Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues. As placental metabolism increases, doses must be higher for fetal toxicity to occur.
Maternal factors include those that affect drug absorption, distribution, metabolism, and excretion. For example, nausea and vomiting may decrease absorption of an oral drug.
Despite widespread concern about drug safety, exposure to therapeutic drugs accounts for only 2 to 3% of all fetal congenital malformations; most malformations result from genetic, environmental, multifactorial, or unknown causes.
Some Drugs With Adverse Effects During Pregnancy
Examples |
Adverse Effects |
Comments |
Antibacterials |
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Ototoxicity (eg, damage to fetal labyrinth), resulting in deafness |
— |
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Gray baby syndrome In women or fetuses with G6PD deficiency, hemolysis |
— |
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Possibly arthralgia; theoretically, musculoskeletal defects (eg, impaired bone growth), but no proof of this effect |
— |
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In women or fetuses with G6PD deficiency, hemolysis |
Contraindicated during the 1st trimester, at term (38 to 42 wk), during labor and delivery, and just before onset of labor |
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Primaquine |
In women or fetuses with G6PD deficiency, hemolysis |
— |
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Ototoxicity |
— |
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Sulfonamides (except sulfasalazine, which has minimal fetal risk) |
When the drugs are given after about 34 wk gestation, neonatal jaundice and, without treatment, kernicterus In women or fetuses with G6PD deficiency, hemolysis |
— |
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Slowed bone growth, enamel hypoplasia, permanent yellowing of the teeth, and increased susceptibility to cavities in offspring Occasionally, liver failure in pregnant women |
— |
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Increased risk of neural tube defects due to folate antagonism |
— |
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Anticoagulants |
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Thrombocytopenia and maternal bleeding |
Compatible with pregnancy |
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Unfractionated heparin |
Thrombocytopenia and maternal bleeding |
— |
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Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban) |
Inadequate human data; possible harm to the fetus because these drugs appear to cross the placenta |
No antidote for reversal; to be avoided during pregnancy |
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When warfarin is given during the 1st trimester, fetal warfarin syndrome (eg, nasal hypoplasia, bone stippling, bilateral optic atrophy, various degrees of intellectual disability) When the drug is given during the 2nd or 3rd trimester, optic atrophy, cataracts, intellectual disability, microcephaly, microphthalmia, and fetal and maternal hemorrhage |
Absolutely contraindicated during 1st trimester of pregnancy |
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Carbamazepine |
Hemorrhagic disease of the newborn Some risk of congenital malformations including neural tube defects |
— |
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Lamotrigine |
No appreciable increased risk with dosage up to 600 mg/day |
Compatible with pregnancy |
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Levetiracetam |
Minor skeletal malformations in animal studies, but no appreciable increased risk in humans |
Compatible with pregnancy |
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Phenobarbital |
Hemorrhagic disease of the newborn Some risk of congenital malformations |
— |
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Phenytoin |
Congenital malformations (eg, cleft lip, GU defects such as hypospadias, cardiovascular defects Hemorrhagic disease of the newborn |
Persistent risk of congenital malformations despite folic acid supplementation |
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Trimethadione |
High risk of congenital malformations (eg, cleft palate; cardiac, craniofacial, hand, and abdominal defects) and risk of spontaneous abortion |
Almost always contraindicated during pregnancy |
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Valproate |
Major congenital malformations (eg, neural tube defects such as meningomyelocele; cardiac, craniofacial, and limb defects) |
Persistent risk of congenital malformations despite folic acid supplementation |
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Bupropion |
Conflicting data on risk of congenital malformations from 1st trimester exposure |
Dosing affected by hepatic or renal impairment |
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Citalopram |
When citalopram is given during the 1st trimester, increased risk of congenital malformations (particularly cardiac) When the drug is given during the 3rd trimester, discontinuation syndrome and persistent pulmonary hypertension of the newborn |
Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
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Escitalopram |
When escitalopram is given during the 3rd trimester, discontinuation syndrome and persistent pulmonary hypertension of the newborn |
Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
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Fluoxetine |
When fluoxetine is given during the 3rd trimester, discontinuation syndrome and persistent pulmonary hypertension of the newborn |
Long half-life; drug-drug interactions possibly occurring for weeks after the drug is stopped Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
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Paroxetine |
When paroxetine is given during the 1st trimester, increased risk of congenital malformations (particularly cardiac) When the drug is given during the 3rd trimester, discontinuation syndrome and persistent pulmonary hypertension of the newborn |
Use during pregnancy not recommended by some experts* Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
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Sertraline |
When sertraline is given during the 3rd trimester, discontinuation syndrome and persistent pulmonary hypertension of the newborn |
Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
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Venlafaxine |
When venlafaxine is given during the 3rd trimester, discontinuation syndrome |
Dosing greatly affected by hepatic or renal impairment Consideration of dose tapering during the 3rd trimester in consultation with a mental health practitioner |
Antiemetics |
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Doxylamine and pyridoxine (vitamin B6) |
No evidence of increased risk of congenital malformations |
— |
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Ondansetron |
No significant teratogenic risk in animal studies When ondansetron is given during the 1st trimester, possible risk of congenital heart disease (evidence is weak) |
Used during pregnancy only for hyperemesis gravidarum when other treatments are ineffective |
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Promethazine |
No significant teratogenic risk in animal studies Generally no increased risk of congenital malformations Possibly decreased platelet aggregation in neonates |
— |
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Amphotericin B |
No significant teratogenic risk in animal studies |
Monitoring recommended for systemic toxicities (electrolyte imbalance, renal dysfunction) in the mother |
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Fluconazole |
Teratogenic at high doses in animal studies No apparent increased risk of congenital malformations after a single dose of 150 mg/day After higher doses (> 400 mg/day) taken for most or all of the 1st trimester, increased risk of various malformations |
— |
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Miconazole |
With oral use, adverse effects in animal studies When applied to the skin, no significant risk of congenital malformations |
Not to be used intravaginally during the 1st trimester unless essential to the mother's welfare |
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Terconazole |
Adverse effects in animal studies No significant risk of congenital malformations |
Not to be used intravaginally during the 1st trimester unless benefit to the mother outweighs risk to the fetus |
Antihistamine/anticholinergic drug |
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Meclizine |
Teratogenic in rodents, but no proof of this effect in humans |
— |
Antihypertensives |
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When the drugs are given during the 2nd or 3rd trimester, fetal hypocalvaria and hypoperfusion (which can cause renal defects), renal failure, and the oligohydramnios sequence (oligohydramnios, craniofacial deformities, limb contractures, and hypoplastic lung development) |
— |
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Aldosterone antagonists |
With spironolactone, possible feminization of a male fetus With eplerenone, no increased risk of birth defects in animal studies |
— |
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Fetal bradycardia, hypoglycemia, and possibly fetal growth restriction and preterm birth |
— |
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When the drugs are given during the 1st trimester, possibly phalangeal deformities When the drugs are given during the 2nd or 3rd trimester, fetal growth restriction |
— |
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Prevention of normal maternal volume expansion, reducing placental perfusion and contributing to fetal growth restriction Neonatal hyponatremia, hypokalemia, and thrombocytopenia |
— |
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Antineoplastic drugs‡ |
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Actinomycin |
Teratogenic in animals, but no proof of this effect in humans |
— |
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Busulfan |
Congenital malformations (eg, fetal growth restriction, mandibular hypoplasia, cleft palate, cranial dysostosis, spinal defects, ear defects, clubfoot) |
— |
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Chlorambucil |
Same as those for busulfan |
— |
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Colchicine |
Possibly congenital malformations and sperm abnormalities |
— |
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Cyclophosphamide |
Same as those for busulfan |
— |
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Doxorubicin |
Teratogenic in animals and humans Potential for dose-dependent cardiac dysfunction |
Use during pregnancy not recommended Effective contraception recommended during pregnancy and for 6 mo after treatment of male or female partner |
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Mercaptopurine |
Same as those for busulfan |
— |
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Methotrexate |
Same as those for busulfan |
Contraindicated during pregnancy Effective contraception recommended for 8 wk after the last dose |
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Vinblastine |
Teratogenic in animals, but no proof of this effect in humans |
— |
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Vincristine |
Teratogenic in animals, but no proof of this effect in humans |
— |
Antipsychotics and mood stabilizers |
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Haloperidol |
Adverse effects in animal studies When haloperidol is given during the 1st trimester, possibly limb malformations When haloperidol is given during the 3rd trimester, increased risk of extrapyramidal symptoms or withdrawal symptoms in the neonate |
— |
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Lurasidone |
No evidence of adverse effects in animal studies When lurasidone is given during the 3rd trimester, increased risk of extrapyramidal symptoms or withdrawal symptoms in the neonate |
— |
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Adverse effects in animal studies When lithium is given during the 1st trimester, teratogenic (cardiac malformations) When lithium is given later in pregnancy, lethargy, hypotonia, poor feeding, hypothyroidism, goiter, and nephrogenic diabetes insipidus in the neonate |
— |
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Olanzapine |
Adverse effects in animal studies When olanzapine is given during the 3rd trimester, increased risk of extrapyramidal symptoms or withdrawal symptoms in the neonate |
— |
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Risperidone |
Adverse effects in animal studies Based on limited data, no increased teratogenic risk When risperidone is given during the 3rd trimester, increased risk of extrapyramidal symptoms or withdrawal symptoms in the neonate |
— |
Anxiolytics |
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When benzodiazepines are given late in pregnancy, respiratory depression or a neonatal withdrawal syndrome that can cause irritability, tremors, and hyperreflexia |
— |
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Chlorpropamide |
Neonatal hypoglycemia |
— |
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Glyburide |
Neonatal hypoglycemia Unknown long-term effects on fetus |
Crosses the placenta |
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Metformin |
Neonatal hypoglycemia Unknown long-term effects on fetus |
Crosses the placenta |
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Tolbutamide |
Neonatal hypoglycemia |
— |
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Aspirin and other salicylates |
Fetal kernicterus With high doses, possibly 1st-trimester spontaneous abortions, delayed onset of labor, premature closing of the fetal ductus arteriosus, jaundice, occasionally maternal (intrapartum and postpartum) and/or neonatal hemorrhage, necrotizing enterocolitis, and oligohydramnios With low doses (81 mg) of aspirin, no significant teratogenic risk |
Use permitted for short durations during the 2nd trimester if the fetus is carefully monitored |
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Nonsalicylate NSAIDs |
Same as those for salicylate NSAIDs |
Contraindicated in the 3rd trimester |
Opioids and partial agonists |
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Buprenorphine |
Adverse effects but no teratogenicity in animal studies Risk of a neonatal opioid withdrawal syndrome (neonatal abstinence syndrome) |
Improved fetal outcomes compared with those when pregnant women use illicit substances |
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Codeine Hydrocodone Hydromorphone Meperidine Morphine |
In neonates of women addicted to opioids, withdrawal symptoms possibly occurring 6 h to 8 days after birth With high doses given in the hour before delivery, possibly neonatal CNS depression and bradycardia |
— |
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Methadone |
Adverse effects in animal studies Specific effects of methadone in pregnant women possibly difficult to differentiate from effects of concomitant drugs (eg, illicit drugs) Risk of a neonatal opioid withdrawal syndrome |
Improved fetal outcomes compared with those when pregnant women use illicit substances Possible need for acute short-acting analgesics to supplement maintenance dosing during labor and delivery |
Retinoids |
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Isotretinoin |
High teratogenic risk (eg, multiple congenital malformations), spontaneous abortion, and intellectual disability |
Contraindicated during pregnancy and in women who may become pregnant |
Sex hormones |
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Danazol |
When these drugs are given during the first 14 wk, masculinization of a female fetus’s genitals (eg, pseudohermaphroditism) |
Contraindicated during pregnancy |
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Synthetic progestins (but not the low doses used in oral contraceptives) |
Same as those for danazol |
Contraindicated during pregnancy |
Thyroid drugs |
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Methimazole |
Fetal goiter and neonatal scalp defects (aplasia cutis) |
To be avoided during the 1st trimester of pregnancy |
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Propylthiouracil |
Fetal goiter and maternal hepatotoxicity and agranulocytosis |
— |
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Radioactive iodine (131I) |
Destruction of the fetal thyroid gland or, when the drug is given near the end of the 1st trimester, severe fetal hyperthyroidism Increased risk of childhood cancer |
Contraindicated during pregnancy |
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Saturated solution of potassium iodide |
Large fetal goiter, which may obstruct breathing in neonates |
— |
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Triiodothyronine |
Fetal goiter |
— |
Vaccines |
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Live-virus vaccines such as the measles, mumps, and rubella vaccine; polio vaccine; chickenpox vaccine; and yellow fever vaccine |
With rubella and varicella vaccines, potential infection of the placenta and developing fetus With other vaccines, potential but unknown risks |
Not given to women who are or may be pregnant |
Others |
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Corticosteroids |
When these drugs are used during the 1st trimester, possibly orofacial clefts |
— |
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Hydroxychloroquine |
No increased risk at usual doses |
— |
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Isoniazid |
Possible transient increases in maternal aminotransferase levels, peripheral neuropathy |
Not to be used with other hepatotoxic drugs |
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Loratadine |
Possible hypospadias |
— |
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Pseudoephedrine |
Placental vasoconstriction and possible risk of gastroschisis |
— |
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Vitamin K |
In women or fetuses with G6PD deficiency, hemolysis |
— |
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*The American College of Obstetricians and Gynecologists (ACOG) recommends avoiding paroxetine use during pregnancy. |
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†Two new ones (brivaracetam, eslicarbazepine) are available; there is little to no information about their effects during pregnancy. |
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‡The European Society for Medical Oncology (ESMO) has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. Generally, if chemotherapy is indicated, it should not be given during the1st trimester but may begin during the 2nd trimester; the last chemotherapy dose should be given ≥ 3 wk before anticipated delivery, and chemotherapy should not be given after wk 33 of gestation. |
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G6PD = glucose-6-phosphate dehydrogenase. |
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Vaccines During Pregnancy
Immunization is as effective in women who are pregnant as in those who are not.
Influenza vaccine is recommended for all pregnant women in the 2nd or 3rd trimester during influenza season.
The tetanus-diphtheria-pertussis (Tdap) vaccine is recommended for all pregnant women during the 3rd trimester.
Other vaccines should be reserved for situations in which the woman or fetus is at significant risk of exposure to a hazardous infection and risk of adverse effects from the vaccine is low. Vaccinations for cholera, hepatitis A, hepatitis B, measles, mumps, plague, poliomyelitis, rabies, typhoid, and yellow fever may be given during pregnancy if risk of infection is substantial.
Live-virus vaccines should not be given to women who are or may be pregnant. Rubella vaccine, an attenuated live-virus vaccine, may cause subclinical placental and fetal infection. However, no defects in neonates have been attributed to rubella vaccine, and women vaccinated inadvertently during early pregnancy need not be advised to terminate pregnancy based solely on theoretical risk from the vaccine. Varicella vaccine is another attenuated live-virus vaccine that can potentially infect the fetus; risk is highest between 13 wk and 22 wk gestation. This vaccine is contraindicated during pregnancy.
Vitamin A During Pregnancy
Antidepressants During Pregnancy
Antidepressants, particularly SSRIs, are commonly used during pregnancy because an estimated 7 to 23% of pregnant women have perinatal depression. Physiologic and psychosocial changes during pregnancy can affect depression (possibly worsening it) and possibly reduce the response to antidepressants. Ideally, a multidisciplinary team that includes an obstetrician and a psychiatric specialist should manage depression during pregnancy.
Pregnant women who are taking antidepressants should be asked about depressive symptoms at each prenatal visit, and appropriate fetal testing should be done. It may include the following:
Clinicians should consider tapering the dose of all antidepressants during the 3rd trimester to reduce the risk of withdrawal symptoms in the neonate. However, the benefits of tapering must be carefully balanced against the risk of symptom recurrence and postpartum depression. Postpartum depression is common, often unrecognized, and should be treated promptly. Periodic visits with a psychiatrist and/or social workers may be helpful.
Social and Illicit Drugs During Pregnancy
Cigarette smoking is the most common addiction among pregnant women. Also, percentages of women who smoke and of those who smoke heavily appear to be increasing. Only 20% of smokers quit during pregnancy. Carbon monoxide and nicotine in cigarettes cause hypoxia and vasoconstriction, increasing risk of the following:
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Spontaneous abortion (fetal loss or delivery < 20 wk)
Neonates whose mothers smoke are also more likely to have anencephaly, congenital heart defects, orofacial clefts, sudden infant death syndrome, deficiencies in physical growth and intelligence, and behavioral problems. Smoking cessation or limitation reduces risks.
Alcohol is the most commonly used teratogen. Drinking alcohol during pregnancy increases risk of spontaneous abortion. Risk is probably related to amount of alcohol consumed, but no amount is known to be risk-free. Regular drinking decreases birth weight by about 1 to 1.3 kg. Binge drinking in particular, possibly as little as 45 mL of pure alcohol (equivalent to about 3 drinks) a day, can cause fetal alcohol syndrome. This syndrome occurs in 2.2/1000 live births; it includes fetal growth restriction, facial and cardiovascular defects, and neurologic dysfunction. It is a leading cause of intellectual disability and can cause neonatal death due to failure to thrive.
Cocaine use has indirect fetal risks (eg, maternal stroke or death during pregnancy). Its use probably also results in fetal vasoconstriction and hypoxia. Repeated use increases risk of the following:
Although marijuana’s main metabolite can cross the placenta, recreational use of marijuana use does not consistently appear to increase risk of congenital malformations, fetal growth restriction, or postnatal neurobehavioral abnormalities. However, a trend toward easier access to and broader use of marijuana in several states may lead to an improved understanding of marijuana's effects over time.
Bath salts refers to a group of designer drugs made from a variety of amphetamine-like substances; these drugs are being increasingly used during pregnancy. Although effects are poorly understood, fetal vasoconstriction and hypoxia are likely, and there is a risk of stillbirth, abruptio placentae, and possibly congenital malformations.
Hallucinogens may, depending on the drug, increase risk of the following:
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Spontaneous miscarriage
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Premature delivery
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Withdrawal syndrome in the fetus or neonate
Hallucinogens include methylenedioxymethamphetamine (MDMA, or Ecstasy), rohypnol, ketamine, methamphetamine, and LSD (lysergic acid diethylamide).
Whether consuming caffeine in large amounts can increase perinatal risk is unclear. Consuming caffeine in small amounts (eg, 1 cup of coffee/day) appears to pose little or no risk to the fetus, but some data, which did not account for tobacco or alcohol use, suggest that consuming large amounts (> 7 cups of coffee/day) increases risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions. Decaffeinated beverages theoretically pose little risk to the fetus.
Use of aspartame (a dietary sugar substitute) during pregnancy is often questioned. The most common metabolite of aspartame, phenylalanine, is concentrated in the fetus by active placental transport; toxic levels may cause intellectual disability. However, when ingestion is within the usual range, fetal phenylalanine levels are far below toxic levels. Thus, moderate ingestion of aspartame (eg, no more than 1 liter of diet soda per day) during pregnancy appears to pose little risk of fetal toxicity. However, in pregnant women with phenylketonuria, intake of phenylalanine and thus aspartame is prohibited.
