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Drugs in Pregnancy

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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 ; for more information, see the FDA's announcement ).

The information required by the FDA has 3 subsections:

  • 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

  • Lactation: Information about using the drug while breastfeeding (eg, the amount of drug in breast milk, potential effects on the breastfed child)

  • 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

  • Constricting placental vessels and thus impairing gas and nutrient exchange

  • Producing severe uterine hypertonia that results in anoxic injury

  • Altering maternal physiology (eg, causing hypotension)

For a list of some drugs with adverse effects during pregnancy, see Table: Some Drugs With Adverse Effects During Pregnancy.

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. The exception is immune globulin G, which is occasionally used to treat disorders such as fetal alloimmune thrombocytopenia. Generally, equilibration between maternal blood and fetal tissues takes at least 30 to 60 min.

A drug’s effect on the fetus is determined largely by fetal age at exposure, drug potency, and drug dosage. Fetal age affects the type of drug effect:

  • 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.

  • 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), or covert embryopathy (a permanent subtle metabolic or functional defect that may manifest later in life), or the drugs may have no measurable effect.

  • 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.

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, or unknown causes.

Some Drugs With Adverse Effects During Pregnancy

Examples

Adverse Effects

Comments

Antibacterials

Aminoglycosides

Ototoxicity (eg, damage to fetal labyrinth), resulting in deafness

Chloramphenicol

Gray baby syndrome

In women or fetuses with G6PD deficiency, hemolysis

Fluoroquinolones

Possibly arthralgia; theoretically, musculoskeletal defects (eg, impaired bone growth), but no proof of this effect

Nitrofurantoin

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

Primaquine

In women or fetuses with G6PD deficiency, hemolysis

Streptomycin

Ototoxicity

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

Tetracycline

Slowed bone growth, enamel hypoplasia, permanent yellowing of the teeth, and increased susceptibility to cavities in offspring

Occasionally, liver failure in pregnant women

Trimethoprim

Increased risk of neural tube defects due to folate antagonism

Anticoagulants

Low molecular weight heparin

Thrombocytopenia and maternal bleeding

Compatible with pregnancy

Unfractionated heparin

Thrombocytopenia and maternal bleeding

Warfarin

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

Anticonvulsants

Carbamazepine

Hemorrhagic disease of the newborn

Some risk of congenital malformations including neural tube defects

Lamotrigine

No appreciable increased risk with dosage up to 600 mg/day

Compatible with pregnancy

Levetiracetam

Minor skeletal malformations in animal studies, but no appreciable increased risk in humans

Compatible with pregnancy

Phenobarbital

Hemorrhagic disease of the newborn

Some risk of congenital malformations

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

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

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

Antidepressants

Bupropion

Conflicting data on risk of congenital malformations from first trimester exposure

Dosing affected by hepatic or renal impairment

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

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

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

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

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

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

Doxylamine and pyridoxine (vitamin B6)

No evidence of increased risk of congenital malformations

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

Promethazine

No significant teratogenic risk in animal studies

Generally no increased risk of congenital malformations

Possibly decreased platelet aggregation in neonates

Antifungals

Amphotericin B

No significant teratogenic risk in animal studies

Monitoring recommended for systemic toxicities (electrolyte imbalance, renal dysfunction) in the mother

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

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

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

Meclizine

Teratogenic in rodents, but no proof of this effect in humans

Antihypertensives

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)

Beta-blockers

Fetal bradycardia, hypoglycemia, and possibly fetal growth restriction and preterm birth

Calcium channel blockers

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

Thiazide diuretics

Prevention of normal maternal volume expansion, reducing placental perfusion and contributing to fetal growth restriction

Neonatal hyponatremia, hypokalemia, and thrombocytopenia

Antineoplastic drugs

Actinomycin

Teratogenic in animals, but no proof of this effect in humans

Busulfan

Congenital malformations (eg, fetal growth restriction, mandibular hypoplasia, cleft palate, cranial dysostosis, spinal defects, ear defects, clubfoot)

Chlorambucil

Same as those for busulfan

Colchicine

Possibly congenital malformations and sperm abnormalities

Cyclophosphamide

Same as those for busulfan

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

Mercaptopurine

Same as those for busulfan

Methotrexate

Same as those for busulfan

Contraindicated during pregnancy

Effective contraception recommended for 8 wk after the last dose

Vinblastine

Teratogenic in animals, but no proof of this effect in humans

Vincristine

Teratogenic in animals, but no proof of this effect in humans

Antipsychotics and mood stabilizers

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

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

Lithium

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

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

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

Benzodiazepines

When benzodiazepines are given late in pregnancy, respiratory depression or a neonatal withdrawal syndrome that can cause irritability, tremors, and hyperreflexia

Hypoglycemic drugs (oral)

Chlorpropamide

Neonatal hypoglycemia

Glyburide

Neonatal hypoglycemia

Metformin

Neonatal hypoglycemia

Tolbutamide

Neonatal hypoglycemia

NSAIDs

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

Nonsalicylate NSAIDs

Same as those for salicylate NSAIDs

Contraindicated in the 3rd trimester

Opioids and partial agonists

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

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

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

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

Danazol

When these drugs are given during the first 14 wk, masculinization of a female fetus’s genitals (eg, pseudohermaphroditism)

Contraindicated during pregnancy

Synthetic progestins (but not the low doses used in oral contraceptives)

Same as those for danazol

Contraindicated during pregnancy

Thyroid drugs

Methimazole

Fetal goiter and neonatal scalp defects (aplasia cutis)

To be avoided during the 1st trimester of pregnancy

Propylthiouracil

Fetal goiter and maternal hepatotoxicity and agranulocytosis

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

Contraindicated during pregnancy

Saturated solution of K iodide

Large fetal goiter, which may obstruct breathing in neonates

Triiodothyronine

Fetal goiter

Vaccines

Live-virus vaccines such as those for measles, mumps, rubella, polio, chickenpox, and yellow fever

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

Corticosteroids

When these drugs are used during the 1st trimester, possibly orofacial clefts

Hydroxychloroquine

No increased risk at usual doses

Loratadine

Possible hypospadias

Pseudoephedrine

Placental vasoconstriction and possible risk of gastroschisis

Vitamin K

In women or fetuses with G6PD deficiency, hemolysis

*The American College of Obstetricians and Gynecologists (ACOG) recommends avoiding paroxetine use during pregnancy.

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.

G6PD =glucose-6-phosphate dehydrogenase.

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.

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 and B, measles, mumps, plague, poliomyelitis, rabies, tetanus-diphtheria, 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

In the amount typically present in prenatal vitamins (5000 IU/day), vitamin A has not been associated with teratogenic risk. However, doses > 10,000 IU/day during early pregnancy may increase risk of congenital malformations.

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:

  • A detailed evaluation of fetal anatomy during the 2nd trimester

  • If a pregnant woman takes paroxetine, echocardiography to evaluate the fetus's heart because paroxetine appears to increase the risk of congenital cardiac anomalies

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:

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:

  • Spontaneous abortion

  • Fetal growth restriction

  • Abruptio placentae

  • Preterm birth

  • Stillbirth

  • Congenital malformations (eg, CNS, GU, and skeletal malformations; isolated atresias)

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.

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:

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.

More Information

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • ANTIVERT
  • LAMICTAL
  • COLCRYS
  • PLAQUENIL
  • MARQIBO KIT
  • DESOXYN
  • ZOFRAN
  • LEUKERAN
  • KEPPRA
  • PANHEPRIN
  • PROMETHEGAN
  • BUPRENEX
  • AFRINOL, SUDAFED
  • DIABETA, GLYNASE
  • TAPAZOLE
  • DURAMORPH PF, MS CONTIN
  • No US brand name
  • COMMIT, NICORETTE, NICOTROL
  • DIFLUCAN
  • MYLERAN
  • DILANTIN
  • EFFEXOR XR
  • CELEXA
  • TEGRETOL
  • KETALAR
  • LITHOBID
  • UNISOM
  • ZYPREXA
  • PAXIL
  • RISPERDAL
  • ZOLOFT
  • DIABINESE
  • TERAZOL 3
  • PURINETHOL
  • LATUDA
  • OTREXUP
  • PROZAC, SARAFEM
  • LEXAPRO
  • ALAVERT, CLARITIN
  • DOLOPHINE
  • COUMADIN
  • DILAUDID
  • CYTOXAN (LYOPHILIZED)
  • HALDOL
  • GLUCOPHAGE
  • SOTRET
  • ACHROMYCIN V
  • MONISTAT 3
  • WELLBUTRIN, ZYBAN
  • DEMEROL
  • AZULFIDINE

* This is the Professional Version. *