drugs used in pregnancy?

Drugs in Pregnancy

Regulatory information about drug safety during pregnancy
Effects of drug use during pregnancy
Vaccines During Pregnancy
Antidepressants During Pregnancy
Antivirals During Pregnancy
Social and Illicit Drugs During Pregnancy

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 over-the-counter (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, or Pregnancy and Lactation Labeling (Drugs) Final Rule [PLLR]).

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 by the drug

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. The final rule does not apply to nonprescription (over-the-counter) drugs.
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. Some 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. More information on a particular drug can be obtained from the drug information section in the THE MANUAL.

Drugs diffuse across the placenta similarly to the way they cross other epithelial barriers (see 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 minutes; 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, placental permeability, maternal factors, 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), 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.

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 adverse fetal effects 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 < 2 to 3% of all fetal congenital malformations; most malformations result from genetic, environmental, multifactorial, or unknown causes.
Table
Some Drugs With Adverse Effects During Pregnancy
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.

The CDC recommends COVID-19 vaccination for all people 5 years and older, including people who are pregnant, breastfeeding, trying to get pregnant now, or might become pregnant in the future. Evidence about the safety and effectiveness of COVID-19 vaccination during pregnancy has been growing. These data suggest that the benefits of receiving a COVID-19 vaccine outweigh any known or potential risks of vaccination during pregnancy. (See also CDC: COVID-19 Vaccines While Pregnant or Breastfeeding.)

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 weeks and 22 weeks gestation. This vaccine is contraindicated during pregnancy.
Antidepressants During Pregnancy

Antidepressants, particularly selective serotonin reuptake inhibitors (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 in some studies, paroxetine appeared to increase the risk of congenital cardiac anomalies

To reduce the risk of withdrawal symptoms in the neonate, clinicians should consider tapering the dose of all antidepressants to the lowest effective dose during the 3rd trimester. 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.
Antivirals During Pregnancy

Some antivirals (eg, zidovudine and ritonavir for HIV infection) have been safely used during pregnancy for many years. However, some antivirals may have significant risks for the fetus.

Whether remdesivir should be used to treat COVID-19 should be decided by the treatment team and the patient after risk-benefit assessment. Generally, recommendations are that theoretical concerns about the safety of drug treatment during pregnancy should not deter use of potentially effective treatment for COVID-19 (including remdesivir) during pregnancy. Data about fetal safety for remdesivir are limited, but a pregnancy registry is available. In a group of 86 pregnant and postpartum hospitalized patients with severe COVID-19, remdesivir was well-tolerated, and the rate of serious adverse effects was low ( 1).

Antivirals for influenza should be started as soon as possible, without waiting for test results to confirm the diagnosis, because treatment within 48 hours of illness onset is most effective. However, treatment at any point during the infection reduces risk of severe complications. Controlled clinical studies of zanamivir and oseltamivir have not been done in pregnant women; however, many observational studies indicate that their use during pregnancy does not increase risk of adverse effects. There are fewer data about the safety of peramivir during pregnancy and no data about baloxavir in pregnant women. Health care practitioners should tell pregnant women what the symptoms and signs of influenza are and advise them to seek treatment as soon as symptoms begin.

Acyclovir (oral and topical) appears to be safe during pregnancy.

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:

Spontaneous abortion (fetal loss or delivery < 20 weeks)

Fetal growth restriction

Abruptio placentae (placental abruption)

Placenta previa

Premature rupture of the membranes

Preterm birth

Intra-amniotic infection

Stillbirth

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.

Exposure to secondhand smoke may similarly harm the fetus.

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 or methamphetamine 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, central nervous system, genitourinary, 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 or fetal growth restriction. Risk of long-term postnatal neurobehavioral abnormalities is debated and is under study. 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:

Spontaneous miscarriage

Premature labor and delivery

Withdrawal syndrome in the fetus or neonate

Hallucinogens include methylenedioxymethamphetamine (MDMA, or Ecstasy), rohypnol, ketamine, methamphetamine, and LSD (lysergic acid diethylamide).

Opioids (eg, heroin, methadone, morphine) readily cross the placenta and thus may result in opioid dependence in the fetus. The neonate may have withdrawal symptoms 6 hours to 8 days after birth. However, use of opioids rarely results in congenital malformations.

Use of opioids during pregnancy increases the risk of pregnancy complications, such as

Spontaneous miscarriage

Abnormal fetal presentation

Preterm delivery

Heroin increases the risk of having a small-for-gestational-age infant.

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.