Approximately 3-5% of live births are complicated by a birth defect each year totaling around 120,000 babies.[1] Drug use is an uncommon cause of birth defects, but certain medications can increase the likelihood of developing a birth defect. Additionally, more women taking any kind of medication has more than doubled in the last 30 years.[2] Current evidence suggests that between 65%-94 % of women take at least one prescription drug during pregnancy.[3, 4] Nearly 70% of women are taking a medication in the first trimester during organogenesis.[3] On average, women are taking 3 medications in pregnancy[4] with over 50% of women using four or more.[3] This includes over the counter medications and herbal supplements.
The purpose of this article is to provide an up to date source of information about medication use in pregnancy, to review the US Food and Drug Administration (FDA) pregnancy and lactation categories, and to further describe the recent FDA changes in drug labeling from December 2014.
Because any medication can present risks in pregnancy, and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. However, women with underlying medical or psychiatric issues frequently require medication throughout pregnancy. In such patients, care must to be taken to select the safest drug from the necessary class of medication. Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist.[5]
Each area of pharmacologic therapy intervention must be assessed separately and specifically for each patient. For example, gastroesophageal reflux disease (GERD) is common during pregnancy and presents difficulties in choosing optimal medications.[6] For most patients, lifestyle modifications are useful, but if these interventions are insufficient to control symptoms, and medication is often required. First-line medical therapy for pregnant woman with GERD entails antacids. If antacids fail, use of histamine-2 receptor antagonists and proton-pump inhibitors can be attempted; these drugs do not seem to be associated with clinically significant risks in pregnancy. In rare cases, promotility agents can be prescribed, though the risks and benefits must carefully be discussed with the patients before the drugs are started.
A physician caring for a pregnant patient who requires medication should take care in choosing dosages and types of drugs that maximize effectiveness while minimizing fetal risk. It is essential to understand the effect of medications and to know the point in fetal development when drugs are most toxic and which fetal organs are most susceptible. In addition, healthcare providers who treat pregnant women must be familiar with methods of gathering information about drugs, and they must be aware of online databases that are most useful for this purpose.
Several resources are available to expand one’s knowledge of teratology. Teratogen Information System (TERIS) and Reprotox are Internet databases that cover this subject. The Organization of Teratology Information Specialists is a network of risk-assessment counselors in the United States and Canada who specialize in researching and communicating the risks associated with drug exposures in pregnancy. All of these are useful resources to learn about drug use in pregnancy. They are frequently updated and should be referenced frequently, particularly when one is prescribing unfamiliar drugs in pregnancy. Primary literature searches via MEDLINE can also provide information about human data, clinical trials, and meta-analyses regarding a particular drug.[3] Finally, the drug label can provide information about toxicity. Since 1979 the FDA has provided a labeling system in an attempt to guide providers in prescribing drugs to pregnant women. This system will be discussed later in the article.
General guidelines for choosing dosages and types of drugs within a class are lacking. Each drug should be assessed, and its risks and benefits should be weighed. Various organizations, including the Organization of Teratology Information Specialists, have performed many studies in this area. Specific drugs should be investigated before they are used.
Risk-benefit assessment and counseling should involve the patient in the setting of her current state of health. The physician must consider the effects of drug exposure on the developing fetus or embryo and acknowledge specific susceptibilities at each point in fetal development, as balanced against the risks of worsening maternal illness. The patient must consider her symptoms, quality of life, and weigh risks and benefits of treatment. The most important consideration is the underlying disease and the consideration of the consequences of interrupting or stopping treatment.[3]
In a 2008 Canadian study, 19.4% of women were found to have used FDA category C, D and X medications at least once during pregnancy, the most common of these being albuterol, co-trimoxazole, ibuprofen, naproxen and oral contraceptives.[7] Analyzing the same data, Yang noted that woman who had such exposure were more commonly characterized by chronic diseases, younger age, increased parity, and receipt of social assistance.[8]
Combinations of medications rather than individual medicines are possibly associated with increased risk of birth defects. Oberlander et al performed a study to determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor antidepressants used alone and in combination with benzodiazepines. In this study, population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births in British Columbia during a 39-month period (1998-2001). Even after controlling for maternal illness profiles, infants exposed to prenatal serotonin reuptake inhibitors in combination with benzodiazepines had an increased incidence of congenital heart disease versus controls who had not been exposed. Serotonin reuptake inhibitor monotherapy was not associated with an increased risk for major congenital anomalies, but was associated with an increased incidence of atrial septal defects, and researchers did not associate risk with first trimester medication dose/day.[9]
Grigoriadis et al concluded that antidepressants do not seem to be associated with increased risk of congenital malformations, but evidence showed a statistical significance for cardiovascular malformations.[10]
A population-based cohort study of 179,007 children by Viktorin et al examined the association of maternal antidepressant medication use during pregnancy with intellectual disability in their children. The study found that intellectual disability was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. The relative risk of intellectual disability after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Although the relative risk was increased in children born to mothers treated with antidepressants, the study found no evidence of an association after adjusting for confounding factors.[11, 12]
For excellent patient education resources, visit eMedicineHealth's Pregnancy Center and Cholesterol Center. In addition, see eMedicineHealth's patient education articles Pregnancy, High Cholesterol, Cholesterol FAQs, and Lovastatin (Mevacor, Altocor).
In 1977 James Wilson proposed six principles of teratology that were subsequently published in the Handbook of Teratology. The six principles he identified are:
1. Susceptibility to teratogenesis depends upon the genotype of the conceptus and how it interacts with environmental Factors.
2. Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure
3. Teratogenic agents act in specific ways on developing cells and tissue to initiate abnormal embryogenesis.
4. The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.
5. The access of adverse environmental influences to developing tissues depends on the nature of the agent.
6. Manifestations of deviant development increase in degree as dosage increases from the no-effect to the totally lethal effect.[13]
Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy. Certain exposures may alter the size, shape, performance, and production of sperm. This observation suggests that drug exposure in the male may put the fetus at risk. Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop. However, unlike teratogenic agents taken by pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development. Animal studies show that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure.[14, 15]
At present, no evidence shows that paternal exposure directly increases the risk of birth defects. A large cohort of over 340,000 pregnancies in Norway did not find paternal drug exposure to be a particularly important cause of birth defects or adverse pregnancy outcomes, especially after controlling for confounding factors with maternal exposure.[16] Agents such as recreational drugs do affect sperm quality and, to a limited degree, indirectly expose the developing fetus to the substance. Rather than affecting the developing fetus, teratogen exposures like illicit drugs and alcohol seem to lower the likelihood of a woman's becoming pregnant rather than resulting in adverse pregnancy outcomes.[14, 15]
Paternal alcohol use may increase the risk of heart defects in newborns. In one study, paternal smoking was associated with heart defects. Chemotherapy or radiation therapy to treat cancer in a father may increase the risk chromosomal abnormalities of the fetus. Studies have demonstrated less-than-normal numbers of chromosomes and damage to the structure of chromosomes in the sperm of men with cancer. No data suggests an increased rate of birth defects in fetuses conceived with sperm from male chemotherapy patients.[17, 18]
Paternal exposure to prescription medications, such as cholesterol- and blood pressure–lowering drugs, has not been linked to a risk of birth defects. Additional research must clearly be conducted to assess the safety of drugs recently released onto the market. Regardless of the lack of evidence supporting a direct influence of paternal exposure on fetal risk, caution is warranted, and the father's physician should provide counseling and active involve the patient.
The first regulations to drug labeling were implemented in 1962 after the exposure of over 10,000 children to thalidomide.[2, 19] The 5-letter classification system (A, B, C, D, X) was then introduced in 1979 by the FDA. These categories were developed based on the amount and quality of research done on the medication, not the safety of the medication in pregnancy or lactation. It has been demonstrated that these categories, while relied upon to guide treatment of pregnant and lactating women, have been misinterpreted and are being misused.[2, 4] Additionally, approximately 66% of all drugs are listed as category C indicating there is limited information about the safety of these medications.[4] Thus, the 5-letter system is being phased out over the next 3 years in favor of a more comprehensive system with a narrative summary of the risks posed by drugs.
The FDA, the government agency that oversees the safety of drugs, provides the most widely used system to grade the teratogenic effects of medications. Each drug summary will have three sections: pregnancy, lactation, and females and males of reproductive potential. “Pregnancy” merges previous categories of “pregnancy” and “labor and delivery.” “Lactation” replaces “breastfeeding mothers” and all medications will be required to have this section.[2] “Females and males of reproductive potential” is a new category to include information about pregnancy testing, contraception requirements, and effects on fertility before, during, and after drug therapy.
An additional requirement with the new FDA classification system, is the inclusion of information about pregnancy exposure registries under the “pregnancy” category. Contact information needed to enroll in the registry or obtain information about the registry will be included as well.
In June 2015, the FDA shifted from the A, B, C, D, X categorization system to a new system for all drugs which enter the market after this time, and requires removal of the old categorization from all drug product labeling for drugs on the market over the next three to four years. The pregnancy subsection is now presented under the following subheadings:
See the list below:
Data for specific agents in the sections that follow were assembled to assist the provider in weighing the risks and benefits before beginning or continuing their use pregnancy. Information was compiled by selecting commonly used drugs, with an emphasis on recently approved agents.
Aminoglycosides (Amikacin, Gentamycin, Kanamycin, Tobramycin, Neomycin, and Streptomycin)
Antiretrovirals (Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zalcitabine, Zidovudine, Delavirdine, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir/ritonavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Raltegravir, Dolutegravir, Elvitegravir, Maraviroc, Enfuvirtide)
In humans, there is no increase in overall birth defects with first-trimester EFV exposure. However, in humans with first- trimester exposure, there have been 6 retrospective case reports and 1 prospective case report of CNS defects and 1 prospective case report of anophthalmia with facial clefts. The relative risk with first-trimester exposure is unclear.
The remainder of the antiretrovirals appear to have minimal risk to the fetus with no higher incidence of birth defects.
Cidofovir (Vistide)
Fluconazole (Diflucan)
Tetracyclines (Doxycycline, Tetracycline, Minocycline, Demeclocycline, Tigecycline)
Tinidazole (Tindamax)
Angiotensin-converting enzyme (ACE) inhibitors (Benzapril, captopril, enalopril, fosinopril, lisinpril, moexipril, perindopril, quinapril, ramipril, and trandolapril)
Amlodipine/atorvastatin (Caduet)
Angiotensin II receptor antagonists, angiotensin II receptor blockers [ARBs] (cadesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan)
Aspirin
Atenolol (Tenormin)
Statins (HMG-CoA reductase inhibitors) (Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Pitavastatin, Cerivastatin, Mevastatin)
Anticonvulsants, first-generation (Phenytoin, carbamazepine, valproate, ethosuximide, primidone)
Carbamazepine (Tegretol, Carbatrol)
Ergotamine (Ergomar, Ergostat, Mirgranal)
Natalizumab (Tysabri)
Phenobarbital or methylphenobarbital
Phenytoin (Dilantin)
Pregabalin (Lyrica)
Trimethadione (Tridione)
Valproic acid (Depacon, Depakene, Depakote, Stavzor)
Benzodiazepines (alprazolam, chlordiazepoxide, clobazam, clonazepam, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, quazepam, temezapam, trazolam)
Bupropion (Wellbutrin, Zyban)
Duloxetine (Cymbalta)
Data: Animal Data — In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.
When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m2 basis, in rat; 7 times the MRHD in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day approximately equal to the MRHD in rats; 2 times the MRHD in rabbits).
When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.
Fluoxetine (Prozac)
See the list below:
Lithium
Ramelteon (Rozerem)
Paroxetine (Paxil)
A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).
Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).
Leukotriene receptor antagonists (montelukast, pranlukast, zafirlukast)
Tiotropium bromide (Spiriva)
Antineoplastics (busulfan, chlorambucil, cyclophosphamide, mechlorethamine)
Lenalidomide (Revlimid)
In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.
Mycophenolate mofetil (Cellcept)
Pemetrexed (Alimta)
Thalidomide (Thalomid)
--In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.
Colchicine
Ibandronate (Boniva)
Penicillamine (Depen, Cuprimine)
Misoprostol (Cytotec, Arthrotec)
Solifenacin succinate (Vesicare)
Trospium chloride (Sanctura)
Ondansetron (Zofran)
Sulfasalazine (Azulifidine, Sulfazine)
Rifaximin (Xifaxan)
Birth control pills (oral contraceptives) and hormone replacement
See the list below:
See the list below:
Corticosteroids (Betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone)
Danazol (Danocrine)
Estradiol gel 0.06% (Estrogel, Elestrin)
Exenatide (Byetta, Bydureon)
Methimazole
Mifepristone, RU-486 (RU-486, Mifeprex, Korlym)
Potassium iodide
Progesterones (medroxyprogesterone/Provera, norethindrone/Micronor/aygestin, prometrium)
Finasteride (Propecia, Proscar)
Folic acid antagonists (aminopterin, carbamazepine, cimetidine, methotrexate, pemetrexed, phenytoin, phenobarbital, proguanil, pyrimethamine, sulfasalazine, triamterene, trimethoprim, valproic acid)
Methylene blue
Retinoids (Absorica, Accutane, Isotretinoin)
Warfarin (Coumadin)