Basic principles of teratogenicity, critical developmental windows, removal of FDA letter categories, pharmacokinetics in pregnancy, and safety summary of commonly used drug groups.
⚕️ Target audience: This clinical review is intended for physicians and healthcare professionals; It is a summary of current literature and guidelines for educational purposes. Clinical decisions should be made based on patient-specific evaluation and applicable institutional protocols.
The question of medication during pregnancy is almost never "is this medication safe?" It cannot be asked in the form The real question is weighing the risk of using the drug versus the risk of leaving the underlying disease untreated; and this comparison varies with gestational age, dose, duration and availability of alternatives. This review addresses the basic principles of teratogenicity, change in the regulatory framework, pharmacokinetic changes in pregnancy, and a safety summary of commonly used drug groups.
Information on drug safety in pregnancy is structurally incomplete, as pregnant women are generally not included in safety and efficacy studies of new drugs. It is estimated that sufficient information is available to determine the risk of congenital anomalies for less than 10% of drugs approved by the US Food and Drug Administration (FDA) since 1980; The teratogenic risk in human pregnancy was classified as “undetermined” for 98% of drugs approved between 2000–2010 (UpToDate Prenatal care v126.0, 2026; Congenital anomalies: Causes v27.0, 2025).
Statistical power is also a key issue. Given the 2–4% background risk of major congenital anomalies, 200 pregnancies exposed to a drug in the first trimester are needed to rule out an overall anomaly risk more than three times the background risk, and 700 pregnancies are needed to rule out a risk more than twice the background risk. Thousands of exposures are needed for a specific anomaly (for example, at least moderately severe congenital heart anomalies occur in 6.5 per 1000 births). Therefore, the statement "studies have not shown an increased risk" often does not mean "there is no risk".
A teratogen is an agent that can cause abnormality in the structure or function of the developing fetus; It acts by causing cell death, altering tissue growth or disrupting cell differentiation. The result may be fetal loss, growth restriction, congenital anomaly, or impaired neurological performance. Approximately 4–6% of congenital anomalies are attributed to environmental teratogen exposure; This title covers maternal diseases (diabetes, phenylketonuria), infectious agents, physical agents (radiation, heat) and drugs/chemicals (UpToDate Congenital anomalies: Causes v27.0, 2025).
Response to teratogens is individualized and shaped by four variables:
The type of malformation depends largely on the time of exposure. Embryonic age is counted from fertilization and is two weeks behind the gestational age calculated from the last menstrual period.
| Period | Development event | Clinical response |
|---|---|---|
| 0–14 days | Preimplantation and implantation (day 5–11) | "All or nothing": pregnancy loss if enough cells die, other cells compensate if few cells are damaged |
| day 16 | Differentiation into three germ layers | Beginning of organogenesis |
| 19–27. day | Neural plate formation and neural tube closure | Critical window of neural tube defects |
| 30th day | Limb buds | Thalidomide limb-defect window: postconception days 21–36 |
| 4–5. week | Branchial arches, optic vesicle | Craniofacial and ocular anomalies |
| 5–7. week | Maturation of the heart and kidneys | Cardiac and renal anomalies |
| 8th week | Mature limb architecture | Organogenesis is largely completed (embryonic period ends at the end of the 10th week of gestation) |
| 7–10. week | Internal and external genitalia differentiation | Risk of virilization/feminization |
| Fetal period | Eye, genital, CNS and hematopoietic system development continues | Growth restriction and CNS disorders not visible at birth |
Exposure during the fetal period is not harmless; For example, ACE inhibitors block angiotensin conversion in the fetal kidney during the second and third trimesters, leading to hypotension, renal tubular dysplasia, anuria/oligohydramnios, growth restriction, and calvarial defects; the same drugs have also been associated with congenital heart defects in the first trimester. While misoprostol causes severe vascular disruption (terminal limb defects, Moebius syndrome) in the first trimester, it is used safely for cervical ripening and induction at birth—two different time-dependent profiles of the same molecule (UpToDate Congenital anomalies: Causes v27.0, 2025).
In 2015, the FDA abandoned the letter categories A, B, C, D, and X in the pregnancy labeling of prescription drugs and switched to the Pregnancy and Lactation Labeling Rule (PLLR). The new rule requires the label to include a summary of the risks of use in pregnancy and lactation, a discussion of the data supporting this summary, and information to guide the physician's prescribing decision and patient counseling (FDA Pregnancy and Lactation Labeling Rule, 2015).
The rationale for the change is clinically important: the single letter obscures the nature of the evidence, time of exposure, dose and absolute risk magnitude. The "C" category puts both a drug for which no human data exists and a drug that has been shown to be effective in animal studies in the same box; The difference between "D" and "X" is related to the benefit-harm balance rather than the magnitude of risk. Counseling based on letter category may unnecessarily prejudge a clearly beneficial treatment. In clinical practice, instead of letters, the current monograph of the drug, teratogen information centers and disease-specific guidance should be taken as basis.
Anatomical and physiological changes of pregnancy affect drug absorption, distribution, metabolism and excretion. In a systematic review of 198 studies covering 121 different drugs, the most consistent finding was increased drug elimination during pregnancy and decreased total (bound + free) drug exposure at a given dose (Pariente 2016, PLoS Med). The most studied groups are antiretrovirals, antiepileptics, antibiotics, antimalarials and cardiovascular drugs.
The clinical consequence of these changes is twofold. On the one hand, some drugs require an increase in dose or a shortening of the dosing interval during pregnancy—protease inhibitors, some antiepileptics, and twice-daily administration of darunavir during pregnancy are examples of this situation. On the other hand, as the review clearly emphasizes, the reflection of pharmacokinetic changes on clinical response and outcomes is unknown for most drugs; Not every low level automatically requires a dose increase. The decision should be based on the therapeutic window of the drug, indicators of control of the disease and therapeutic drug level monitoring, if available (Pariente 2016, PLoS Med).
| Agent | Reported impact | Approach |
|---|---|---|
| Oral isotretinoin | Ear anomalies (microtia with or without atresia), CNS malformations, hydrocephalus, neuronal migration defects, cerebellum anomalies, severe intellectual disability, seizure, optic nerve/retina anomalies, conotruncal heart defects, thymic defects, dysmorphic face | Absolutely avoided during pregnancy; effective contraception and pregnancy prevention program |
| Valproate and other antiepileptics | Neural tube defect and other major malformations (valproate is the highest risk agent) | Valproate should not be used during pregnancy as much as possible; Switch to the lowest risk agent that provides seizure control before conception; folic acid support |
| ACE inhibitors and ARBs | Second–third trimester: hypotension, renal tubular dysplasia, anuria/oligohydramnios, growth restriction, calvarial defects; first trimester: congenital heart defects | Discontinues during pregnancy; Replace with antihypertensives with the most experience in pregnancy |
| Methotrexate and other folic acid antagonists | Neural tube defects; possible cardiovascular defects, oral clefts and urinary tract defects | Contraindicated in pregnancy; stopped before conception |
| Statins (HMG-CoA reductase inhibitors) | Potential fetal harm remains a concern. Observational studies adjusted for confounding have not shown an increase in major birth defects; this does not establish zero risk (FDA, 2021). | In 2021, the FDA requested removal of the blanket pregnancy contraindication. Discontinuation is advised for most pregnant patients; for those at very high cardiovascular risk, continuation is an individual decision shared by the cardio-obstetric team and the patient (FDA, 2021; ESC, 2025). |
| Thalidomide | Limb reduction defects (window: postconceptional day 21–36) | Contraindicated in pregnancy |
| Misoprostol (first trimester) | Vascular interruption: terminal limb defects, Moebius syndrome | Not for use to maintain pregnancy; It can be used safely at birth as indicated. |
| High dose fluconazole (400–800 mg/day, first trimester) | Appears to be teratogenic; magnitude of risk is unknown | Topical treatment is preferred in vulvovaginal candidiasis |
| Lithium, penicillamine, methylene blue, antineoplastics | Teratogenic potential identified | Indications and alternatives are evaluated disease-specific |
| Alcohol | Fetal alcohol spectrum disorder; alcohol-related birth defects; neurobehavioral disorder | No safe threshold has been defined in pregnancy |
| Lead, methylmercury | Neurobehavioral disorder; severe CNS damage in methylmercury | Occupational exposure is questioned; species limitation in fish consumption |
| Warfarin, mycophenolate (*) | Warfarin: embryopathy and central nervous system anomalies. Mycophenolate: characteristic facial and external ear anomalies, increased pregnancy loss | Switch to an alternative before conception (low molecular weight heparin instead of warfarin; immunosuppressive with experience in pregnancy instead of mycophenolate) |
Differences between sources on statins: The FDA (United States, 2021) requested removal of the blanket pregnancy contraindication; the 2025 ESC guideline states that continuation may be considered with established atherosclerotic cardiovascular disease (IIb, C). In the local archive, UpToDate’s Acquired heart disease and pregnancy (updated 19 August 2026) discourages routine use and describes shared individual decisions for high-risk patients, whereas Congenital anomalies: Causes (updated 19 December 2025) retains the statement that statins are completely contraindicated. These sources do not give the same recommendation. The FDA regulatory decision applies to the United States and does not mean that all Turkish product labels have changed. Individual medication decisions belong with the treating clinician and cardio-obstetric team.
(*) The table's agent list is based on the UpToDate "Congenital anomalies: Causes" (v27.0, 2025) compilation with detailed effect descriptions. Since warfarin and mycophenolate are not discussed in detail in this document, their effects are given at the headline level only; For dosage and gestational week-specific decisions, the current monograph of the drug and disease-specific guidance should be consulted.
Paracetamol remains the agent of choice in the treatment of short-term fever and significant pain in pregnancy. Although the FDA has raised concerns about its use, SMFM, ACOG, AWHONN, SOGC, RCOG, FIGO and the European Medicines Agency (EMA) have continued to rate paracetamol as the drug of choice for fever and pain (ACOG Practice Advisory, September 2025). In practice, as with every drug, the principle of lowest effective dose and shortest duration applies; The therapeutic dose in adults is 325–1000 mg/dose, the highest daily dose in oral immediate-release preparations is approximately 3 g (UpToDate Prenatal care v126.0, 2026).
Both sides of the argument must be clearly presented:
The risk of not treating must be taken into account. Maternal fever in the first trimester is associated with the risk of neural tube defects, and fever later in pregnancy is associated with the risk of spontaneous preterm birth; Severe pain causes loss of function and can aggravate depression and anxiety. Alternatives also have their own risks: NSAIDs cause ductus arteriosus constriction and oligohydramnios, opioids cause maternal dependence and neonatal withdrawal syndrome. Unnecessary restriction of access to paracetamol during pregnancy produces measurable harm—following a public statement in the US, requests for paracetamol to pregnant patients in emergency departments were reported to have fallen below the expected level for three weeks (UpToDate Prenatal care v126.0, 2026).
Detailed examination has not supported a causal relationship for autism, ADHD, cerebral palsy, and small for gestational age; In topics such as cryptorchidism and premature duct closure, the data either have observational limits or the relationship is extremely rare (Ahlqvist 2024, JAMA; UpToDate Prenatal care v126.0, 2026).
Use of NSAIDs other than low-dose aspirin for more than 48 hours may lead to in utero constriction of the ductus arteriosus starting from the 24th week of gestation; this effect is most common after 31–32 weeks. Additionally, after the 20th week, NSAIDs may act on the fetal kidney—typically after at least 48 hours of treatment—leading to oligohydramnios. These two mechanisms are the main justification that makes the use of NSAIDs in the second half of pregnancy dependent on duration and indication (UpToDate Prenatal care v126.0, 2026).
Information regarding the effects of long-term (≥1 month) prescription opioid use is limited; The main concerns are maternal physiological dependence and neonatal abstinence syndrome. In a retrospective study, the likelihood of withdrawal syndrome was not increased in neonates exposed to opioids for 1–6 days in utero, but increased at least twofold in those exposed for ≥30 days, especially in late pregnancy exposure (Wang 2023, Obstet Gynecol). In pregnant women with moderate to severe pain, immediate-release opioids should be prescribed at the lowest effective dose and for the shortest duration when alternative pain management is ineffective or expected to be ineffective (ACOG Committee Opinion 711, 2017).
In a 2024 meta-analysis for congenital anomalies, exposure to any opioid in the first trimester was not associated with a significant increase in major congenital anomalies (RR 1.04, 95% CI 0.98–1.11; cardiovascular RR 1.07, 0.96–1.20; CNS RR 1.06, 0.92–1.21); however, the studies carry a high risk of bias (UpToDate Prenatal care v126.0, 2026). Three epidemiological studies reported an association with neural tube defects (OR 1.7–2.9). Because the absolute risk of open neural tube defect is low (approximately 3 per 10,000 live births in the United States), a twofold increase would represent a small increase in absolute risk even if there is true causality. Methadone or buprenorphine treatment is recommended for pregnant women with opioid use disorder; medical withdrawal is not preferred (ACOG Committee Opinion 711, 2017).
| Group | Evaluation |
|---|---|
| No known teratogenic effects | Cephalosporins, penicillins, clindamycin, amoxicillin-clavulanate, metronidazole, aztreonam. Fosfomycin is also generally considered safe. Of the carbapenems, meropenem and ertapenem are preferred (adverse fetal effects have been reported in animal studies with imipenem). Medications with very high protein binding, such as ceftriaxone, may not be suitable the day before birth due to bilirubin displacement (UpToDate Prenatal care v126.0, 2026) |
| Aminoglycosides | Risk of fetal (and maternal) ototoxicity and nephrotoxicity; not associated with structural anatomical anomaly |
| Tetracyclines | Generally contraindicated due to maternal hepatotoxicity and effects on fetal bone and teeth (permanent discoloration of primary teeth upon second–third trimester exposure; transient growth inhibition of long bones). Because doxycycline binds less to calcium, these events are extremely rare; In a systematic review, no teratogenic effects or tooth staining were detected in 2049 exposures (in one case, slight discoloration of the upper incisors). If a safe and effective alternative is available, it is used; Otherwise (e.g. Rocky Mountains spotted fever), doxycycline is preferred over tetracycline (Cross 2016, Expert Opin Drug Saf) |
| Fluoroquinolones | Generally avoided during pregnancy and lactation because they are toxic to developing cartilage in experimental animal studies; Adverse effects on cartilage or increased malformation in human pregnancy have not been documented in meta-analyses and registries, but data are limited (Yefet 2018, BJOG) |
| Trimethoprim | Since it is a folic acid antagonist, it should be avoided in the first trimester if a safe and effective alternative is available. It is not proven teratogenic in humans; If exposure has occurred, the patient is advised of the background risk of 2–4% and the possibility of a small, unproven increase (Hernández-Díaz 2000, N Engl J Med) |
| Sulfonamides and nitrofurantoin | During the first trimester, it is safest to avoid if a safe and effective alternative is available; It is appropriate to use if there is no good alternative. In a meta-analysis of 10 studies involving more than one million participants, sulfonamide exposure was found to be possibly associated with congenital malformations (OR 1.21, 95% CI 1.07–1.37), but the data were retrospective and the timing of exposure could not be reliably determined. Both can lead to hemolysis in G6PD deficiency. No cases of kernicterus associated with maternal sulfonamide use were detected in the systematic review (Li 2020, PLoS One; ACOG Committee Opinion 717, 2017) |
| Macrolides | Studies diverge. In a cohort of over 100,000 children in the United Kingdom, a first-trimester macrolide prescription compared with penicillin was associated with an increased risk of any major malformation (27.65 vs. 17.65 per 1,000; aRR 1.55, 95% CI 1.19–2.03) and cardiovascular malformation (10.60 vs. 6.61 per 1,000; aRR 1.62, 95% CI 1.05–2.51) (Fan 2020, BMJ). By contrast, a larger study comparing first-trimester macrolides (>140,000 pregnancies) with amoxicillin (>592,000 pregnancies) found no increase in major congenital anomalies (aRR 0.99, 95% CI 0.94–1.04); a possible weak association with spina bifida was reported (Tran 2025, PLoS Med). The absolute risk is low, and macrolides are mostly used for post-organogenesis indications |
The following summary is at the policy level; Decisions based on dose, gestational age and disease severity should be based on the relevant disease-specific guide.
| Group | Policy |
|---|---|
| Antiemetics | There are multiple options for nausea and vomiting during pregnancy; Agent selection and staging are done according to the hyperemesis/nausea-vomiting guide. In this review, no recommendations are given based on agent. |
| Antihypertensives | ACE inhibitors and ARBs are contraindicated (see Table 2). For selection and target blood pressure, refer to the hypertension guideline during pregnancy. |
| Antidepressants | SSRIs and other antidepressants cross the placenta and the fetal blood-brain barrier. Teratogenicity, pregnancy complications, and neonatal adaptation issues are evaluated separately; The risk of recurrence of maternal disease upon discontinuation of treatment is included in the decision |
| Antiepileptics | As a class, antiepileptics carry teratogenic potential; valproate is avoided whenever possible. Folic acid may help protect against the risk of open neural tube defects in patients taking antiepileptics. Regimen changes are planned prior to conception in conjunction with neurology. |
| Antidiabetics | Insulin has the longest experience in pregnancy; The place of oral agents and their long-term childhood outcomes are controversial. The decision is left to the gestational/pregestational diabetes guideline |
| Anticoagulants | Warfarin is teratogenic (see Table 2); the standard approach during pregnancy is low-molecular-weight heparin. The thromboprophylaxis guideline serves as the basis for indications, dosing, and peripartum management. |
| Cold and allergy medications | Numerous prescription and over-the-counter options exist; safety profiles differ by individual agent and must be verified in the relevant clinical reviews |
The most frequently overlooked part of the drug decision during pregnancy is the cost of untreated disease to the fetus and mother. There are seizures in uncontrolled epilepsy, severe maternal and fetal complications in uncontrolled hypertension, a two- to three-fold increase in the risk of congenital anomalies in uncontrolled diabetes, and poor pregnancy outcomes in untreated maternal depression. Maternal diseases themselves can act as teratogens: the risk of congenital heart disease, cleft palate, coloboma and spina bifida increases in insulin-dependent diabetes; Maternal phenylketonuria uncontrolled by diet is associated with microcephaly, intellectual disability, and congenital heart disease (UpToDate Congenital anomalies: Causes v27.0, 2025).
Prescribing principles can therefore be summarized as follows: avoid fetal drug exposure if possible, especially during the first trimester when organogenesis is ongoing; If medication is necessary, discuss with the patient the risk of taking or not taking medication based on best evidence; minimize the number of medications used; prefer older drugs with a good safety record to newer drugs (pregnancy data are often negligible for new drugs); use the lowest effective dose for the shortest duration; and instruct the patient to consult their physician before discontinuing or starting any medication (including prescription, over-the-counter, or herbal product).
In pregnancies exposed to a drug of uncertain safety in the first trimester, a fetal anatomy scan at 18–20 weeks may be recommended, with fetal echocardiography if congenital heart disease is suspected (UpToDate Prenatal care v126.0, 2026).
Drug counseling during pregnancy should not be satisfied with label information alone; teratogen information services and pregnancy exposure registries should be used. Common sources: REPROTOX (Reproductive Toxicology Center), TERIS and Shepard's Catalog of Teratogenic Agents, MotherToBaby / OTIS (Organization of Teratology Information Specialists), pregnancy exposure registries, and the Teratology Society's free teratology handbook. Drug-drug interactions should also be questioned; For example, folic acid may protect against the risk of open neural tube defects in people taking valproic acid or carbamazepine.
The decision in lactation is based on a different calculation than the decision in pregnancy: what is decisive here is not organogenesis, but the amount of the drug passed into the milk, the relative dose received by the baby and the baby's capacity to clear this substance. It cannot be assumed that a drug used during pregnancy is also suitable for lactation; The opposite is not true either.
Practical principles: for most drugs the benefit of continuing breastfeeding outweighs the benefit of discontinuing the drug or discontinuing breastfeeding; Agents with known passage into milk and relative infant dose, short half-life and low oral bioavailability are preferred; In preterm and newborn babies, drug clearance is slower and more care should be taken. Updated lactation-specific databases such as LactMed (Drugs and Lactation Database, US National Library of Medicine) should be used for agent-by-agent decisions (LactMed, NLM—accessed 2026). The lactation title of the current monograph is now more informative, as the FDA's PLLR regulation also requires a lactation section on the label (FDA PLLR, 2015).
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