DRUGS AND TERATOLOGY .pptx

TERATOLOGY

1. DRUGS IN PREGNANCY AND TERATO LOGY

2. Teratogen: any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function. Teratology: The study of birth defects and their etiology is termed as teratology. 2-3% of all newborns have a major congenital abnormality detectable at birth. 80% of the birth defects do not have an obvious etiology. FDA estimates that less than 1% of all birth defects are caused by medications.

3. CRITERIA FOR DETERMINING TERATOGENICITY GIVEN BY SHEPHARD (1994) ESSENTIAL CRITERIA ANCILLARY CRITERIA The defect should be completely characterized by a geneticist or dysmorphologist . The agent must cross the placenta. Exposure must occur during the critical period. Epidemiological findings must be consistent: By at least 2 epidemiological studies with relative risk of 3 or more. OR For a rare environmental exposure associated with a rare defect, at least three reported cases. 5. The association should be biologically plausible. 6. Teratogenicity in experimental animals is important but not essential

4. TYPES OF MALFORMATIONS Vestibulum congue tempus Lorem ipsum dolor sit amet, consectetur adipiscing elit, sed do eiusmod tempor. MAJOR One which is incompatible with survival, such as anencephaly; or one requiring major surgery for correction, such as cleft palate or congenital heart disease; or one producing major dysfunction (e.g., mental retardation). MINOR For example ear tags or extra digits

5. DOSAGE SPECIFICITY OF AGENT STAGE OF EMBRYONIC DEVELOPMENT DRUG INTERACTIONS GENOTYPE VARIABLES AFFECTING TERATOGENESIS

6. SPECIFICITY OF AGENT Some agents are more teratogenic than others. For example, thalidomide produces phocomelia in primates but not in rodents. Within a given species, however, a given teratogen may affect many organ systems. Some organ systems are preferentially affected, but the pattern of anomalies also reflects the organ systems differentiating at the time the agent was administered. For example, administering thalidomide between days 35 and 37 causes ear malformations; administering the agent between days 41 and 44 causes amelia or phocomelia.

7. DOSAGE At any given time, an embryo can respond to a teratogen in one of three ways: at a low dose - no effect at an intermediate dose - organ-specific malformations can result at a high dose, the embryo may be killed, causing the organ-specific teratogenic action to go unrecognized. The route of administration must be considered because some agents are teratogenic only if administered in a particular fashion. Such an effect probably is related to absorption phenomena . In addition, small doses administered over several days may produce a different effect than an equal total amount administered at one time. Sequential administration of small doses may induce an enzyme system that can degrade the teratogen, causing less damage than if the entire dose were administered at one time. Conversely, a drug administered sequentially might destroy those cells that catabolize the drug, leading to more deleterious consequences than otherwise might be expected.

8. STAGES OF EMBRYONIC AND FETAL DEVELOPEMENT

9. the embryo is relatively resistant to teratogenic insults during the first few weeks of life, perhaps 2 weeks after conception in humans. 2 A large insult might kill the embryo, but surviving embryos usually manifest no organ-specific anomalies. Presumably, the explanation is that early embryonic cells have not differentiated irrevocably. If one cell is destroyed, a surviving cell may be able to assume its function Teratogens act in an organ-specific fashion; a teratogen may affect one organ system at one stage of development but another system at another stage. The precise time at which the insult occurs thus determines not only whether a malformation will occur but also the specific spectrum of anomalies. after organogenesis, embryonic development is characterized primarily by increasing organ size. For most human organ systems, this period begins by 8 to 10 embryonic weeks. During this interval, a teratogen can affect the overall growth of the embryo or the size of a specific organ. However, visible malformations are not expected.

10. GENOTYPE The genotype of the mother and the fetus influences the efficacy of a teratogen. For example, in humans, only 18% of girls had clitoral hypertrophy after administration of norethindrone to their mothers during a specific time and at a specific dose. Differences in genetic susceptibility could logically result from either of two well-established genetic mechanisms: polygenic inheritance and monogenic or Mendelian inheritance .

11. DRUG INTERACTIONS Simultaneous administration of two teratogens may produce a different effect from that existing when the two are administered separately. For example, folic acid reduces the frequency of cortisol-induced teratogenesis in mice, possibly because of induction of enzyme systems that catabolize the teratogen or compete for binding sites. Conversely, one agent may enhance the teratogenic potential of another. For example, the food preservative benzoic acid enhances aspirin teratogenicity in rats. Possible mechanisms include enzyme inhibition, destruction of enzyme-producing cells, and saturation of binding sites on carrier proteins that, if available, would decrease levels of the unbound active teratogen.

12. OTHER FACTORS Variability in teratogenic response sometimes is associated with other environmental or morphologic factors: maternal or fetal weight, in utero position of the fetus, proximity to other affected litter mates, uterine vasculature, and diet. However, further investigation usually reveals that these factors are correlated with other factors already cited.

13. The Problem with Letters Pregnancy letter category system was overly simplistic Misinterpreted as a grading system A drug with adverse effects in animals could be labeled as the same category as a drug with no animal information Example: Pregnancy Category C Animal reproduction studies have shown an adverse effect on the fetus, there are no well controlled studies in humans, BUT the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks Studies in pregnant women and animals are not available

14. PREGNANCY AND LACTATION LABELING RULE (PLLR), 2015 Provide the prescriber with relevant information for critical decision-making when treating pregnant or lactating women More complete statement of the known risks based on the available data Considerations of medical/disease factors Animal data put in context of human exposure Human data added when available Explicitly states when no data are available

15. PLLR – Changes to Labeling 17

16. ANTIEPILEPTICS

17. About 0.5-2% of pregnant women are on antiepileptic medication A benefit-risk assessment is important for the mother and the child and usually there is more risk for both mother and child if the mother’s seizures are not controlled. Women with epilepsy planning conception should have their epilepsy properly controlled before conceiving and should be started on high doses of folic acid supplementation. In pregnant patients with epilepsy; 50% show no change in status, 40% show improvement, 10% patients worsen. The goal of therapy is optimal seizure control with minimum fetal exposure to AEDs. Single drug therapy with the lowest possible dose should be aimed for.

18. DRUG ABNORMALITIES RISK FDA CATEGORY PLACE IN THERAPY VALPROATE NEURAL TUBE DEFECTS, CLEFTS, SKELETAL ABNORMALITIES, DEVELOPMENTAL DELAY 1-2% WITH MONOTHERAPY 9-12% WITH POLYTHERAPY D BENEFITS >RISKS PHENYTOIN FETAL HYDANTOIN SYNDROME 5-11% D BENEFITS >RISKS CARBAMAZEPINE SPINA BIFIDA 1-2% D BENEFITS >RISKS PHENOBARBITAL CLEFTS, CARDIAC ANOMALIES, URINARY TRACT ABNORMALITIES 10-20% D BENEFITS >RISKS AT LOWEST EFFECTIVE DOSE LAMOTRIGINE INCREASED RISK FOR CLEFTS 4-FOLD WITH MONOTHERAPY 10-FOLD WITH POLYTHERAPY C LOW RISK

19. DRUG ABNORMALITIES RISK FDA CATEGORY PLACE IN THERAPY ETHOSUXIMIDE PATENT DUCTUS ARTERIOSUS, CLEFT LIP/PALATE, HYDROEPAHLUS, SPONTANEOUS HEMORRHAGE 1-2% C DRUG OF CHOICE FOR ABSENCE SEIZURES IN FIRST TRIMESTER. CONSIDERED COMPATIBLE LORAZEPAM FLOPPY INFANT SYNDROME, RESPIRATORY DISTRESS 2-4% D BENEFITS>RISKS TOPIRAMATE INCREASED RISK FOR CLEFTS 2% C AVOID IF POSSIBLE IN FIRST TRIMESTER AS DATA IS LIMITED LEVETIRACETAM THEORETICAL RISK-SKELETAL ABNORMALITIES <2% C NO RISK. CONSIDERED SAFE

20. FETAL VALPROATE SYNDROME:

21. FETAL HYDANTOIN SYNDROME

22. FETAL HYDANTOIN SYNDROME

23. FOLIC ACID SUPPLEMENTATION RISK GROUPS DOSE OF FOLIC ACID 1. LOW RISK GROUP FO ALL WOMEN WITH NO RISK FACTORS 400mcg DAILY ONE MONTH BEFORE CONCEPTION TILL 3 MONTHS POST CONCEPTION 2. MODERATE RISK GROUP FAMILY HISTORY OF NTD IN FIRST/ SECOND DEGREE RELATIVE MATERNAL DIABETES MATERNAL MALABSORPTION 1mg DAILY ONE MONTH BEFORE CONCEPTION TILL 3 MONTHS POST CONCEPTION 3. HIGH RISK GROUP H/O NTDs IN WOMEN OR THEIR PARTNER H/O NTDs IN PREVIOUS PREGANACY ON ANTIEPILEPTICS KNOWN MTHFR MUTATION BMI >30kg/m2 HEMOGLOBINOPATHIES 4mg DAILY ONE MONTH BEFORE CONCEPTION TILL 3 MONTHS POST CONCEPTION

24. ANTIHYPERTENSIVES

25. Hypertension complicates 10% of pregnancies out of which 1-6% have preexisting hypertension. The aim of antihypertensive therapy in pregnancy is to prevent maternal and fetal complications and if possible to prolong pregnancy till fetal maturity is achieved. All antihypertensive agents can cross the placental barrier and are present in varying concentrations in fetal circulation thus provoking varying effects on the cardiocirculatory apparatus and fetal metabolism. No commonly used antihypertensive agent is known to be teratogenic.

26. DRUGS FDA CATEGORY MECHANISM OF ACTION FETAL AFFECTS INDICATIONS METHYLDOPA B ALPHA-2 AGONIST CONSIDERED SAFE NON EMERGENT BP CONTROL CLONIDINE C ALPHA-2 AGONIST LIMITED DATA NON EMERGENT BP CONTROL LABETALOL C BETA AND ALPHA BLOCKER CONSIDERED SAFE. HIGHER DOSES CAN CAUSE NEONATAL HYPOGLYCEMIA. NON EMERGENT AND EMERGENT BP CONTROL NIFEDIPINE C CALCIUM CHANNEL BLOCKER CONERN REGARDING CONCOMITANT USE WITH MAGNESIUM NON EMERGENT AND EMERGENT BP CONTROL HYDRALAZINE C ARTERIOLAR SMOOTH MUSCLE REALAXATION NEONATAL THROMBOCYTOPENIA AND LUPUS. NOT TERATOGENIC NON EMERGENT AND EMERGENT BP CONTROL

27. DRUG FDA CATEGORY MOA FETAL CONCERNS INDICATIONS SODIUM NITROPRUSSIDE C DIRECT NO INHIBITOR LIMITED DATA ONLY FOR EMERGENT BP CONTROL DIURETICS: 1. THIAZIDE B BLOCKS SODIUM CHANNELS IN DISTAL TUBULES VOLUME CONTRACTION MAY LIMIT FETAL GROWTH, THOUGH NOT PROVEN IN STUDIES. NON EMERGENT BP CONTROL 2. FUROSEMIDE C BLOCKS SODIUM CHANNELS IN DISTAL TUBULES PIH WITH PULMONARY EDEMA/ CHF ACE INHIBITORS AND ARBS D ACE-I: INTERFERES WITH THE CONVERSION OF ANGIOTENSIN TO ANGIOTENSIN 2 ARB: ANTAGNISES ATI RECEPTOR RENAL DYSGENESIS, CALVARIAL, OLIGOHYDRAMNIOS, PULMONARY HYPOPLASIA, SKELETAL ABNORMALITIES, , LIMB REDUCTION DEFECTS, NEONATAL ANURIC RENAL FAILURE NOT INDICATED

28. ANTIMICROBIALS IN PREGNANCY

29. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut microbiome , asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy

30. AMINOGLYCOSIDES Nephrotoxic , cause 8 th nerve damage QUINOLONES R/O permanent arthropathy in animals (data ltoo limited in animals) CHLORAMPHENICOL Grey baby syndrome if given close to term MACROLIDES Small risk of neonatal jaundice

31. ANTIFUNGALS Amphotericin B remains the first-choice parenteral drug in spite of its well-established toxicity. Topical drugs are used throughout pregnancy because of limited absorption. Recent data have clarified the teratogenic effect of high-dose fluconazole during the first trimester and provided reassuring cumulative data regarding its use at a single low dose in this key period. Fluconazole is associated with a pattern of congenital malformation resembling ANTLEY BIXLEY SYNDROME Recent data have also provided additional safety data on itraconazole and lipidic derivatives of amphotericin B. Regarding newer antifungal drugs, including posaconazole and echinocandins, clinical data are critically needed before considering prescription in pregnancy.

32. ANTLEY BIXLER SYNDROME Oral cleft Abnormal facies Cardiac abnormality Joint and skull abnormality

33. ANTI TUBERCULAR DRUGS Monitoring of liver enzymes is important and is recommended throughout pregnancy.59, 60 An elevation of 3–5 times the upper limit of normal may prompt discontinuation of anti-TB therapy. Pyridoxine (B6) daily oral supplementation (25–50 mg/day) is advised in all pregnant women receiving INH to mitigate neurologic complications in the mother and newborn. The newest anti-TB agent, bedaquiline , is considered Pregnancy Category B. Capreomycin , Ethionamide , PAS ---Contraindicated in pregnancy due to teratogenic effects.

34. ANTIVIRAL DRUGS RIBAVIRIN Associated with birth defects – including skull, palate, eye, skeleton, and GI abnormalities. EFAVIRENZ In animal studies it has shown CNS and ocular abnormalities .

35. ANTICOAGULANTS

36. ANTICOAGULANTS IN PREGNANCY Some pregnant women require anticoagulation during pregnancy and/or in the postpartum period, including women at high risk of deep vein thrombosis and women with prosthetic heart valves, atrial fibrillation, cerebral venous sinus thrombosis, left ventricular dysfunction, and some women with fetal loss. Use of anticoagulants during pregnancy is challenging due to the potential teratogenic effects and dosing complexities of the various agents, and the management of anticoagulation around the time of labor. In addition, women receiving chronic anticoagulation who are contemplating pregnancy need counseling regarding how to avoid the potential teratogenic effects

37. Select Anticoagulant Agents and Implications in Pregnancy

38. Delivery is the highest period of bleeding for a pregnant woman, including the placement of regional anesthesia and Cesarean delivery. Low molecular weight heparin (LMWH) is recommended to be discontinued 12-24 hours prior to lumbar instrumentation, along with an international normalized ratio (INR) ≤1.5. Vitamin K antagonists (e.g., warfarin) cross the placenta and have a dose-dependent relationship with adverse outcomes (e.g., miscarriage, stillbirth, embryopathy). These usually occur with doses >5 mg/day. Women with mechanical heart valves are at high risk of thromboembolic complications. These patients can either be treated with continued warfarin therapy (especially if daily dose is ≤5 mg and INR ≤5) or use of weight-based LMWH dosed twice daily. Use of direct oral anticoagulants (e.g., dabigatran) should NOT be used given their risk of mechanical valve thrombosis. Women with a history of thrombophilia or VTE on chronic anticoagulation should continue anticoagulation during (and after) pregnancy. Weight-based LMWH is the preferred agent, but warfarin (daily dose ≤5) is an alternative. Use of direct oral anticoagulants (e.g., rivaroxaban) has not been systematically studied, but they do cross the placenta and their safety cannot be substantiated. Women with a history of thrombophilia, but no personal VTE history should receive surveillance or prophylactic doses of LMWH antepartum, but strongly consider full therapeutic doses postpartum. Women with a personal history of VTE on chronic anticoagulation should receive therapeutic doses of LMWH antepartum and postpartum. Weight-based LMWH should be accompanied by peak anti- Xa levels drawn 4-6 hours post-dose to achieve a goal level of 1.0-1.2 U/ml.

39. HYPOGLYCEMIC AGENTS

40. Drugs approved for use in Diabetes in pregnancy: Insulin Metformin Glyburide Neither insulin nor metformin or glyburide use in pregnancy has been associated with newborn with birth defects. Long term metabolic effects of offspring exposed in utero to oral hypoglycaemic agents are less well known.

41. RECOMMENDATIONS ACOG ADA SMFM FIRST LINE INSULIN INSULIN INSULIN OR METFORMIN SECOND LINE METFORMIN METFORMIN OR GLYBURIDE GLYBURIDE ALTERNATIVE GLYBURIDE

42. INSULIN METFORMIN GLYBURIDE FDA CATEGORY B B B/C CROSS PLACENTA - + + WEIGHT GAIN + - + HYPOGLYCEMIA + - + ADVERSE FETAL EFFECTS NOT KNOWN PLACENTAL INSUFFIENCY. SHOULD BE USED WITH CAUTION IN PREECLAMPSIA AND FGR FETAL HYPERINSULINEMIA AND DIABETIC FETOPATHY. NO LONG TERM SAFETY DATA AVAILABLE. PLACE IN THERAPY DRUG OF CHOICE FOR DIABETES IN PREGNANCY SECOND LINE HYPOGLYCEMIC AGENT NOT FDA APPROVED FOR USE IN PREGNANCY

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