DRUGS USED DURING PREGNANCY
Traditionally, medical professionals have measured pregnancy from a number of convenient points, including the day of last menstruation, ovulation, fertilization, implantation and chemical detection. In medicine, pregnancy is often defined as beginning when the developing embryo becomes implanted in the endometrial lining of a woman's uterus. Common health problems encountered during pregnancy: 1. Stress, insomnia & depression 2. GI disturbances 3. Pain & Fever 4. Infections 5. Asthma & Cough 6. Allergy 7. Hypertension 8. Epilepsy 9. Diabetes Drugs used during pregnancy can have temporary or permanent effects on the fetus. 1991 WHO International Survey of Drug Utilization in Pregnancy: 86% of women took medication during pregnancy. Despite this high rate of medication intake, most drugs are not labeled for use during pregnancy. Adverse effects drugs used during pregnancy: Spontaneous abortion Fetal growth retardation Teratogenicity (permanent anatomical/physiological abnormality) Direct drug toxicity Neonatal drug withdrawal Long term effects on neurobehavioral development Carcinogenesis Factors to be considered while prescribing drugs during pregnancy: Minimize use of medications and for shortest duration possible Timing of exposure (sensitive period) “All-or-none” period *Organogenesis* (Avoid drug administration, if at all possible during 1st trimester) Brain development (fifth week of pregnancy) Dose of drug (threshold, dose-response) Genetic susceptibility Role of underlying maternal disease Other exposures such as alcohol and cigarette smoking The first 12 weeks (upto 3 months) of pregnancy are considered to make up the first trimester. Weeks 13 to 28 (upto 7 months) of the pregnancy are called the second trimester. Weeks 28 onwards of the pregnancy are called the third trimester. Influence of physiological changes in pregnancy on drug dose requirements: • prolonged gut transit time • plasma albumin concentration • amounts of body water and fat • renal blood flow in 3rd trimester • liver blood flow does not change • enzymatic activity changes CYP 3A4, 2D6, 2C9 (by progesterone)
CYP 1A2, 2C19 hyperventilation placenta
Factors that affect placental drug transfer & drug effects on fetus: 1. Physicochemical properties of the drug a. lipid solubility b. degree of drug ionization c. molecular size d. degree of protein binding 2. Dose & duration of exposure to the drug 3. Stage of placental & fetal development at time of exposure to the drug 4. Genetic predisposition & susceptibility The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast milk. In 1979, the United States Food and Drug Administration (FDA) introduced a classification of fetal risks due to pharmaceuticals. This was based on a similar system that was introduced in Sweden one year earlier. The United States FDA has the following definitions for the pregnancy categories: United States FDA Pharmaceutical Pregnancy Categories Pregnancy Category A Pregnancy Category B Pregnancy Category C Pregnancy Category D Pregnancy Category X Pregnancy Category N Adequate and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. FDA has not classified this drug.
One characteristic of the FDA definitions of the pregnancy categories is that the FDA requires a relatively large amount of high-quality data on a pharmaceutical for it to be defined as Pregnancy Category A. As a result of this, many drugs that would be considered Pregnancy Category A in other countries are allocated to Category C by the FDA. Classification of a few important drugs/vaccines Antibacterial agents Category B : Penicillin, metronidazole, nitrofurantoin, cephalosporins, clindamycin, terbinafine, some macrolides e.g. azithromycin, erythromycin Category C : Some aminoglycosides, chloroquine, quinolones, mebendazole, fluconazole Category D : Tetracyclines, gentamicin, tobramycin Cardiovascular drugs Category B : Heparin (LMW)
Category C : Heparin (conventional), beta-blockers, (dihydropyridine) calcium antagonists, furosemide, digoxin, methyldopa Category D : ACE inhibitors, ARBs, coumarins, thiazides, diltiazem Central nervous system drugs Category B : Acetaminophen, caffeine Category C : Aspirin, clonidine, rofecoxib Category D : Carbamezapine, valproic acid, diazepam, lithium vac Others Category C : Vaccines such as Tetanus toxoid, polio vaccine , BCG vaccine, hepatitis A vaccine, hepatitis B vaccine and rabies vaccine. Category D : Alcohol is one of the most dangerous drugs for a pregnant women ,especially in the early weeks of pregnancy.