PHARMACY AND PREGNANCY: A REVIEWHTML Full Text
PHARMACY AND PREGNANCY: A REVIEW
Aditi Thakur*1, Harman Kaur Gill 1, Ajay Sharma 2, Nipun Mahajan 1 and Shruti Rawal 1
Department of Pharmaceutical Sciences, Lovely School of Pharmaceutical Sciences, Lovely Professional University 1, Phagwara- 144402, Punjab, India
Department of Chemistry, Lovely School of Sciences (Chemistry), Lovely Professional University 2, Phagwara- 144402, Punjab, India
Pregnancy is a state of double danger i.e. any drug that a pregnant woman takes can easily cross placenta and can produce a teratogenic effects on fetus. It can interfere with normal embryonic or fetal development and induce abnormal post natal structure or function. Teratogens alter the genetic function of fetus. This review provides practitioners with summary of information regarding teratology risks for drugs, chemical exposure during pregnancy.
INTRODUCTION: Pregnancy is the term used to describe when a woman has a growing fetus inside of her. In most cases, the fetus grows in the uterus. Human pregnancy lasts about 40 weeks or just more than 9 months, from the start of the last menstrual period to childbirth. Each pregnancy is divided into three trimesters. These three trimesters have different emotional and physical happenings that make them unique.
- The First Trimester (Weeks 1-12)
- The Second Trimester (Weeks 13-27)
- The Third Trimester (Weeks 28-40)
A Double Danger: For a pregnant woman, drug abuse is doubly dangerous. First, drugs may harm her own health, interfering with her ability to support the pregnancy. Second, some drugs can directly impair prenatal development. Drugs taken by a pregnant woman reach the fetus primarily by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the fetus's growth and development.
Drugs that a Pregnant Woman takes during Pregnancy can affect the Fetus in several ways:
- They can act directly on the fetus, causing damage, abnormal development (leading to birth defects), or death.
- They can alter the function of the placenta, usually by causing blood vessels to narrow (constrict) and thus reducing the supply of oxygen and nutrients to the fetus from the mother. Sometimes the result is a baby that is underweight and underdeveloped.
- They can cause the muscles of the uterus to contract forcefully, indirectly injuring the fetus by reducing its blood supply or triggering preterm labor and delivery.
How Drugs Cross the Placenta: Some of the fetus's blood vessels are contained in tiny hair like projections (villi) of the placenta that extend into the wall of the uterus. The mother's blood passes through the space surrounding the villi (intervillous space). Only a thin membrane (placental membrane) separates the mother's blood in the intervillous space from the fetus's blood in the villi. Drugs in the mother's blood can cross this membrane into blood vessels in the villi and pass through the umbilical cord to the fetus 1.
Drug Metabolism in Pregnancy: During pregnancy, changes in drug absorption, metabolism, distribution, and elimination occur. Because of the dynamic nature of these changes, it is often difficult to predict which factors will have a significant impact on drug pharmacokinetics. Changes in gastrointestinal function that occur during pregnancy may affect the drug absorption 2. Delayed gastric emptying may delay peak drug levels 3. Prolonged intestinal transit time may increase the absorption of some relatively water-insoluble drugs or increase the metabolism of drugs by intestinal wall enzymes. Decreased gastric acid secretion may change the gastric pH and alter drug solubility.
Changes in body fluid compartments during pregnancy can profoundly affect drug distribution. Increases in maternal plasma volume and the enlarging fetal compartment increase the volume of distribution of many drugs, altering maternal plasma drug concentrations and elimination half-life. The progressive decrease in maternal albumin concentration causes a corresponding increase in unbound drug fraction.
Because pharmacological efficacy and toxicity are related primarily to the concentration of unbound drug, pregnancy-induced changes in protein binding may have important clinical implications, especially for acidic drugs that are highly protein-bound 3. The 50% increase in the maternal glomerular filtration rate that occurs during pregnancy results in the increased elimination of renally excreted drugs. Drug levels of phenytoin (Dilantin) and carbamazepine (Tegretol) decrease in pregnancy, presumably because of increased P450 activity 4. Progesterone induces certain cytochrome P450 enzymes and other mixed function oxidase enzymes. These hormone activities can have confounding effects on drug metabolism and make drug levels difficult to predict. Placental and fetal factors influence the effect of maternal medications on the developing fetus. Although most chemicals enter the fetal circulation by simple diffusion, some cross the placenta by facilitated or active transport processes 5. The placenta contains enzymes capable of drug oxidation, reduction, hydrolysis, and conjugation.
Placental cytochrome P450 enzymes may play a role in fetal protection in the bio-oxidation of xenobiotics; including drugs 6. Fetal tissues are also capable of metabolizing drugs. Although this contributes little to drug clearance, which is largely effected by maternal systems, it may contribute to fetal toxicity through the accumulation of toxic drug metabolites.
This mechanism may be particularly important for polar drugs, which do not readily cross the placenta back to the maternal circulation. Fetal albumin concentrations are below maternal levels early in pregnancy and then rise progressively. Early in pregnancy, fetal unbound drug concentrations may be high, even when maternal drug concentrations are low, resulting in toxicity to the fetus. This potential toxicity during the first trimester, the period of major organogenesis, underlies the recommendations for the conservative use of medications during early pregnancy.
Drugs and the Stages of Pregnancy: Some drugs can be harmful when used at any time during pregnancy; others, however, are particularly damaging at specific stages.
The stage of Organ Formation: Most of the body organs and systems of the baby-to-be are formed within the first ten weeks or so of pregnancy (calculated from the date of the last menstrual period). During this stage, some drugs and alcohol in particular can cause malformations of such parts of the developing fetus as the heart, the limbs, and the facial features.
The Stage of Prenatal Growth: After about the tenth week, the fetus should grow rapidly in weight and size. At this stage, certain drugs may damage organs that are still developing, such as the eyes, as well as the nervous system. Continuing drug use also increases the risk of miscarriage and premature delivery. But the greatest danger drugs pose at this stage is their potential to interfere with normal growth. Intrauterine growth retardation (IUGR) is likely to result in a low-birth weight baby- a baby born too early, too small, or both.
The Stage of Birth: Some drugs can be especially harmful at the end of pregnancy. They may make delivery more difficult or dangerous, or they may create health problems for the newborn baby.
TERATOGEN: Teratogen is a substance, organism, physical agent, or deficiency state present during gestation that is capable of inducing abnormal postnatal structure or function (biochemical, physiologic or behavioral) by interfering with normal embryonic or fetal development if fetal exposure to these agents occurs during pregnancy. A child born with any kind of malformation or with any birth defect may create societal problems and therefore this subject needs concern 7.
FDA Rating System for the Teratogenic Effects of Drugs: FDA provides the most widely used system to grade the teratogenic effects of medications. The FDA assigns a safety category for medications by using a 5-letter system: A, B, C, D, and X. This safety category must be displayed on the labels of all drugs intended to be used during pregnancy 8. The category & the labeling of drugs are summarized in table 1.
TABLE 1: SUMMARY AND LABELING ON DRUGS TO BE INTENDED DURING PREGNANCY
|Category of drugs||Summary and labeling on drugs to be intended during pregnancy|
|A||Fetal risk not revealed in controlled studies in humans. Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).|
|B||Fetal risk not confirmed in studies in humans but has been shown in some studies in animals. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.|
|C||Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus. Animal reproduction studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, and the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.|
|D||Fetal risk shown in humans; use only if benefits outweigh risk to fetus. Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).|
|X||Contraindicated; benefit does not outweigh risk|
Principles of Teratogenesis:
- Susceptibility to a teratogenic agent is dependent upon the genotype of the embryo and the manner in which the agent interacts with environmental factors.
- Susceptibility to teratogenic agents is dependent on the timing of the exposure and the developmental stage of the embryo.
- Teratogenic agents act in specific ways on cells or tissues to cause pathogenesis.
- The final manifestations of abnormal development are death, malformation, growth restriction and functional disorders.
- Access to the embryo by environmental Teratogens depends on the nature of the agent.
- As the dosage increases, manifestation of deviant development increases.
Drug Exposure in the Male Partner: 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 affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development. Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure 9 10.
TABLE 2: LIST OF TERATOGENIC AGENTS AS PER FDA
|S. NO||Name of the drug||Uses of the drug||Pregnancy category by FDA||Trimester of risk||Defects & Complications associated with the use of Drug|
|1||Acamprosate Calcium 11||To Treat Alcohol Dependence||C||Unknown||Possible hydronephrosis, malformed iris, retinal dysplasia|
|To treat heart failure, hypertension||C or D||First trimester (category C); second and third trimesters (category D)||IUGR premature labor, and fetal and neonatal renal failure, patent ductus arteriosus, respiratory distress syndrome|
|3||Acetohydroxamic acid||To treat chronic urinary infections||X||First, second, and third||Cardiac anomalies included atrial septal defects, ventricular septal defects. Skeletal anomalies|
|4||Acitretin 12||Used to treat severe psoriasis||X||first||Severe limb defects, craniofacial anomalies|
|5||Aminocaproic Acid 13||To treat excessive postoperative bleeding||C||First, second, and third||Possible fetal haemorrhage|
|Used as antibiotics||D||Not consistent||Some neonates have had hearing defects, inner ear defect, and vestibular problems.|
|7||Amitriptyline 15||Used in migraine, ankylosing spondylitis.
|C||First||Hydrocephaly, Abnormally small head ,heart defect, Jaw anomaly, foot deformities, extra digits, ambiquous genitalia, hypospadias, oral cleft, absent eyes|
|Used in hypertension, diabetic neuropathy, congestive heart failure||D||First, second, and third||Hypotension, renal dysplasia, anuria or oliguria, IUGR, patent ductus arteriosus, incomplete ossification of the skull|
|To treat epilepsy as anticonvulsant, bipolar disorder||C||First, second, and third||Neural tube defects, hydrocephaly, pulmonary stenosis, wide set eyes, small jaw, extra digits , club foot, long thin fingers absent, ear canal opening|
|10||Atorvastatin 16||Used to treat high cholesterol and high triglycerides||X||First, second, and third||spina bifida
|11||Apomorphine 17||Used to treat Parkinson’s disease, erectile dysfunction, Alzheimer’s disease||C||Unknown||Limb defects in chicken, birth defects in chicken|
|12||Aspirin 18||NSAIDs||D||First, second, and third||Unclear; may be associated with an increased risk of gastroschisis|
|13||Atenolol 19||Used to treat angina, high blood pressure, heart failure, migraine||D||First, second, and third||IUGR|
|14||Azacitidine 20||Antineoplastic||D||First, second, and third||CNS anomalies, limb anomalies (e.g., micromelia, club foot, syndactyly, oligodactyly), and others (e.g., micrognathia, gastroschisis, oedema, rib abnormalities)|
|15||Azathioprine21||Immunosuppressant||D||First||Flattened back of skull, pulmonary stenosis, club foot, extra digits, Failure of bile ducts to develop, hypospadias,|
|16||temazepam, triazolam, flurazepam||Used to treat alcohol dependence, GAD, insomnia, seizures||X||The first, second, and third||Unclear; potential for isolated oral cleft|
|17||Bevacizumab 22||Chemotherapeutic agent||C||Unknown||Decrease in maternal and fetal body weights, increased number of fetal resorptions|
|18||Birth control pills 23||Oral contraceptives/ hormone replacement therapy||X||First, second, and third||Variable; inflammatory complications common|
|19||Bleomycin 24||Used in treatment of cervical cancer, neck cancer ,skin cancer, testicular cancer, Hodgkin’s disease||D||Second and third||Leucopoenia, neutropenia|
|20||Bromides 25||Used to treat scrofula (as bromide of potassium), bromide ion is used as antiepileptic||D||First, second, and third||Polydactyl, GI anomalies, clubfoot, and congenital dislocation of the hip, IUGR|
|21||Busulfan 26||Used to treat symptoms of leukaemia||D||First, second, and third||Mild anaemia, neutropenia, sterility in both male and female offspring.|
|22||Carbamazepine 27||Used to treat epilepsy, neuralgia, bipolar disorder||D||First, second, and third||underdevelopment of the fingers, toes, and nails; developmental delay|
|23||Captopril 28||Used to treat hypertension, congestive heart failure.||D||First||Decreased fetal limb contractures, hypoplastic lung development, IUGR, and patent ductus arteriosus|
|24||Cetuximab 29||Used to treat cancer||C||Unknown||Unknown|
|25||Colchicine 30||Anti-gout||C or D||unknown||Down syndrome|
|26||Cidofovir 31||Treatment for CMV retinitis in AIDS patients, as broad-spectrum anti-viral, nucleoside analogue||C||Unknown||Possible external, soft tissue and skeletal anomalies (i.e., meningocele, short snout, short maxillary bones) of the foetus.|
|27||Cinacalcet 32||Used to treat hyperparathyroidism||C||Unknown||Possible reduced postnatal maternal weight gain.|
|28||Clomiphene 33||Used to treat infertility in women||X||First||Retinal aplasia ,Syndactyly, Clubfoot, Microcephaly, Cleft lip/palate, Down's syndrome|
|29||Clonazepam 34||Used to treat anxiety , seizures||D||First||Neonatal withdrawal syndrome|
|30||Clorazepate 35||Used to treat anxiety , seizures||D||First||Neonatal withdrawal syndrome|
|31||Cocaine 36||Drug of abuse||X||First, second, third||Death, growth retardation, Premature labor and abruption placentae|
|32||Colchicine 37||Used in arthritis and Mediterranean fever||C or D||Unknown||Down’s syndrome, syndactly, cleft palate|
(hydrocortisone, clobetasol propionate)
|For inflammatory and autoimmune diseases||C||First||Reduced birth weight, preeclampsia, oral and lip clefts|
|34||Cyclophosphami-de 39||Used to treat breast cancer, leukemia, ovarian cancer||D||First||Flattened nasal bridge, palate defect, Haemangioma, umbilical hernia, growth retarded|
|35||Cytarabine 40||Used in treatment of leukemia||D||First and second||Bilateral microtia and atresia of external auditory canals, right hand lobster claw with three digits, bilateral lower limb defects|
|36||Danazol 41||For endometriosis, angioedema||X||First, second, and third||virilisation of the external genital organs, Masculinisation of female foetus|
|37||Diazepam||Used in treatment of agitation, tremors, seizures, anxiety.||D||First||Neonatal withdrawal syndrome, neonatal apnea and hypotonia|
|38||Diethylstibestero-l 42||Was used as a treatment for gonorrhoeal vaginitis, atrophic vaginitis and other symptoms of menopause, and to suppress postpartum lactation and prevent associated breast engorgement after childbirth||X||First, second and third||Structural uterine, cervical, or vaginal abnormalities in female offspring. Epididymal cysts, undescended testes, and small testes in male offspring. Still birth|
|39||Duloxetine 43||For depression, GAD, diabetic neuropathy||C||First, second, and third||Variable|
|40||Ergotamine44||To treat migraine||X||First, second, and third||Low birth weight and preterm birth|
|41||Estradiol 45||Used treatment of symptoms associated with menopause, prevention of bone fracture associated with osteoporosis, dysfunctional uterine bleeding||X||First, second, and third||Structural uterine, cervical abnormalities,
|42||Ethanol 46||Recreational Drug||D||First, second||growth retardation, Foetal alcohol syndrome|
|43||Etretinate 47||Used to treat severe cases of psoriasis||X||First||cerebral abnormalities, including meningomyeloceles|
|44||Exenatide 48||Used in treatment of renal failure, type 2 diabetes||C||Unknown||Possible skeletal effects|
|45||Finasteride 49||Used in Male Pattern Baldness Treatment, Enlarged Prostate Treatment||X||First, second, and third||Abnormalities of the sex organs|
|46||Fluconazole 50||Antifungal||C||Unknown||Craniofacial, skeletal, and cardiac effects|
|47||Fluoxetine 51||To treat depression, bulimia, panic attacks, premenstrual disorder||D||First, second, and third||Variable; possible self-limited neonatal behavioural syndrome|
|48||Fluorouracil 52||Used to treat precancerous and cancerous skin growth||D||First||radial aplasia; absent thumbs and three fingers; hypoplasia of lungs, aorta, thymus, and bile duct|
|49||Flurazepam 53||Used as hypnotic to treat insomnia||X||First||Polydactyl, oral clefts, cardiovascular defects|
|50||Flutamide||Used to treat prostatic carcinoma||D||Third||Male pseudohermaphroditism|
|51||Folic acid antagonists 54
|To treat megaloblastic anaemia||D in general||First, during normal closure of the fetal neural tube||Variable; neural tube defects|
|52||Hydroxyurea 55||Used to treat melanoma, polycythemia, thrombocythemia||D||First||IUGR , hip dysplasia, unilateral renal dilatation and pilonidal sinus|
|53||Ibandronate 56||To treat osteoporosis||C||Unknown||Unknown|
|54||Imipramine 57||Used to treat symptoms of depression, childhood enuresis||D||First and third||Bilateral Amelia, dyspnoea, lethargy|
|55||Isotretinoin 58||Used in treatment of severe , cystic acne||X||First||ear abnormalities ( micropinna, small or absent external auditory canals); eye abnormalities (microphthalmia); facial dysmorphia; cleft palate, CNS abnormalities ( hydrocephalus,|
|56||Kanamycin 59||Used to treat bacterial infection, antibiotic||X||First||foetal eighth cranial nerve toxicity and hearing loss|
|57||Lithium carbonate 60||Used in treatment of manic episodes of bipolar disorder||D||First||Cardiovascular defects (rudimentary left ventricle without inlet or outlet, aorta and pulmonary artery arising from right ventricle, patent ductus arteriosus, Mitral atresia) Ebstein’s anomaly, spina bifida|
|58||Leflunomide 61||To treat rheumatoid sarthritis||X||First||Microcephaly and mental retardation|
|59||Lenalidomide 62||To treat myelodysplastic syndromes (MDS) and other cancers||X||First, second, and third||Possible reduction in fetal body weight and increase in post implantation losses and fetal variations|
|60||Leukotriene receptor antagonists 63
|To treat asthma||C||Unknown||Unknown|
|61||Leuprolide 64||Used to treat prostate cancer, uterus endometriosis||X||First||Spontaneous abortion, intrauterine growth retardation, low birth weight|
|62||Lithium 65||To treat bipolar disorder||D||Unknown||Variable; possible cardiac effects|
|63||Medroxyprogest-erone||Used to treat abnormal bleeding from uterus, to restore normal menstrual period in females, to reduce risk cancer of uterus||D||First||ventricular septal defect and tricuspid Artesia|
|64||Mercaptopurine||Used to treat lymphocytic leukaemia, ulcerative colitis||D||First||Neural tube defects, oral clefts, heart defects, retarded foetal growth, small eyes|
|65||Methimazole66||To treat hyperthyroidism||D||First, possibly second, and third||scalp defects; possible choanal and oesophageal atresia|
|66||Methylene blue 67||To treat malaria, cancer, resistant plaque psoriasis, cyanide poisoning, AIDS-related Kaposi's sarcoma||C||Unknown||Intestinal Artesia’s|
|67||Mifepristone 68||To treat cancer, cushing syndrome, AIDS-related Kaposi's sarcoma||D||First||Unknown; possible sexual function|
|68||Minoxidil 69||To treat hypertension, male pattern baldness||C||First, second, and third||Hypertrichosis of the back and extremities, dysmorphic facial features, uneven fat distribution, omphalocele|
|69||Misoprostol 70||Reducing the risk of NSAID (nonsteroidal anti-inflammatory drugs,) in induced gastric ulcers||X||First, second, and third||Mobius syndrome, Labor induction|
|70||Mycophenolate mofetil 71||To treat autoimmune renal disease, and prevent organ transplant rejection||D||First||External ear and facial defects; cleft lip and palate; heart, oesophagus, kidney and distal limb defects|
|71||Mysoline 72||To treat epilepsy||D||Unknown||Variable|
|Used to treat urinary tract infections||C||First||Haemolysis in children with glucose-6-phosphate deficiency|
|73||Natalizumab 73||To treat multiple sclerosis||C||Unknown||Unknown|
|74||Nelarabine||To treat T-cell acute lymphoblastic leukemia||D||First, second, and third||Variable; disrupting DNA synthesis in rapidly diving cells|
|75||Nicotine 74||(for smoking)
Depression, anxiety, schizophrenia
|D||First||Death, growth retardation, musculoskeletal malformations|
|76||Norethisterone 75||used to treat premenstrual syndrome, painful periods, abnormal heavy bleeding, irregular periods, menopausal syndrome||X||First||Masculinisation of female infant|
|77||Pegaptanib 76||For recurrent and non-clearing vitreous haemorrhage in proliferative diabetic retinopathy||B||Unknown||Unknown|
|78||Pemetrexed 77||Used as chemotherapy drug||C||Unknown||Unknown|
|79||Penicillamine 78||To treat Wilson’s disease, cystinuria, scleroderma, rheumatoid arthritis||D||Unknown||Variable; possible connective-tissue defects, cerebral palsy, hydrocephalus, skeletal defects, cleft palates, and fetal toxicity|
|80||Phencyclidine||Used as veterinary anaesthetic||X||Third||Triangular-shaped face with pointed chin, antimon- goloid slanted eyes, nystagmus|
|81||Phenobarbital 79||To treat epilepsy hypnotics||D||Third||cleft palate or lip and congenital heart disease, can cause fetal addiction and newborn withdrawal symptoms|
|82||Phensuximide 80||Used to treat epilepsy and other seizure disorders||D||Third||Ambiguous genitalia, inguinal hernia, pyloric stenosis|
|83||Phenytoin 81||To treat epilepsy||D||Unknown||Finger like thumbs, clubfoot, abnormal palmar creases and nail hypoplasia or aplasia. hirsutism, microcephaly,mild micrognathia,foetal hydantoin syndrome|
|84||Potassium iodide 82||To treat thyroid cancer, used as an expectorant||D||Unknown||Hypoplasia, goitre|
|85||Povidone-iodine 83||Used to treat wounds, infections, as antiseptic, in mouthwashes, gargles||D||First||Enlarged heart, goitre, foetal growth retardation|
|86||Progesterones 84||To treat menstrual problems, lowers the risk of estrogens-related cancer of the uterus||D or X||First, second, and third||Possible cardiovascular defects, hypospadias|
|87||Propylthiouracil 85||Used to treat hyperthyroidism||D||Second and third||Hypothyroidism, neonatal goitre|
|88||Quinine 86||Used to treat malaria, fever, also acts as analgesic||X||First||Hydrocephaly, dysmelia, auditory defects, optic nerve damage|
|89||Ramelteon||To treat insomnia||C||Unknown||Unknown|
( arotinoids RO 13-7410, RO 13-6298, RO 15-1570)
|To treat acne, psoriasis, skin cancers, inflammatory skin disorders, photo aging||X||The first, second, and third trimesters are times of risk. The critical window of exposure is at 3-5 weeks of pregnancy.||hydrocephalus; microcephalusf, cleft palate,thymic aplasia; psychological impairments; absent or defective ears; small jaw|
|91||Ribavirin 88||Used for treatment of hepatitis C, cirrhosis||X||First||Stillbirth, abortion|
|92||Rifaximin 89||To treat traveller’s diarrhoea, also as antibiotic||C||Unknown||cleft palate, agnathia, jaw-shortening, haemorrhage, eyes partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae|
|93||Simvastatin 90||It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease||X||First||Extra digits, clubfoot, duodenal atresia ,Pyeloureteral junction constriction, cleft lip, retarded fetal growth, fetal death|
(I-131, I-125) 90
|Used to treat and cure iodine deficiency, goitre||X||First||hydrocephaly, cardiopathy, genital hypotrophy, limb deformity, congenital hypothyroidism|
|95||Solifenacin succinate 91||To treat the symptoms of an overactive bladder, such as frequent urination, leaking accidents, and urinary urgency||C||Unknown||Unknown|
|96||Sorafenib 92||Used to treat hepatocellular carcinoma, renal cell carcinoma||D||First, second, and third||Variable|
|97||Streptomycin 93||Used in treatment of tuberculosis, plague, respiratory, endocardial, and meningeal infection||D||First, Second and third||Ototoxicity, deafness|
|98||Sulfasalazine 94||To treat inflammatory bowel disease||B||First||Microcephaly, ventricular septal defect and coarctation of the aorta, cleft palate|
|99||Tamoxifen 95||Used to treat breast cancer, infertility, gynecomastia, bipolar disorder.||D||First||craniofacial anomalies include facial asymmetry, microtia, micrognatha and U-shaped cleft of the secondary palate|
|100||Telithromycin 96||To treat wide variety of bacterial infections.||C||Unknown||Variable; potential liver failure and liver damage in the mother|
|101||Temazepam||used as hypnotic, used in in insomnia therapy||X||First||Neonatal withdrawal syndrome|
|To treat bacterial infections||D||Second and third||Dental staining|
|103||Thalidomide 98||Was used as tranquilizer and painkiller, for morning sickness.||X||First, second, and third||Malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies, phocomelia|
|104||Thioguanine 99||Used in treatment of non lymphocytic leukemia||D||First and second||Generalized oedema, cranial defects, general skeletal hypoplasia, hydrocephalus, ventral hernia|
|105||Tinidazole 100||To treat giardiasis, trichomoniasis||C||First, second, and third||Variable|
|106||Tiotropium bromide 101||To treat chronic obstructive pulmonary disease (COPD)||C||Unknown||Unknown|
|107||Tobramycin||used to treat eye infection, intra abdominal infections, meningitis||C||First and second||Hearing problem to off spring, neural tube defect, cleft lip, cleft palate|
|108||Toluene||Solvent Sniffing||D||Growth retardation|
|109||Triazolam||Used in treatment of insomnia||X||First||Neonatal withdrawal syndrome, oral clefts, extra digits, heart defects, hydrocephaly, retarded fetal growth.|
|110||Trimethadione 102||To treat seizure disorders||D||First, second, and third||Malformed ears, cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities; delayed mental and physical development also observe|
|111||Trospium chloride 103||To treat Overactive Bladder||C||Unknown||Unknown|
|112||Valproic acid 104||To treat epilepsy, bipolar disorder||D||First, second, and third||Spina bifida with meningomyelocele or meningocele, often accompanied by midfacial hypoplasia, deficient orbital ridge|
|113||Vinblastine 105||Used in treatment of Lymphocytic lymphoma, Advanced carcinoma of the testis||D||First||Olygodactyly, respiratory distress syndrome|
|114||Vincristine 106||Used in treatment of Acute Lymphoid Leukemia, Diffuse Large B-Cell Lymphoma.||D||First, second, third||Fetal death. Increased incidence of skeletal and eye defects, spina bifida, exencephaly, syndactyly|
|115||Warfarin 107||To treat the risk of pulmonary embolism||X||First, second, and third||Deformities of the axial and appendicular skeleton; also, a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly, and scoliosis.|
Drugs Withdrawn From Market Because Of Their Teratogenic Effects:
Diethylstilbestrol (DES): It is a synthetic nonsteroidal estrogen that was first synthesized in 1938. Human exposure to DES occurred through diverse sources, such as dietary ingestion from supplemented cattle feed and medical treatment for certain conditions, including breast and prostate cancers. From about 1940 to 1970, DES was given to pregnant women under the mistaken belief it would reduce the risk of pregnancy complications and losses. In 1971, DES was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in uterus 108. The US FDA subsequently withdrew DES from use in pregnant women.
Thalidomide: Thalidomide is an immunomodulatory agent used for the acute treatment of erythema, nodosum leprosum, a cutaneous manifestation of Hansen's disease (leprosy). Thalidomide was introduced into clinical medicine in West Germany in 1956.
Although a wide range of indications was promoted for the drug; it was used as hypnotic and sedative. Thalidomide was one of the first drugs that was clearly shown to be a human teratogen and probably has caused more known severe malformations in humans than any other drug 109.
Several reviews have described the various human systems affected by thalidomide-induced embryopathy. One of these reviews presented the pregnancy history of two children (twins), born in the United States, who had very different severity of thalidomide embryopathy The first twin, a 2211-g female, was born with duodenal atresia, a rectoperineal fistula, and hypoplastic, dislocated thumbs (right thumb worse than left). The other twin, a 2240-g male, had phocomelia of both upper extremities and a midline hemangioma on the forehead. Missing or hypoplastic digits were noted on both hands.
Because of the concern over birth defects, thalidomide was withdrawn from the market in most countries in late 1961.
Teratogenic Counseling: In counseling the pregnant patient exposed to a potential human teratogen, it is important to emphasize the significance of exposure to the patient 109. Ascertaining the clinical facts regarding the nature of the exposure: the length, dosage, and timing of exposure during pregnancy, as well as other exposures of concern about which the patient may not ask (e.g., alcohol, cigarette smoking). All available current data regarding the agent are then collected, and conclusions regarding the risks of exposures are drawn.
Counseling should include the background human baseline risk for major malformations, whether the fetus is at increased risk, which anomaly has been associated with the agent in question, a risk assessment, methods of prenatal detection, when available, limitations in our knowledge, and limitations of prenatal diagnostic capabilities. Additional aspects include the potential risk of the medical condition for which a drug is prescribed, known interactions (in both directions) between the disease state and the pregnancy and preventive measures, when applicable (e.g., folic acid supplementation in the case of carbamazepine exposure).
Because more than 50% of pregnancies in North America are unplanned, teratogenic risk assessment should be started prior to pregnancy.
CONCLUSION: There are no absolute teratogens; however, many agents can exhibit teratogenic effects under certain circumstances. The dose and the time of exposure to a particular agent often determine the severity of the damage and the type of defect that occurs. The dose response is obvious: the greater the dose, the greater the effect. The time of exposure is another important concept, as certain stages of embryonic and fetal development are more vulnerable than others.
In general, the embryonic stage (first trimester) is more vulnerable than the fetal period (second and third trimesters). Thalidomide provides a classic example. The critical period of exposure is during organogenesis (the formation of the organs) from the 35th-48th day after the last menstrual period. The specificity of the malformations is linked to the time of exposure: 35-37 days, no ears; 39-41 days, no arms; 41-43 days, no uterus; 45-47 days, no tibia; and 47-49 days, triphalangeal thumbs. The types or severity of abnormalities caused by a teratogenic agent is also dependent on the genotype of the pregnant woman and the genotype of the fetus (genetic susceptibility).
For example, variation in maternal metabolism of a particular drug will determine what metabolites the fetus is exposed to and the duration of exposure. Differences in placental membranes, placental transport and biotransformation all affect fetal exposure. The genetic susceptibility of the fetus to a particular teratogenic agent will also have an effect on the final outcome.
It is therefore advised to go for the genetic counseling before conceiving the baby.
- The use of teratogenic drugs should be avoided during pregnancy in less severe (non life-threatening) diseases such as acne and psoriasis.
- It is necessary to select non-teratogenic drugs instead of teratogenic drugs during pregnancy if possible and not harmful for pregnant women. The best example for this strategy is to replace coumarin derivative with heparin in early pregnancy.
- The necessary use of teratogenic drugs may have to be continued in severe maternal diseases such as epilepsy and cancer if the discontinuation of treatment causes worsening of the disease and pregnant women agree with it.
- Teratogenic drugs cannot cause CAs if the exposure is in the first month of gestation and in general after the third month of pregnancy. However, the fetotoxic effect of some drugs should be considered in the second part of pregnancy.
- Recent effective ultrasound scanning can detect major fetal defects about the 18th-20th week of gestation with a high degree of efficacy. Thus we have a chance to evaluate the risk after the inadvertent or necessary use of teratogenic drugs during pregnancy. If serious fetal defects are detected, the couple can then be given information to help them decide whether to terminate their pregnancy or not.
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Aditi Thakur*, Harman Kaur Gill , Ajay Sharma , Nipun Mahajan and Shruti Rawal
Department of Pharmaceutical Sciences, Lovely School of Pharmaceutical Sciences, Lovely Professional University, Phagwara- 144402 Punjab, India
24 April, 2011
21 May, 2011
29 July, 2011
01 August, 2011