Placental barrier Placenta allows the transfer of many

• Placental barrier • Placenta allows the transfer of many drugs and dietary substances. • Lipid soluble compounds rapidly crosses the placenta, water soluble substances pass less. • The greater the molecular weight the less it passes through placenta. • The degree to which a substance is bound to plasma protein.

Congenital malformations • The incidence of major malformation in general population is 2 -3 % • Major Malformation : incompatible with survival such as Anencephaly or requiring major surgery for correction such as cleft palate or congenital hear disease, or producing major dysfunction in life (cerebral palsy). • Minor Malformation : if is included such as ear tag, extra finger … the rate is as high as 7 -10%

Marked Species Specificity in Drug Teratogenicity Thalidomide was not found to be teratogenic in rats and mice but a potent human teratogen. Corticosteroids cause cleft palate in mice while cause no harm in humans.

Congenital malformations Genetic 25% Environmental Unknown 65% Drug exposure accounts for 2 -3 % of all birth defects

The Food & Drug Administration (FDA) list 5 categories of labeling drugs in pregnancy A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester. B Animal studies do not indicate a risk t the fetus, there are no controlled human study. C Studies have shown the drug to have animal teratogenic or embryocidal effects, but no controlled studies are available in women.

The Food & Drug Administration (FDA) list 5 categories of labeling drugs in pregnancy D X Positive evidence of human fetal risk exists, but benefits in certain situations may make use of the drug acceptable inspite its risk. Studies in animals or humans have demonstrated fetal abnormalities or evidence demonstrated fetal risk based on human experience, or both, and the risk clearly outweigh any possible benefits

• • Drugs should ONLY used when necessary. The risk - benefit ratio should justify the use of certain drug. The minimum effective dose should be employed. As long term effects of drug exposure in utero may not be revealed for many years caution with regards to the use of any drug in pregnancy is warranted ( DES ).

• Until about day 3 after conception any cell is thought to be totipotential able to develop to any organ system. • Separation of the cells during this period can give the rise to monozygotic twins.

• The blastocyst is located in the uterus where implantation occurs 6 -9 days after conception. • One group of cells forms the inner cell mass that will develop into the fetus. • The inner cell mass will differentiate into three cell layers

Ectoderm Brain – Nerves – Skin Endoderm Lining of digestive tract – Respiratory tract – Part of the bladder – Liver Pancreas Mesoderm Connective tissue – cartilage – muscle- blood vessels – heart – kidneys - Gonads.

• The group of cells forming the periphery of the blastocyst is termed the trophoblast. The placenta and fetal membranes will develop from this outer cell layer.

• From 3 – 8 weeks the embryonic disk undergoes major development and will lay the foundation for all organ systems and the blueprints for this human are set

5 weeks • After conception embryo assume features of human • • • appearance. Face is recognizable formation of eyes ears and nose. Limbs emerges, digits cartilage and muscles develop. Liver producing blood cells and bile. Cerebral hemisphere begins to fill the brain area The heart is beating at 5 weeks and completely developed by 8 th week.

Effects of Specific Drugs

Estrogen & Progesterone X • Oral contraceptives and other hormones blamed in the past for a variety of birth defects but recent studies have NOT confirmed any teratogenic risk for these drugs. • Data from the Collaborative Perinatal Project (studied 50. 000 pregnancies) found NO association between exposure and fetal congenital malformation.

Androgenic Steroids X • Progestational agents-testosterone derivatives (Danazol) causes clitoromegaly and labial fusion if given before 13 weeks. • Can be corrected surgically

Anticonvulsants Valproic Acid (Depakene) D • Carries 1 -5 % risk of neuro • tubal defect and other abnormalities Spina bifida occurs in Depakene more than anencephaly with a ratio of 5: 1 Fetal Valproate Syndrome

Phenytoin (Dilantin) D • Decreases folate absorption and lowers the serum folate which has been implicated in birth defects so it is recommended to give folic acid supplement to women taking Dilantin (4 mg /day). • Fewer than 10% of offspring show the fetal hydantoin syndrome : Microcephaly - Growth deficiency – Developmental delay – Mental retardation – Dysmorphic craniofacial features. Cleft lippalate – Hypoplasia of nails and distal phalanges.

Trimethadione (Tridione) & Carbamazepine (Tegretol) C • Also associated with dysmorphic syndrome, but children exposed to Dilantin scored 10 points less in the IQ score than those exposed to Tegretol. • It is recommended to adjust the dose of medications and obtain monthly blood levels to give the least possible dose.

Isotretinoin (Accutane) X • Used mainly in the treatment of cystic acne. • 154 exposed human pregnancies reported to date 21 reported birth • • defects, 12 spontaneous abortions, 95 elective abortions and 26 normal infants. Structural defects and mental retardation Microtia anotia (small absent ears) micrognathia, cleft palate, heart defects (great vessels transposition and VSD), thymic defects, CNS malformations including hydrocephalus and optic nerve and retinal anomalies. It is not detected after 5 days from ingestion in serum. Topical tretinoin has not been associated with any teratogenic risk.

Vitamin A A • There is NO evidence that vitamin A itself in normal doses is teratogenic. • The levels in prenatal vitamins are 5. 000 IUday orally. • 18 cases of birth defects reported after exposure to levels of 25. 000 IUday. • Vitamin A in doses greater than 10. 000 IUday increases the risk of malformations.

Lithium D • In the International Register of Lithium Babies 217 are exposed at • • • least during the first trimester of pregnancy 25 (11. 5 %) were malformed, 18 had cardiovascular anomalies including six cases of the rare Ebstein anomaly. (anomaly of tricuspid valve) of the 60 unaffected infants were followed to age 5 years were normal. 2 cases of polyhydramnios reported because of nephrogenic diabetes insipidus in adults taking Lithium the presumed mechanism of polyhydramnios if fetal diabetes insipidus and polyhydramnios may indicate fetal Lithium toxicity. It is recommended to change medication during pregnancy although replaces are as high as 70% in one year as opposed to 20% to those who remain on Lithium

Antidepressants Imipramine (Tofranil) D • The original tricyclic antidepressant claimed to be associated with cardiovascular defects but the number of cases studied are small (75 newborn 6 had CVS anomalies) Fluoxetine (Prozac) B • Widely used 2 major studies showed NO increased risk of major malformations in so far 237 infants exposed in utero.

Warfarin (Coumadin) • The drug has been associated with Warfarin embryopathy seen in 5% of exposed pregnancies includes : Nasal hypoplasia – Bone stippling – ophthalmalgics anomalies including bilateral optic atrophy and mental retardation (seen even when exposed later than 1 st ). • Heparin is an alternative drug does NOT cross the placenta because of high molecular weight. D

Thyroid & Antithyroid Drugs D • Propylthiouracil (PTU) and Methimazole (Tapazole) both cross the placenta and may cause a degree of fetal goiter while thyroid hormones T 3 & T 4 cross the placenta poorly so that fetal hypothyroid can not be corrected by giving the mother thyroid hormone. • It is suggested to keep the mother slightly hyperthyroid. • Methimazole (Tapazole) has been associated with scalp defects in infants, so Propylthiouracil (PTU) is the drug of choice

Radioactive Iodine • Radio active Iodine for thyroid ablation 131 I & 125 I or for diagnostic studies is not concentrated by the fetal thyroid till 12 weeks. • Early inadvertent exposure carries NO specific risk. • Topical Iodine preparation are absorbed through vagina.

Digoxin C • In 52 exposures reported NO teratogenicity of digoxin • • • was noted It is used in fetal therapy. Maternal blood levels should be monitored during pregnancy. In hydropic fetuses digoxin may not easily cross the placenta.

Antihypertensive Drugs • Alpha Methyl Dopa (Aldomet) has been widely used for • the treatment of chronic hypertension in pregnancy. Hydralazine (Apresoline) has also been widely used in pregnancy. B No Unusual Fetal Effects

Sympathetic Blocking Agents C • Propranolol (Inderal) b - adrenergic blocking agent, theoretically might increase uterine contractility but this has not been reported. As the drug is not specific for b 2 receptors in the uterus. NO evidence of teratogenicity. Fetal bradycardia is seen. • • • New studies associated Inderal with increased risk of IUGR.

Angiotensin-Converting Enzyme Inhibitors (ACE) D • Enalapril (Vasotec), Captopril (Capoten) can cause fetal renal failure in the 2 nd and 3 rd leading to oligohydramnios, fetal limb contractures, craniofacial deformities and hypoplastic lung development. • Its use during the 1 st teratogenic. has NOT been reported to be

Antineoplastic Drugs & Immunosuppressants Methotrexate D • Folic acid antagonist appears to be human teratogen although experience with it is limited. Azathioprine (Imuran) D • Used in patients with renal transplants or SLE of 80 women treated in the 1 st anomalies was NOT increased. 2 infants has leukopenia, one has IUGR

Cyclosporine C • 67 infants exposed in utero NO increased risk of • anomalies. Increased risk of prematurity and IUGR. Chloroquine C • NO risk of anomalies when given in prophylactic doses • for Malaria among 169 infants exposed to 300 mg weekly. Doses of 250 -500 mg daily TWO cases reported of cochleovestibular paresis.

Antiasthmatics Theophylline & Aminophylline C • Both are SAFE for the treatment of asthma in pregnancy. NO evidence of teratogenic risk in 76 exposures in the Collaborative Perinatal Project. Epinephrine C • Minor malformations have been reported with sympathomimetic as a group in 3082 exposures in the 1 st Terbutaline B • Used in preterm labor NO Risk of birth defects has been reported

Corticosteroids • All steroids cross the placenta to some degree but Prednisone • • • and Prednisolone are inactivated by the placenta. B Only 10% of the maternal dose reaches the fetus, the drug of choice in treating asthma in pregnancy. Betamethasone & Dexamethasone they are minimally C inactivated by placenta. Used for fetal lung maturity. Several hundred infants exposed to corticosteroids in the 1 st NO abnormalities was noted. Iodide D • Saturated solution of potassium Iodide (SSKI) expectorant crosses the placenta causes large fetal goiter to produce respiratory obstruction.

Vitamin B 6 A • Vitamin B 6 (Pyridoxine) reported in 2 randomized placebo • • controlled studies to be effective for treating nausea and vomiting in pregnancy. In several other controlled trial NO evidence of teratogenicity. C Diphenhydramine (Benadryl) In 595 patients treated in the Collaborative Perinatal Project NO teratogenicity was noted. (Drowsiness can be a problem)

Phenothiazine Chlorpromazine (Thorazine) • • • C Very effective in the treatment of hyperemesis gravidarum. 976 patients treated in the Kaiser Health Plan. 1309 patients treated in the Collaborative Perinatal Project NO Fetal Malformations Noted Promethazine (Phenergan) C • 58 mothers treated NO risk of malformation

Antihistamines • NO increased risk of anomalies has been associated with • • most antihistaminics used. An association between exposure during the last 2 weeks of pregnancy to antihistaminics in general and retrolental fibroplasia in premature infants has been reported. One retrospective study showed increased risk of gastroschisis was associated with 1 st pseudoephedrine (Sudafed) use.

Antibiotics Penicillins B • Penicillin, ampicillin and amoxicillin are safe in • • pregnancy 3546 patients in the Collaborative Perinatal Project mothers took penicillin in the 1 st with NO increased risk of anomalies Transplacental passage of penicillin is by simple diffusion, high protein binding penicillins e. g. oxacillin, cloxacillin and dicloxacillin cross the placenta less than poorly bound penicillin e. g. penicillin and ampicillin

Cephalosporins B • In a study of 5000 Michigan Medicaid Recipients there was a suggestion of possible teratogenicity with Cefaclor, Cephalexin and Cephradine Sulfonamides B • 1455 human infants exposed to sulfonamides in the 1 st • • NO teratogenic effects. These drugs should be avoided in women deficient in G 6 PD. There is a theoretical risk of hemolysis in the fetus if drug is used near delivery as fetal red cells are deficient in glutathione.

Sulfamethoxazole (Bactrim) C • Two published trials have failed to show any increased risk of • birth defects. One Unpublished study of 2000 Michigan Medicaid Recipients suggested increased risk of cardiovascular defects after exposure in the 1 st Nitrofurantoin (Macrodantin) B • 590 infants were exposed in the Collaborative Perinatal • Project 80 in the 1 st NO increased risk of abnormality, more recent studies confirmed these findings. Macrodantin cause anemia in patients deficient in G 6 PD and theoretically in infants.

Tetracycline D • Readily crosses the placenta and firmly bound by chelation to • • • calcium in the developing bone and tooth structures. This leads to brown discoloration hypoplasia of the enamel and inhibition of bone growth. The staining of the teeth takes place in the 2 nd & 3 rd Hepatotoxicity has been reported in pregnant women using large doses of tetracycline. 341 exposed infants in the 1 st in the collaborative perinatal Project and another 174 women in other study found NO teratogenic effects.

Erythromycin B • 9 patients in Collaborative Perinatal project and 260 patients • in another study NO teratogenic risk or increased birth defects. Erythromycin estolate (Ilosone) has been associated with subclinical reversible hepatotoxicity during pregnancy. Metronidazole B • Several studies showed NO risk of congenital defects with the • use of Flagyl early and late in pregnancy. Some controversy rose when Metronidazole showed to be mutagenic in bacteria by the Ames test, which correlates with carcinogenicity in animals. Its carcinogenicity in human has not been confirmed

Quinolones (Cipro) C • The quinolones have a high affinity for bone tissue and • cartilage and may cause bone stippling and arthralgia if given in utero or to young children. 38 infants exposed to quinolones in utero in the 1 st NO abnormalities noted. Acyclovir (Zovirax) C • The Acyclovir Register has recorded 601 exposure during • pregnancy including 425 in the 1 st with NO increased risk of abnormalities. The CDC recommended its use in pregnant women with disseminated infection (herpes encephalitis or hepatitis)

Antifungal B • Nystatin (Mycostatin) poorly absorbed from intact skin and • • mucus membranes, topical use has NOT been associated with teratogenesis. The Imidazoles are absorbed in small amounts from vagina has NOT been associated with congenital malformation One study showed a statistically significantly increased risk of 1 st abortion.

Aspirin C • NO evidence of any teratogenic effect of aspirin taken in the • • 1 st Aspirin inhibits prostaglandin synthesis leads to decrease uterine contractions and delay onset of labor. Aspirin also decrease platelets aggregation increase risk of bleeding. As well as in infants up to 5 days after exposure. Acetaminophen (Tylenol-Panadol) B • NO evidence of teratogenicity. • It inhibits prostaglandin synthesis but in reversible manner.

NSAD B • NO evidence of teratogenicity has been reported for • nonsteroidal anti-inflammatory drugs. Chronic use may lead to oligohydramnios and constriction of fetal ductus arteriosus or pulmonary hypertension has been reported with Indomethacin use. Codeine C • In the Collaborative perinatal Project NO increased risk of • malformations Codeine can be addictive and may lead to infant withdrawal symptoms.

Smoking • • Spontaneous abortion PROM PTL Low birth weight IUGR Placenta Previa Placenta Abruption SID (Sudden infant death syndrome)

Smoking • • • The physiologic mechanism responsible for adverse effects of pregnancy and smoking are carbon monoxide and nicotine Carbon monoxide crosses the placenta and binds to hemoglobin forming carboxyhemoglobin which reduces the oxygen carrying capacity of the blood Nicotine also crosses the placenta causes elevation of catecholamine and vasoconstriction at the uterine artery and fetal

Marijuana • NO teratogenic effect of marihuana. In a prospective study of 35 pregnancies no birth defects but more meconium staining. Also increased incidence of precipitate labor (<3 h).

Alcohol • • • Fetal Alcohol Syndrome (FAS) Growth retardation before and/or after birth Facial anomalies CNS dysfunction including microcephaly, varying degrees of mental retardation as well attention deficit disorder (ADI) with hyperactivity. Cocaine • It is difficult to access the effects of cocaine on the infants because • • those mothers usually abuse other drugs. Increased rate of spontaneous abortions abruptio placenta preterm birth and SGA. three studies showed increased risk of congenital anomalies mainly cardiac & CNS and microcephaly.

Caffeine B • 5773 women in the Collaborative Perinatal Project showed • • NO evidence of teratogenic effects in human. Some studies showed that taking more than 8 cups of coffee a day (cup contains 100 mg caffeine) was associated with low birth weight, spontaneous abortions, prematurity and stillbirth. Maternal coffee decrease iron absorption may contribute to maternal and fetal anemia. Aspartame (Nutrasweet) B • The major metabolite of aspartame is phenylalanine. Sustained high levels of phenylalanine in the fetus are associated with mental retardation (PKU). High doses is required to produce fetal toxicity.