Any agent chemical, viruses,environmental agents , physical factors and drugs that acts during embryonic or fetal development to produce a permanent alteration of form or function HADEGAN-agent that interferes with normal maturation and function of an organ TROPHOGEN-agent that alters growth (affects process occuring after organogenesis or even after birth)
Careful delineation of clinical cases Rare environmental exposure associated with rare defect,with atleast 3 reported cases- easiest if defect is severe Proof that the agent acts on the embryo or fetus directly or indirectly Proven eposure to agent at critical times in prenatal development The association must be biologically plausible
Consisitent findings by 2 or more epidimiological studies of high quality. Teratogenicity in experimental animals,especially primates.
Almost all drugscross the placenta toSome extent Weigh therapeutic benefitsof drug to mother againstits risk potential to developing fetus
1. Animal species and Race often animal study data of either safety or teratogenicty don not indicate the definite and conclusive proof of being same in human being . 2. Chemical- nature , dose , specificity , Dose . Gestation period of exposure , duration of exposure , their absorption and circulation as free / protein bound form ,rate of detoxification . Excretion / clearance from body, ability to cross placenta , concentration in fetal tissue etc. Physiological changes in pregnancy also modify drug effect and on fetus --- (a) Absorption is altered due to delay in gastric emptying by increased progesterons. (b) increased GFR increases clearance thruogh Kidneys.
(c). Increased liver enzyme activity byincreased levels of Estrogen and progestonlead to fast clearance . (d). How and how much drug / chemical isable to cross placental barrier ---to reach tofetus , water soluble substances passthrough easily by direct effusion dependingupon concentration gradient ,Low molecularweight substances cross fast, while macrosized and with high molecular weightsubstances do not cross placenta , Freemolecules cross easily as compared toProtein bond .Some chemicals need activetransfer mechanism like Phosphorilization.
4. Period of Gestation and Exposure to teratogen Teratogens can cause cell death , alter tissue proliferation and growth pattern( hypoplasia , aplasia , asynchronous growth)., interferring with cellular differentiation or other morphogenic process. Tertogenic effect is maximum during period of organogenesis ( bb3-8 -10 weeks )after LMP( 35 – 70 days post LMP ).Mental physical / maturaton of organ function and their coordination to each other and growth of ear , eye , gonads occur in later weeks of gestation .
DEPENDS ON :1. Molecular weight2. Concentration of free drugs3. Lipid solubility4. Utero placental blood flow5. Placental surface area.6. More transfer of drugs at term
86%of women take medication during pregnancy Despitethis , most drugs are not labeled for use during pregnancy 1/2 of pregnancies unplanned <50% of women know they are pregnant by 4th week and ~20% still don’t know by 8th week
Category Animal Human Risk Administration risk A No No risk Yes risk B No No adequate Yes risk studies C Risk No adequate If benefits> studies Risk D Risk< Benefit If No alternative X Risk> Benefit Contraindicated
A review of 152531 pregnant women in 4yrs- 64% women were prescribed other drugs then vitamins in 270 days, which were Category C – 37.8% Category D -4.8% Category X -4.6% Hence a planned pregnancy should be the answer
Nature of agent Dose Route Frequency of exposure Duration of exposure Gestational timing Concurrent illness Genetic susceptibility(mother, fetus)
BEFORE DAY 31 : All or none effect(cell death or malformation) Day31 to 71 : Effects depend on amount of drugs and duration of exposure. AFTERDAY 71 : DES related anomalies around 20 weeks.Fetal alcohol syndrome in late pregnancy.
DISRUPTION OF FOLIC ACID METABOLISM Leadsto deficient methionine production and RNA, DNA synthesis. Preconceptional folate deficiency leads to neural tube defects, cleft lip and palate
EPOXIDE AND ARENA DRUGS Are oxidative inter metabolites of drugs like hydantoin and carbamazipine Havecarcinogenic and teratogenic potential unless detoxified by fetal epoxidehydrolase
ENVIRONMENT AND GENES : Genotype of the embryo and their susceptibility to teratogens. MATERNAL disease AND DRUGS EXPOSURES : Causes gene mutation and chromosomal anomalies. HOMEOBOX GENES : Regulatory genes are dysregulated by teratogens.
Paternal Exposures The process by which germ cells mature into functional spermatogonia takes 64 days, drug exposure at any time during the 2 months prior to conception could result in a mutation. During intercourse a drug in seminal fluid could directly contact the foetus. Paternal germ cell exposure to drugs or environmental agents may alter gene expression
DIURETICS: Reduced placental perfusion and fetal compromise , thrombocytopenia and hyponatremia IUGRSPIRONOLACTONE(ANTI-ANDROGEN) Feminisationof male fetus (short phallus and bifid scrotum) Amiodaron –Category D (hypothyroidism)
VITAMIN A•avoid doses higher than the recommended dailyallowance of 5000 IUBEXAROTENE•contraindicated during pregnancy.•eye and ear abnormalities.• cleft palate and incomplete ossification.•male patients who have partners who could becomepregnant are advised to use condoms during sexualintercourse if they are taking bexarotene and for onemonth after discontinuing therapy
ISOTRETENOIN(used in acne)•first-trimester exposure- high rate of foetal loss•malformations (26 fold)•microtia or anotia-agenesis or stenoses of the external ear canal-cleft palate and maldevelopment of the facial bones andcranium-cardiac anomalies-hydrocephalus- thymic abnormalities
ETRETINATE -TERATOGENECITY SIMILAR TO ISORETINOIN -anomalies are observed even when conception occurs after discontinuation (2yrs)TRETINOIN first-trimester topical use results in fetal defects similar to those associated with isotretinoin
DRUGS SIDE EFFECTS AND COMPLICATIONSAminoglycosides –Category D Auditory or vestibular damage and nephrotoxicityQuinolones Arthropathy in animal studiesAnti Fungal- Griseofulvin Central nervous system and skeleton anomalies in animalsFluconazole and Itraconazole: skull abnormalities, cleft palate,Category C humeral-radial fusion, and other arm abnormalitiesANTILEPROBIC DRUGS Dapsone to be avoided in third trimester.
DRUGS FETAL OR NEONATAL AFFECTION AND COMMENTLong acting Neonatal hemolysis,jaundice andsulphonamides kernicterusNitrofurantoin Hemolysis In newborn if used at termMetronidazole No evidence of foetal or neonatal toxicity, high dose regimen should be avoided
DRUGS SIDE EFFECTS AND COMPLICATIONSAminoglycosides Auditory or vestibular damage and nephrotoxicityQuinolones Arthropathy in animal studiesSulphonamides Hyperbilirubinemia and neonatal jaundice when used in 3rd trimester
MEFLOQUINE- 5 fold increased risk of still births chloroquine,quinineand quinidine are generally considered safe in pregnancy in therapeutic doses Quinine Category D drug
Amantadine , efavirenz and rabavarin are in category x- Hydrocephalus and limb abnormalities in rodentsAnti retrovirals eg.lamivudine, nelfinavir, nevirapine, stavudi ne, or zidovudine are Category C drugs
CORTICOSTEROIDS -CAUSES FETAL AND NEONATAL(PREDNISOLONE, ADRENAL SUPPRESSIONHYDROCORTISONE)- HIGH DOSES -IUGR(PROLONGED USE)MYCOPHENOLATE MOFETIL -CATEGORY D CAUSES -bilateral microtia -anotia -atresia of the external auditory canals - oral clefts
CYCLOPHOSPHAMIDE -missing and hypoplastic digits, -cleft palate - single coronary artery -imperforate anus - fetal-growth restriction - microcephalyMETHOTREXATE AND -growth restrictionAMINOPTERIN -failure of calvarial ossification, - craniosynostosis - hypoplastic supraorbital ridges, -small posteriorly rotated ears, -- micrognathia - severe limb abnormalitiesTAMOXIFEN Category D (Human data awaited)
Extreme and irreversible virilization Liver dysfunction Mood and libido disorders Exposure of a female fetus results in virilization, (labioscrotal fusion after first- trimester exposure and phallic enlargement from later fetal exposure )
All live viral vaccines are potentially dangerous to the foetus RELATIVE CONTRINDICATED DRUGS BIOLOGICS eg etanercept infliximab adalimumab
most notorious human teratogen Bone defects- abnormal shape or size to total absence of a bone or limb segment—phocomelia. upper limb phocomelia after exposure during days 27 to 30 days Lower limb phocomelia was associated with exposure during days 30 to 33 gallbladder aplasia at 42 to 43 days duodenal atresia at 40 to 47days
Phocomelia (limb reduction defects)Bone defectsAnomalies of ear, CVS
AMPHETAMINES Methamphetamine - associated with symmetrical fetal-growth restriction (NO TERATOGENECITY)COCAINE -vascular disruption within the embryo, foetus, or placenta, highest after the first trimester -stillbirth -skull defects ,microcephaly,behaviour problems -limb reduction -urinary tract defects -ileal atresia -cardiac anomalies, -visceral infarcts -seizures -hyperthermia and sudden death
HEROIN -foetal-growth restriction -perinatal death -withdrawal symptoms such as tremors, irritability, sneezing, vomiting, fever, diarrhea, and occasionally seizures are observed in 40 to 80 percent of newborns born to heroin-addicted women -postnatal growth -normal in most cases may be mild developmental delay and behavioural disturbancesMETHADONE -low birth weight babies -withdrawal symptoms similar to heroin but more frequent and prolonged(upto 3wks)
TOBACCO •foetal growth restriction •abortions •pre term delivery •placenta previa and abruption •subfertility •cleftsMARIJUANA -low birth weight -teratogenic in high doses
Pregnancy Category X Oxytocic properties could cause IUGR by vascular disruption or increased uterine tone Chronic exposure is contraindicated
CategoryC Limited human data exists, sumatriptan has been associated with VSDs in several cases
DRUGS COMMENTSPethidine (Meperidine) Pethidine does not inhibit uterine contraction so has less adverse effects on baby.Fentanyl serious respiratory depression. So require continuous pulse oximetry monitoring and close nursing surveillanceButorphanol (Stadol). Causes drowsiness and dizziness. Less nausea and vomiting. Less respiratory depression
Most commonly used mixture is Entonox (an equal mixture of NO & Oxygen). Provides quick with short duration of effect. Not suitable for prolonged use from early labor, so most suitable is late in labor or while awaiting epidural analgesia. Adverse effects include nausea & light headedness.
chemical properties of drug Molecular weight lipid solubility of the drug the mechanism of transport, the degree of ionization, and change in plasma pH degree of protein binding the plasma pH Drug concentration Exposure time
MATERNAL MEDICATION EFFECTS ON LACTATION AND THE NEONATEOral pill Suppression of lactationBromocriptine Suppression of lactationErgot Suppression of lactationMetronidazole Anorexia, blood dyscrasias ,irritabilityAnti-thyroid drugs,radio active iodine Hypothyroidism,goitre, granulocytosisWarfarin Safe in therapeutic dosesCytotoxic drugs Risk of immune suppression.Risks may outweight the benefits depending on individual drugLithium Lethargy, hypotonia, lithium toxicity
Minimum therapeutic dose to be given for shortest duration. Welltried drugs preferable to newer alternatives Drugs should be avoided for first 71 days of pregnancy. Patient must be counseled about the beneficial effects of the drugs and potential risk to the foetus.