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DR JOSEPH EIGBEFOH

FWACS;FMCOG;FICS;D.MAS
 TERM PLACENTAL BARRIER IS A
CONTRADICTION: Most drugs pass thru
 > 2/3 of women in pregnancy took non

prescription medications
 Risk-benefit ratio of drugs info should be

available otherwise no drugs or one or


minimum effective dose should be used
 No recreational drug:
 long term effect of drugs in utero may take

yrs to surface: caution for all


 Lipid solubility> water soluble( lower
molecular wt)
 Degree of binding to plasma protein
 All drugs cross except large organic ion :

heparin and insulin


 Unknown cause : 65- 70% of congenital
malformations;
 20-25% secondary to genetic abnormalities
 3-5% intrauterine infection
 4% - maternal dx DM, Phenyketonuria,

epilepsy
 < 1% drug exposure maybe( main suspect by

physicians and pt, lawyers)


 Major malformation: 2% - 3%
 Defn: one incompatible with

survival(anencephaly), or that requires major


surgery for correction( cleft palate or CHD)
 Minor malformations: ear tags, extra digits
 Minor+ major: incidence : 7- 10 %
 Few medications are known teratogens; no

inadequate info to asses risk for > 60% of


medications
 Specie specificity: thalidomide innocuous in
lower species; corticosteroids safe in humans
but not in mice
 Teratogenic effects or foetal effects
 Teratogenic effect; period of

organogenesis(embryonic period): 2- 8 wks


post conception; menstrual age is 2 wks
ahead
 Embryonic period; early part: heart or neural

tube, end of period :ear and palate


 B/4 organogenesis: teratogen all or none
 Conception to day 31/ 2 wks post

conception: survive or survive without


anomaly
 Period of the fetus : 9 weeks post conception

to delivery: fetal effect are alterations in the


structure/ function of organ systems
normally formed during organogenesis
 Category A: medications felt to be relatively safe
for use during pregnancy e.g prenatal vit
 Category B: agents in which no known risk but
human studies are lacking e.g ampicillin
 Category C: agents for which there is little or no
info available ; all new drugs are here
 Category D: agents for which there is a definite
risk but which may be deemed necessary for use
in preg based on a risk: benefit assessment e.g
anticonvulsants
 Category X: drug use is a definite risk risk >
benefits e.g isotretinoin
 FDA classification not an absolute science
 Gestational age
 FDA classification of drug
 Risk/ benefit ratio
 Drugs known to be harmful
 Therapeutic drugs/inadvertent exposure/

social drugs exposure/breast feeding


 Vit A: essential nutrient prototype retinoid
 Recommendation: < 10,000 IU/day

 15,000/day ; teratogenic
 Isotretinoin (accutane)& etretinate (tegison);

derivatives of vit A
 Isotretinoin: intractible cystic acne; drug

anomalies of ear, brain heart & thymus: short


½ life (96hrs) ; safely D/C b/4 conception.
Risk of mal is 25%
 Topical tretinoin ( Retin –A) not teratogenic
 Etretinate : tx of psoriasis: CNS craniofacial,
and skeletal anomaly
 Long ½ life ; effect up to 2 months after,

sometimes 5 yrs; best to tx psoriasis with


topical rather than systemic med
 Hypnotic/ sedative : popular
 Days 27- 42 postconception: phocomelia,

absence of long bones in upper/lower limbs


 External ear and heart defects
 Used in S. America to tx leprosy/T.B
 Malignancy : 0.1% of pregnancy;
breast,melanoma,hodgins,s lymphoma
 Akylating, antimetabolite, plant alkaloid,

antibiotic, miscellaneous: often regarded as


teratogenic
 1st TM : Definite yes
 2nd & 3rd TM: IUGR
 Overall benefit> risk : must use irrespective

of TM
 Busulphan, cyclophosphamide, chlorambucil,
melphalan, carmustine, thiotepa
 Teratogenic:
 Busulphan for leukemia( iugr, cleft palate, eye

defects
 Cyclophosphamide for ovarian endometrial

and breast ca(cleft palate, absent digits, iugr,


craniofacial defects)
 Overall 14% of exposed have major anomalies
 melphalan, carmustine, thiotepa
 Methotrexate, mercaptopurine, thioguanine
cytarabine, and fluorouracil.
 Folate antagonist: aminopterin,

methotrexate : popular teratogen: avoid in


1st TM
 Cleft palate, IUGR, hydrocephalus,

hypertelorism
 Vincristine, vinblastine( onconvin, vincasar):
teratogenic ? Causal or casual
 Benefit> risk
 Daunorubicin, doxorubicin, bleomycin,
dactinomycin: ? Teratogenic benefit> risk
 Same applies to the miscelaneous agents like

hydroxyurea
 Tx of autoimmune dx and post organ
transplant
 Azathioprine ; renal transplant? Anomaly

inconclusive evidence benefit> risk


 Cyclosporin A ; renal transplant? safe
 Epilepsy +Anticonvulsants increase risk x2 :
5% : cleft lip + or – palate and CHD
 Valporic acid& carbamezepine : 1% risk of

NTD
 Offsprings of epileptic: 5 x risk of

epilepsy( 2-3%)
 Teratogen: epilepsy or + drugs
 Epilepsy with no drugs teratogenic

Mechanisms of teratogenicity in epilepsy


 Epilepsy itself
 Genetic predisposition to epilepsy and
malformation
 Genetic diff in drug metabolism: Anticonvulsant
med have metabolites eliminated by enzyme
epoxide hydrolase. Def causes problems
 Effects of medication
 Def of follic acid
 Notorious drugs phenytoin, carbamezepine
 Overall benefit> risk
 Warfarin/heparin
 Warfarin: 1st TM: fetal warfarin syndrome;

nasal hypoplasia, malformed vertebrae,


hydrocepaly, microcephaly, iugr,
 2nd TM/3RD TM; MICROCEPHALY;

opthamo;ogical problemsdue intracerebral


haemorrhage
 3rd TM: FETAL/MATERNAL haemorrhage,
 Heparin : large mol; does not cross; no cong
anomalies
 Osteoporosis, thrombocytopenia in mother
 Testoterone: virilization of female fetus
 Danazol:virilization; no effect in males
 DES:nonsteroidal synthetic estrogen: clear

cell adenocarcinoma of the vagina, vaginal


adenosis, t-shaped uterus, uterine
hypoplasia, paraoarian cyst, incompetent
cervix
In males: epididymal cyst, hypoplastic testes,
cryptorchidism
 Little or no risk due to inardvertent exposure
to ocp or progestogens in pregnancy,
 Same for bromocriptine and clomiphene and

spermicides
 Antibacterial, antifungal ,antivirals,
antiparasitic
 Antibacterials: only known teratogenic is
tetracycline , effect is cosmetic and
transient(yellowish to brown discoloration of
decidous not permanent teeth, except given
in childhood.(6/12-5yrs) no risk of structural
malformations
 Penicillins: ok
 Sulfonamides: no risk except in premature/;
jaundice
 Sulfa with trimethoprim; not a known
teratogen
 Sulfasalazine: ok
 Nitrofuantoin: ok
 Aminoglycosides and other antiTB drugs:

Streptomycin/kanamycin(dose related):
Ototoxicity in 3-11% of exposed. Ok for short
term course.
 No teratogenic risk with rifampicin, PAS, or

ethambutol,
 Metronidazole: ok , nil teratogenic effects
 Erythromycin;ok
 Cephalosporins:ok
 Clindamycin:ok
 Fluroquinolones: no info, do not use in preg.
 Clotrimazole, miconazole, nystatin: not
teratogenic
 Amphotericin B: systemic mycotic infections:

not teratogenic
 Griseofulvin: mycotic infection of skin and

nails: not enough information, probably safe


 Zidovudine, acyclovir,
amantadine,ramamtadine, ribavirin,
idoxuridine, and vidarabine
 Zidovudine; not enough info, benefit>risk
 Acyclovir: herpes infection( pry genital herpes

and varicella); tx of active herpes : not


teratogenic
 Amamtadine: not teratogenic
 Ramamtadine: not enough info
 Ribavirin: teratogenic in rodents; use limited

in preg. In lassa benefit> risk


 Idoxuridine/vidarabine : incomplete info
 Metronidazole; safe
 Lindane: tx of pediculosis pubis, and scabies:

local tx leads to minimal systemic effect.


Potential for cns toxicity if used sytemically;
caution in pregnancy
 Antimalarials genrally safe , exceptions
known
 Antihelminthics generally safe
 Psychiatic illness : 1-2%, tx of of benefit to
mother/baby
 Hypnotics, sedatives and tranquilizers e.g

phenobarbital,
secobarbital,butalbital,diazepam,chlordiazep
oxide, chloral hydrate and meprobamate,
 Barbiturates: no evidence of teratogenicity
 Diazepam: no evidence of teratogenicity ,

floppy baby syndrome when used close to


delivery
 Chordiazepoxide: safe
 Mebromate : avoid in preg b/c of conflicting

evidence
 Chloral hydrate: safe in preg.
 Antidepressants; tricyclic/non tricyclic agents
 Tricyclic: Limb reduction defects found with

amitriptyline, but other studies say no. Other


tricyclic found to safe overall risk: none to
negligible
 Fluoxetine (Prozac)antidepressant: not

teratogenic
 Others relatively safe
 Phenothiazines ; also used as antiemetics in
preg.( chlorpromazines,
perphenazine,triflupromazine): not
teratogenic
 others,; halpoperidol: no evidence of

teratogenicity
 Avoid in preg, however leads to 70% chance
of relapse of affective disorder vs 20% with
continuation
 Risk: 1st tm;11.5% risk; CVS and ebstein

anomaly: not proven to be cause and effect


 Others , goiter ,

hypothyroidism,Polyhydraminos; b/c of
diabetes insipidus
 Perinatal effect: hypotonia, lethargy and poor

feeding
 Propylthiouracil and methimazole cross
placenta to cause goiter in fetus
 T3 and T4 do not
 PTU> METIMAZOLE which causes scalp

defects in infants. Use dose to keep woman


slightly hyperthyroid
 Radioactive iodine: diagnosis/ablation: not

concentrated in fetal thyroid till 12 wks, safe


before then
 Always used in 1st tm: frequent suspect for
problems(medically and legally)
 Nausea/vomitting : non pharmacological is 1st

option; eating cracker at bedside on waking,


omitting iron tablets, frequent small meals,
protein snacks at night
 Pharmacological; bendectin(10mg

doxylamine+10mg pyridoxine(vit B6): non


teratogenic
 Vit B6 : effective tx for nausea /vommitting
 Doxylamine (unisom 25mg)
 Tx: vit B6; 25mg and unisom 25mg nocte,

one half of each in morning and afternoon:


non teratogenic
 Ginger safe and effective: 250mg 4 x daily
 meclizine: not teratogenic
 Dimenhydrinate: non teratogenic, same for

trimethobenzamide, phenothiazines and


emetrol( phosphorylated carbonhydrate
stops smooth muscle contration)
 No increased of anomaly with
chlorpheniramine but not with
brompheniramine; not constitent
 Overall: cold should be mx

nonpharmacologically e.g humidifier, rest and


fluids
 If medications use one not two
 Allergy: use antihistamine; decongestion:

topical nasal spray


 Avoid drugs for trivialities
 Most common medications in preg, mostly
safe
 Use nonpharmacological methods
 NSAIDS(Indomethacin,ibuprofen,etc); risk is

premature PDA closure and pulmonary ht,


oligohydraminos; use outside 3rd tm and
acutely
 Aspirin: non teratogenic; perinatal effect:
decreased uterine contractility, delayed onset
of labour & prolonged preg. Risk of APH and
PPH, in 3rd tm may cause pda closure (not
proven)low dose safe
 Reversible prostangladin synthetase
inhibition: no teratogenic or perinatal effect
except fetal liver toxicity with suicide
attempts
 Narcotic analgesia: codeine, morphine,
pentacozine: all safe except for resp
depression and neonatal withdrawal with
some
 Theophylline and aminophylline: safe
 Epinephrine: no evidence of teratogenic

effects
 Terbutaline: (preterm labor): not teratogenic
 Cromolyn sodium: safe
 Isoproterenol and metaproterenol: (topical

aerosols; safe as such . Systemic effects


includ red in uterine blood flow: caution
 Cortecosteroids : good
 Prednisolone and prednisone : inactivated

largely by placenta unlike dexamethasone


and bethamethasone
 Iodide: (saturated solution of KI iodide

expectorant ) crosses and cause fetal goiter.


 Digoxin: safe
 Most antihypertensive safe: prolonged use

uniformly cause IUGR


 ACE INHIBITORS: fetal renal failure;

oligohydraminos and consequences, fetal


skull ossification defects
 Smoking in caucasians most abused: 16.3%-
52%
Placental complications: miscarriage , placental
abruption, placental insufficiency, LBW,
placenta preavia., SCBU admission and SIDS
 Protects against PET
 Risk related to nos of sticks
 Passive smoking risk same as 1-5 sticks per

day
 Others: neurodevelopmental delay
FAS: at least 1 from of each of 3 categories
 Growth deficiency pre & postnatally
 Facial anomalies including small palpebral
fissure, indinstict or absent philtrium,
epicanthic folds, flattened nasal bridge, short
nose length of nose, thin upper lip, low set
unparallel ears and retarded mid facial dev.
 CNS dysfunction including microcephaly ,
various degree of mental retardation or other
neurodev anomaly like attention deficit and
hyperactivity
 Overall nos drinks/ occassion was the
alchohol strongest predictor; binge drinking
dangerous
 Overall nos drinks/ occassion parralels

poorer adolescent performance


 No level of alchohol is safe
 Non teratogenic
 Some suggest a LBW
 Cigarrete smoking+ caffeine : LBW
 Coffee intake decrease iron absorbtion
 Nutrasweet matabolized into aspartic acid,
methanol, and phenylalanine: non teratogenic
 No teratogenic effects from opiates
 LBW, PRETERM ,IUGR, fetal distress and scbu

admission,SIDS
 Social problems may be more important,

CRIME DX, HIV infection


 Neonatal withdrawal
 Tx : methadone in preg: comfirm addiction
Cocaine addiction: vasocative drug, direct fetal
vascular effects and placental damage,
 2 types: pure cocaine; coke (white powder,

snorted thru nasal mucosa


 Crack cocaine: powder or crystal mixed with

water and baking soda or NAHCO3.boiled to


evaporate water leaving brown/white rocks,
smoked or injected after mixing
 High in 6-8 mins
 Phychological rather than physical dependence
 More secretive , and difficult to identify
 Risk: mother; dehydration no sleep, nutritional
 Social problems preeminent;
 ? TERATOGENIC, urinary tract problems, limb
dysplasia intracranial bleeding,LBW, IUGR, Fetal
distress, abruptio placenta preterm delivery,
neurodevelopmental defect in offspring and
social dislocation
 In europe most frequently used illicit drug: 14%
 Few studies but no teratogenic effect noted, no
risk of LBW, preterm del or abruptio
 Study in jamaica:? Beneficial effect other suggest
LBW(?SOCIAL)
 Mother: relieves nausea and vomiting of early
pregnancy
 Exposed babies: at one month better autonomic
stability, refexes, general irritability, and wt
 Problem : social and a gateway drug
 Synthetic amines similar to epinephrine:
exaggeration of the normal response to
emergency/stress, unpopular addicts as very
violent
 Common names: speed, crystal, meth,pep pills,
diet pills, co-pilot, eyeopener,
 Risk: orally , injected or sniffed; produces a high
and a very down low
 Baby ; little, cleft lip
 HT, PET,IUGR
 Prematurity(social factors)
 Long term growth impaired in offspring
 Psychological dependance
 D-lysergic acid diethylamide-25 ; LSD, OR
ACID
 Orally sniffed or injected
 Effect dependent on personality and thots of

individuals.compatible with normal life


 Teratogenic in animals but insufficient info in

humans
 Barbiturates; uncommon
 Problem; effect of withdrawal

Solvent abuse: gateway drugs; spray paint,


liquid correction fluid, hair sprays, nail polish
remover, paint thinner, felt tip markers, air
freshener acetone products, carburettor
cleaner, gasoline, propane gas, gas inside
ping pong balls, VCR head cleaner
 Risk: irritation and sores around mouth
 nose, nausea and headache odd behaviour,

damage to brain, liver kidneys


 Baby: prematurity(42%), LBW(52%),

MICROCEPHALY(32%), neonatal death(10%)


 Developmental delay and craniofacial defects
 Most drug passed in breast milk
Rate of transfer
 Lipid solubility, mol wt, degree of protein

binding, degree of drug ionization,


absence/presence of active secretion
 Dose to infant is usually sutherapeutic; 1-2%
of mat dose. If drug toxic, this matters
 Drugs more not easily detoxified in infants
 Drug of abuse: amphetamines, cocaine ,
heroin, marijuana, phencyclidine, and
nicotine: C/I in preg.
 Cyclophospamide, cyclosporine &

doxorubicin : risk outweigh benefit cause


immunosuppressant
 ? Methotrexate : benefit> risk not a C/I to B/F
 BUSULPHAN is safe
 Bromocriptine : may suppress lactation, 5mg
may not
 Ergotamine: migraine headache: may cause

infant vomiting, diarrhoea and convulsions:


avoid
 Ergot is no however
 Lithium: infant has 40% of mat. Level . Long
term effect not known
 Radiopharmaceuticals: interrupt B/F for

variable periods; gallium 67-2/52; iodine


131-2 to 14/7; radioactive sodium-4/7,
technetium 99-24hrs to 3/7
 Psychotropic drugs inc antianxiety,
antidepressants & antipyschotic may be cause
for concern; effect of developing nervous
system not known
 Metronidazole :single dose preferred.

Interrupt B/F for 12-24 hrs


 Safe; narcotics, analgesics, and
anticonvulsants e.g carbamezepines,
phenytoin, mgso4 , codeine, morphine: no
neonatal effect
 Barbiturates/benzodiazepines: observe

infants for sedation. As fetus eliminates


slowly. Not so with carbamezepines
 Analgesics: aspirin safe pass into milk: 16
300mg tabs in a day can cause platelet
dysfunction in infants
 Acetaminophen ; very safe
 Antihistamines and phenothiazines: safe ;

avoid decongestants in women having


inadequate milk flow
 Aminophyline; max milk conc.: 1 and 3 hrs
after oral dose. Infant receive 1% of mat,
dose: no effect
 Amphetamines; no insomnia or stimulation in

infant
 Antihypertensives: thiazide diuretics may

decrease milk in 1st month


 Propanolol/atenolol: infant 1 % of mat. Dose ;

no effect
 Clonidine ; safe
 Heparin : do not cross
 Warfarin; 98% bound to plasma protein:

insignificant in breasmilk; safe to breastfeed,


same for bishydroxycoumarin
 Phenindione: C/I in B/F
 CORTICOSTEROIDS:safe in B/F mother
 Digoxin: safe

Antibiotics
 Penicillin; safe
 Cephalosporins: safe
 Tetracyclines; tooth staining & delayed bone

growth not reported with use ; high binding


of drug by calcium and protein, level too low
 Sulfonamides: ?avoid in 1st 5 days of life esp
in premature: not contrindicated in breast
feeding
 INH/acyclovir: safe
 OCP ; IN 1ST 3 weeks affects quality/quantity
of brestmilk
 Progestins are sasfr
 Alchohol: level in breast milk similar to mat.
Blood level :slight but significant detrimental
effect on motor not mental dev. Also alters
odor of the milk- infant consume less milk
 Lithium: level in milk one half of serum levels:
benefit>risk
 Propythiouracil:continue B/F. Watch infant for

hypothyroidism
 Caffeine: exccess; infant wakefulness; limit

intake
 Smoking: infant risk from passive smoking
 Diagnostic radiation is not tratogenic
< 5 to 10 cGy : non teratogenic
 Mat chest radiograph 0.008cGy
 IVU-0.4cGY
 CT-0.25cGy per slice
 Barium enema-1cGy
 Technetium 99m scan -1to 3 cGy
 Thallium 201 scan-0.5 to 1 cGy
 Maternal consideration : do not hesitate: ?
Fetal irradiation of 2 cGy is associated with
child risk of leukemia by 1.3 to 1.8 fold
 Uss is safe
 MRI: no ionizing irradiation
 Therapeutic radiation : teratogenic
 Fetilization to implantation: all or none
 Teratogenic effects: microcephaly, mental

and growth retardation,


 Other TM ; cns , eye and haemopoetic

system
 Fever in 1 st tm may cause NTD and
dysmorphic syndromes?
 Saunas? teratogenic
During period of organogenesis
 Is medication a known teratogen
 Potential adverse fetal/neonatal effect
 Risk benefit ratio to mother
 Is dx more of factor than drug
 Sources of info on medication
 Counselling of pt
 Unknown: 65- 70% of congenital
malformations;
 20-25% secondary to genetic abnorm
 3-5% intrauterine infection
 4% - mat dx DM, Phenyketonuria, epilepsy
 < 1% drug exposure maybe( main suspect by

physicians and pt, lawyers)



 Textbooks
 Computer data base: TERIS, TOXLINE
 Referral to a teratologist
exposure to medication
 Accurate details of exposure , esp G.A, DRUG
EXPOSURE(class, dose , route of admin., timing,
dx tx), info on concomitant exposure, medical
condition which may affect
 Check for confounding family or medical hx
 Get up to date info on drug
 Emphasize background risk
 Be clear about what is known, but do not assume
that absence of data means no risk
 Medication should be used only if expected
benefits usually to mother are greater than
the risks usually to fetus
 Try and avoid 1ST TM
 Use known drugs rather than new untried

drugs
 Use minimum dose for desired effect
 Absence of data does not imply safety