Medication in pregnancy

Dr.Huda Adnan
C.A.B.O.G
Medication in pregnancy

INTRODUCTION

More than (50%) of the women consume drugs (other than tonics) during pregnancy (the average is 3 to 4 drugs during the 9 months period ) in addition to non pharmacological substances that contain drugs which are potentially dangerous to the fetus such as cigarettes. Most drugs are safe to use in pregnancy ,however some harmful effects had been described to the fetus or to the neonate.

Prescribing drugs during pregnancy must be considered in 2 points:

1st : the physiological changes during pregnancy may alter the therapeutic agent (e.g . by affecting absorption).
2nd :the therapeutic agent may affect the fetus or neonate.

Maternal pharmacokinetics:

1.Drugs absorption: during pregnancy the gastrointestinal transit is prolonged due to slow emptying of the stomach & reduce gastric & intestinal motility.
2.Drugs distribution: lipid solubility & protein binding affect drugs distribution ( drugs which is low lipid solubility & highly bound to plasma protein result in low free drugs to be transferred to the fetus). There is also an increase in total body water & plasma volume therefore there will be more dilutional effects on the drugs . plasma albumin is also decreased.


3.Drugs metabolism: water soluble drugs are eliminated unchanged, while lipid soluble drugs are metabolized by oxidation, conjugation in placenta & fetal liver before being excreted in bile or urine.
4.Drugs excretion : renal blood flow increases as well as GFR & creatinin clearance, so water soluble drugs are excreted rapidly.

Fetal pharmacokinetics:

Almost all drugs with systemic effect on the fetus ( except heparin & insulin with molecular Wt, more than 1000 unit ) cross the placenta to reach the fetus by simple diffusion that depends on its plasma conc, degree of ionization & lipid solubility . the drugs distributes into the placenta , fetal liver & fetal adrenal glands . the fetus has limited ability to metabolite drugs in the liver & inefficient blood brain barrier.

Effect of the drugs on the fetus:

The effects range from killing the embryo to no effects. Drugs or their metabolites can cause adverse fetal effects.
The harmful fetal effects depend on:
1-the amount of the drug that enters fetal circulation.
2-dosage & rout of administration.
3-duration of use .
4-physical condition of the mother & the fetus.
5-maturity of the fetus.

6-time of gestational age during which the drug has been use.

7-concurrent use of other agents.
8-fetal metabolism.
Timing of embryo & fetal development:
Pre embryonic period: (0-2 weeks) during the1 st 2weeks after ovulation the embryo is thought to be resistant to any teratogenic effects of medicines.
Embryonic period: (2 weeks- 8 weeks ) it’s the most critical period as it’s a period of organogenesis , exposure during this period may cause birth defect & congenital malformation.


Fetal period : ( after 8 th weeks – delivery) exposure in this period may affect growth & functional development.
The harmful effect includes :
1. Mutagen : causes a change in a gene structure leading to miscarriage , congenital abnormalities, mental retardation. E.g radiation.
2.Carcinogen : induces or promotes cancer , e.g stillbisteroll.
3.teratogen: interferes with fetal development after conception leading to permanent alteration in the structure & function in the offspring (like limb deformities , deafness , cardiac defect , growth retardation ).

These include hormones (androgen) ,anticancer (methotrexate) ,anticonvulsant (phenytoin, sodium valproate) , oral anticoagulant (warfarin) & antithyroid(thiouracil &carbimazole) &radioactive iodide.
The FDA classifies drugs in one of 5 categories based on their teratogenic potential :

Category A

No risk
Controlled studies in pregnant women shows no risk.
Category B
No risk in human
Controlled animal studies have not shown fetal risk but no studies in human .
Category C
Risk not ruled out
Controlled animal studies have shown adverse fetal effect & there are no human studies or there are no Controlled studies in human or animals.

Category D

Positive evidence of risk
Controlled studies in human show adverse fetal effect but the benefit are greater than the risk
Category x
Contra indicated
Controlled studies in animal & human show adverse fetal effect but the risk are greater than benefit


Examples of common drugs in pregnancy:
Analgesia :
Aspirin: its safe in low dose SE: oligohydrominous , premature closure of ductus arteriosus , pulmonary hypertension & peripartum bleeding.
*paracetomol: is the analgesic of choice in pregnancy .
*other NSAIDs that commonly used are indomethacin, Ibuprofen,&naproxen. SE: like aspirin but in large doses may cause fetal renal failure .

Narcotic: safe but cause addiction, neonatal withdrawal &respiratory depression.

Anticoagulant :
*heparin: safe in pregnancy ,large molecular Wt does not cross the placenta .
UFH: SE: osteoporosis, thrombocytopenia, sterile abscess.
LMWH: once daily dose so less SE .
*warfarin: cause warfarin embryopathy(nasal hypoplasia, stippled bone epiphyses, microcephaly, IUGR, mental retardation .

Antihypertensive :

*methyldopa: (aldomate): safe SE: GIT upset, headache, dizziness, & postural hypertension.
*hydralazine :safe SE: GIT upset, tachycardia, palpitation, & fluid retention.
*B.blocker: safe SE: IUGR, mask fetal response to hypoxia, &neonatal hypoglycemia.
*ACEI: contraindicated causing renal anomalies, pulmonary hypoplasia, oligohydrominous & skull defect.

diuretics: usually not used in pregnancy because it reduce blood volume.

Thyroid drugs:
Propylthouracil: cross the placenta lead to fetal goiter,hepatotoxic.
*methimazole: associated with cutis aplasia, , esophageal atrasia, agranulocytosis.
*thyroid drugs: poorly cross the placenta so safe.
*radioactive iodine: contraindicated.


Psychotropic drugs:
*lithium: causing cardiac defect especially Ebstain's anomalies
*TAD : imipramine may cause heart defect & withdrawal symptoms & amitriptyline not cause birth defect.
*SSRI: fluoxetine may cause withdrawal symptoms in the neonate, pulmonary hypertension, & cardiac defect.
*diazepam: no birth defect but in late pregnancy may induce transient hypotonia, hypothermia, & respiratory depression.
*phenothiazine & chlorpromazine no birth defect but in late pregnancy induce extra pyramidal effects.

Anti convulsants :

*carbamazepine: cause malformation like hydantoin groups & induce neural tubes defect.
*phenytoin: cause cleft palate & lip, broad nasal bridge, cardiac defect ,IUGR,& mental retardation.
*Na valproate: cause neural tubes defect
*lamotrigine & gabapentin : are less teratogenic.

Antibiotics :

Ampicillin: safe but augmentin advisable to avoid because has adverse fetal effect (necrotizing enterocolitis) but no birth defect.
*erythromycin succinate: safe but ineffective for treatment of fetus.
*cephalosporin :safe
*aminoglycosides :teratogenic cause ototoxicity & nephrotoxicity.
tetracycline :cause teeth discolouration & bone chelation

sulfonamide : safe but not used in T3 due to neonatal hyperbilirubinemia.

*trimethoprim :avoided due to neural tube defect & cardiac defect.
*chlormphenicol: avoided grey baby syndrome.


*nitrofurantoin: safe
*ciprofloxacin: bone & cartilage defect & arthropathy.
*metronidazole: safe in early & late pregnancy.
Steroid :cleft palate.
Cytotic drugs : not safe.
Retinoids: not safe
Danazole : virilization of femle fetus.
DES: clear cell carcinoma & congenital anomalies of uterus

Thank you