Drug during pregnancy

• More than 50% of pregnant women take prescribed or non-prescribed (OTC) drugs or use social drugs (such as tobacco and alcohol) or illicit drugs at some time during pregnancy
• In general, drugs should NOT be used during pregnancy unless absolutely necessary because many can harm the fetus
• About 2-3% of all birth defects result from drugs that are taken to treat a disorder

  
• Pharmacokinetics


  The study of the movement of drugs within the body
• Types of pharmacokinetics that might affect the transfer of drugs toward the fetus

  • Maternal
  • Fetal
  • Placental

  
• Maternal pharmacokinetics


  1. Changes in body fluid volume

  2. Changes in CVS parameters

  3. Changes in pulmonary functions

  4. Changes in gastric functions

  5. Changes in kidney functions

  6. Changes in serum binding proteins
• Fetal pharmacokinetics


  • Fetus has lower binding protein than his mother
  • Immature fetal kidney
  • Fetal liver metabolism "first pass effect"
• Placental pharmacokinetics


  • Blood flow in placenta is high during gestation so the transfer of flow-limited drugs will be more easy
  • Placental metabolism (hydroxylation,demethylation,dealkylation) will affect the transfer of the drug through the placenta
• The processes that govern the passage of a drug into milk are similar to the placenta

  
• Maternal serum concentration

  The main determinant of drug transfer to milk
• Milk pH

  Slightly acidic in comparison to serum pH, so weak bases could become trapped in milk (ion trapping)
• Drug transfer to fetus

  1. Main determinant is the mother's blood concentration

  2. Most drugs cross the placenta by diffusion

  3. Factors determining crossing: lipid solubility & protein binding, degree of ionization at physiologic pH, placental blood flow & surface area available for transfer

  
• Types of drug effects

  • Teratogenicity
  • Long term latency
  • Predisposition to metabolic diseases
  • Impaired intellectual or social development
• Teratogenicity

  Structural or functional dysgenesis of the fetal organs, including congenital malformations, intrauterine growth restriction, carcinogenesis, and fetal demise

  
• In humans, the critical time for drug-induced congenital malformations is in the first trimester

  
• Fetal age and drug effect

  1. Before the 20th day after fertilization: all-or-nothing effect, teratogenesis is unlikely

  2. During organogenesis (between 20 and 56 days after fertilization): teratogenesis is most likely

  3. After organogenesis (in the 2nd and 3rd trimesters): teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues

  
• The critical time for drug-induced congenital malformations is usually the period of organogenesis, about 20 to 55 days after conception

  
• The overall incidence of major congenital malformations is around 2-3%, minor malformations is 9%, 25% are due to genetic or chromosomal abnormalities, 10% due to environmental causes including drugs, and 65% of unknown aetiology
• Alcohol


  Increases the risk of early abortion, decreases birth weight, one of the leading preventable causes of mental retardation, binge drinking can cause fetal alcohol syndrome
• Smoking


  Carbon monoxide and nicotine cause hypoxia and vasoconstriction, increasing risk of spontaneous abortion, fetal growth restriction, placenta previa, premature rupture of the membranes, preterm birth, chorioamnionitis, stillbirth, and neonatal deficiencies
• Caffeine


  Consuming large amounts may increase risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions, but consuming small amounts (e.g. 1 cup of coffee/day) appears to pose little or no risk
• Aspartame


  The metabolite phenylalanine is concentrated in the fetus, which may cause mental retardation, but moderate ingestion (e.g. no more than 1 liter of diet soda per day) appears to pose little risk
• Warfarin


  Adverse effects when given during the 1st trimester (fetal warfarin syndrome), 2nd or 3rd trimester (optic atrophy, cataracts, intellectual disability, microcephaly, microphthalmia, and fetal and maternal hemorrhage), FDA Pregnancy category X, the only indication is for women with mechanical heart valves at high risk for thromboembolism
• Heparin


  Heparins are used for the management of venous thromboembolism in pregnancy because they do not cross the placenta, FDA Pregnancy category: low molecular weight heparin B, unfractionated heparin C

  
• Omeprazole (PPI)

  Safe to use during pregnancy
• Ranitidine (H2 blocker)


  Crosses the placenta, although the manufacturer advises use should be avoided during pregnancy, epidemiological study reveals no increased prevalence of adverse fetal outcomes

  
• Metoclopramide


  FDA Pregnancy category B
• Topical corticosteroids are generally considered safe for use at any stage of pregnancy
• Pseudoephedrine


  FDA pregnancy category C, possible risk of gastroschisis
• Loratadine


  FDA pregnancy category B, possible risk of hypospadias

  
• Carbimazole/Methimazole and Propylthiouracil (PTU)

  Both drugs cross the placenta and may cause fetal hypothyroidism in high doses, PTU is preferred in 1st trimester as Mazoles are teratogenic, Mazoles are preferred in 2nd and 3rd trimesters to minimize PTU-induced risk of liver failure

  
• Corticosteroids


  FDA pregnancy category B, when used during the 1st trimester, possibly orofacial clefts, hydrocortisone largely metabolized by placental dehydrogenase, fluorinated corticosteroids (e.g. betamethasone) and dexamethasone are not, making them the drugs of choice when treating the fetus is the aim of therapy, such as for fetal lung maturation

  
• Diethylstilbestrol


  Human teratogen, FDA Pregnancy category X, synthetic form of estrogen used in the past to prevent miscarriages and premature labor, side effects can extend along 2 generations including increased risk of breast cancer in the mother, cervical and uterine abnormalities, vaginal adenosis, and vaginal clear cell adenocarcinoma in the female fetus, and low sperm counts in the male fetus

  
• In general the safest antibiotics in pregnancy are penicillins, cephalosporins, and clindamycin
• Diethylstilbestrol (DES)


  Synthetic estrogen drug prescribed to pregnant women to prevent miscarriages, premature labor and complications of pregnancy in the past
• Diethylstilbestrol (DES)


  • Its side effects can extend along 2 generations
  • Increased risk of breast cancer in the mother
  • Cervical and uterine abnormalities leading to infertility in the female fetus
  • Vaginal adenosis (metaplastic endometrial/cervical tissue in vagina) in the female fetus
  • Vaginal clear cell adenocarcinoma in the female fetus
  • Low sperm counts in the male fetus

  
• Some studies said Diethylstilbestrol (DES) may cause breast cancer
• Antibiotics


  • Aminoglycosides [streptomycin – gentamicin]
  • Aminoglycoside [neomycin – tobramycin]
  • Penicillin
  • Tetracycline
  • Quinolones
  • Cephalosporin
  • Trimethoprim
  • Macrolides
  • Chloramphenicol
  • Nitrofurantoin
  • Metronidazole
  • Vancomycin
• Category B


  Animal studies showed risk but human no risk or no risk but no human studies performed
• Category C


  Risk on animal studies but no human studies, used if benefit outweigh risk