# Presentation: 811531

## Interface of Clinical Pharmacology & Drug Safety

**Gideon Koren, MD**

## The Challenge:

**How to Treat the Mother Without Adversely Affecting the Fetus?**

## A Relative QuestionIn many instances, not treating - increase maternal and fetal risks:

**HIV - both**
**Toxoplasmosis - fetus**
**Asthma - both**
**NVP - mother**

## Common Misperceptions

**“****Sulfonamides replace drugs/bilirubin from protein binding”**
**“****Antidepressants affect fetal brain”**
**“****Bendectin causes malformations”**

## How Many Medicinal Drugs Adversely Affect the Embryo?

**Less than 30**
**examples: **
** ****Accutane**
** ****Antiepileptics (barbiturates, carbamazepine, phenytoin, valproate)**
**ACE inhibitors**
**Drug for hyperthyroidism**
**Lithium**

## Examples of Drugs Proven Safe

**Acetaminophen**
**Bendectin (doxylamine, B6)**
**Salicylate**
**Penicillins**
**Cefalosporines**

## Pregnancy Conditions

**First Trimester**
**NVP**
**Infections**
**Transplant**
**Nicotine**

**Second-Third Trimester**
**Pre-eclampsia**
**Hypertension**
**Gestational Diabetes**
**Replacement therapy**
**Infections**
**Heart diseases**

## How Safe is Safe?

**The numbers studied define the power**
**Example:**
**Bendectin, after 130,000 case-controls**
**OR:  1.01 [95% CI 0.66 -1.55]**

## Bendectin-Fetal Safety/Risk

**Einarson et al (1988):**
**Meta-analysis:**
**17 studies with 130,000 cases**
**OR:  1.01 (0.66-1.55)**
**McKeigue et al (1994):**
**Meta-analysis:**
**16 studies**
**OR: 0.95 (0.68-1.04)**
**Seto-et al (1997):**
**All studies on H1 blockers in pregnancy**
**Meta-analysis:**
**23 studies: 200,000 cases/controls**
**OR: 0.78 (0.6-0.94)**

## How Safe is the Unsafe?

**Example **
** ****Misoprostol:**
**	****Moebius sequellae occurs in 1:100,000 in Brazil *Among kids with Moebius 47 of 96 moms(49%) took misoprostol compared to 3 of 96 controls OR: 29.7 (NEJM 1998; 338:1881).  This means 1:2000 risk of Moebius.  *Yet, in prospective follow-up of 67 women taking misoprostol, **_**none**_** had Moebius. (Reprod Tox 1999; 13:147)**

## Evidence of Safety

**Case reports/series**
**Case control studies**
**Cohort studies**
**prospective**
**retrospective**
**Meta-analysis**

## Gestational Diabetes

**“****Rarely treated with a sulfonylurea drug because of concern about teratogenicity and neonatal hypoglycemia” Lange, NEJM 2000**
**Randomized 404 singleton pregnancies at 11-33 weeks**

## Transplacental Kinetics of Glyburide

**Glyburide does not cross the human placental cotyledon in appreciable quantities (in contrast to older sulfonylureas and metformin) (Am J Obstet Gynecol 1991; 165:807).**
**In vivo: mothers had 50-150 ng/mL glyburide whereas cord blood-zero level.**
**No hyperinsulinemia or hypoglycemia in neonates.**
**Tritiated glyburide crossed rat placenta (Diabetologia 1995; 38:753).**

## Langer 2000

**No differences in:**
**Maternal glycemic control**
**Neonatal size of complications**
**Congenital malformations**
**Neonatal glucose**
**Cord insulin**

## “Must” Drugs

**Transplant (cyclosporine)**
**Infections that are lethal (HIV)**
**Infections that damage the fetus (Toxo, Varicella)**

## Zidovudine - HIV(JAMA 1999; 281:151)

**122 AZT - exposed not different from controls (treated with placebo on:**
**Physical growth**
**Immunology**
**Cognitive/developmental**
**Mortality at 4.2 yr/3.2-5.6)**

## Zidovudine (Lancet 1999; 354: 1084-89)

**Case series of 8**
**Mitochondrial dysfunction**
**5 (2 died): delayed neurological symptoms**
**4 of themreceived AZT plus lamivudine**
**4 received only AZT**
**Low absolute respiratory-chain complex I & IV activities months-yr later**

## AZT-Mitochondria

**AZT incorporates into fetal DNA in the monkeys (JNCI 1887; 89: 1602)**
**Antiretroviral nucleoside analogues: toxic to mitochondria in children and adults**
**Inhibition of g polymerase, the enzyme that causes duplication of mt DNA**
**Depletion of mt DNA**
**None of the children showed depletion of mt DNA**

## Cyclosporine

**It is not realistic to d/c cyclosporine when pregnancy is diagnosed in a transplanted women.**
**Cyclosporine crosses the placenta**
**Meta-analysis: OR 3.83 (95% CL 0.75-19.6) based on 4 studies (410 patients**

**First Trimester**
**Carbamazepine: NTD**
**Phenytoin: Dev. Delay**
**Valproic cid: NTD**
**Isotretionoin: Dev. Delay**
**Coumadi: Dandy Walker malfunction**

**Second Trimester**
**Coumadin?**