Teratology Assignment

Abstract

BACKGROUND: Recently we reported the development and optimization of a zebrafish teratogenicity assay using dechorionated AB strain embryos, a promising assay that was 87% concordant in correctly identifying in vivo teratogens and non-teratogens from a set of 31 compounds (Brannen et al., 2010: Birth Defects Res 89:66–77). METHODS: This assay utilizes a zebrafish morphological score system to characterize adverse effects and identify the no-observed-adverse-effect level (NOAEL). RESULTS: This report describes in detail the morphological score system used in the dechorionated zebrafish embryo culture teratogenicity assay. The morphological assessment includes evaluation of most structures and organ systems and grades relative severity of abnormalities. CONCLUSIONS: To this end, the morphological score system provides information of tissue-specific teratogenicity that has been found to have good concordance with structures found affected in vivo and can also be used to rank compounds based on the severity of malformations. Birth Defects Res (Part B) 89:382–395, 2010. © 2010 Wiley-Liss, Inc.

Because any medication can present risks in pregnancy, and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. However, women with underlying medical or psychiatric issues frequently require medication throughout pregnancy. In such patients, care must to be taken to select the safest drug from the necessary class of medication. Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist. [5]

Each area of pharmacologic therapy intervention must be assessed separately and specifically for each patient. For example, gastroesophageal reflux disease (GERD) is common during pregnancy and presents difficulties in choosing optimal medications. [6] For most patients, lifestyle modifications are useful, but if these interventions are insufficient to control symptoms, and medication is often required. First-line medical therapy for pregnant woman with GERD entails antacids. If antacids fail, use of histamine-2 receptor antagonists and proton-pump inhibitors can be attempted; these drugs do not seem to be associated with clinically significant risks in pregnancy. In rare cases, promotility agents can be prescribed, though the risks and benefits must carefully be discussed with the patients before the drugs are started.

A physician caring for a pregnant patient who requires medication should take care in choosing dosages and types of drugs that maximize effectiveness while minimizing fetal risk. It is essential to understand the effect of medications and to know the point in fetal development when drugs are most toxic and which fetal organs are most susceptible. In addition, healthcare providers who treat pregnant women must be familiar with methods of gathering information about drugs, and they must be aware of online databases that are most useful for this purpose.

Several resources are available to expand one’s knowledge of teratology. Teratogen Information System (TERIS) and Reprotox are Internet databases that cover this subject. The Organization of Teratology Information Specialists is a network of risk-assessment counselors in the United States and Canada who specialize in researching and communicating the risks associated with drug exposures in pregnancy. All of these are useful resources to learn about drug use in pregnancy. They are frequently updated and should be referenced frequently, particularly when one is prescribing unfamiliar drugs in pregnancy.  Primary literature searches via MEDLINE can also provide information about human data, clinical trials, and meta-analyses regarding a particular drug. [3]  Finally, the drug label can provide information about toxicity.  Since 1979 the FDA has provided a labeling system in an attempt to guide providers in prescribing drugs to pregnant women. This system will be discussed later in the article.

General guidelines for choosing dosages and types of drugs within a class are lacking. Each drug should be assessed, and its risks and benefits should be weighed. Various organizations, including the Organization of Teratology Information Specialists, have performed many studies in this area. Specific drugs should be investigated before they are used.

Risk-benefit assessment and counseling should involve the patient in the setting of her current state of health. The physician must consider the effects of drug exposure on the developing fetus or embryo and acknowledge specific susceptibilities at each point in fetal development, as balanced against the risks of worsening maternal illness.  The patient must consider her symptoms, quality of life, and weigh risks and benefits of treatment.  The most important consideration is the underlying disease and the consideration of the consequences of interrupting or stopping treatment. [3]

In a 2008 Canadian study, 19.4% of women were found to have used FDA category C, D and X medications at least once during pregnancy, the most common of these being albuterol, co-trimoxazole, ibuprofen, naproxen and oral contraceptives. [7] Analyzing the same data, Yang noted that woman who had such exposure were more commonly characterized by chronic diseases, younger age, increased parity, and receipt of social assistance. [8]

Combinations of medications rather than individual medicines are possibly associated with increased risk of birth defects.  Oberlander et al performed a study to determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor antidepressants used alone and in combination with benzodiazepines. In this study, population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births in British Columbia during a 39-month period (1998-2001). Even after controlling for maternal illness profiles, infants exposed to prenatal serotonin reuptake inhibitors in combination with benzodiazepines had an increased incidence of congenital heart disease versus controls who had not been exposed. Serotonin reuptake inhibitor monotherapy was not associated with an increased risk for major congenital anomalies, but was associated with an increased incidence of atrial septal defects, and researchers did not associate risk with first trimester medication dose/day. [9]

Grigoriadis et al concluded that antidepressants do not seem to be associated with increased risk of congenital malformations, but evidence showed a statistical significance for cardiovascular malformations. [10]

A population-based cohort study of 179,007 children by Viktorin et al examined the association of maternal antidepressant medication use during pregnancy with intellectual disability in their children. The study found that intellectual disability was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. The relative risk of intellectual disability after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Although the relative risk was increased in children born to mothers treated with antidepressants, the study found no evidence of an association after adjusting for confounding factors. [11, 12]

For excellent patient education resources, visit eMedicineHealth's Pregnancy Center and Cholesterol Center. In addition, see eMedicineHealth's patient education articles Pregnancy, High Cholesterol, Cholesterol FAQs, and Lovastatin (Mevacor, Altocor).

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