The return of thalidomide: Are birth defects surveillance systems ready?

Abstract

In the 1960s, thalidomide caused limb deficiencies in thousands of infants worldwide. The limb deficiencies were frequently of the intercalary type. As a result, numerous countries started birth defect surveillance programs. In 1967, the Centers for Disease Control (CDC) started the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based surveillance system, to provide early warning against new teratogens. Recent studies have shown that thalidomide may be beneficial for a range of conditions, including cancer and AIDS, and it may once again become widely available. Here, we examine the ability of MACDP to detect an increase in the birth prevalence of limb deficiency as an early warning of fetal exposure to thalidomide. We calculated base rates for all limb deficiencies, for bilateral nonsyndromic intercalary or preaxial deficiencies, and for all nonsyndromic intercalary limb deficiencies among Atlanta infants born from 1968 through 1993. We used relative risk estimates from previous studies and a range of pregnancy exposure rates for thalidomide. We tested the statistical power of MACDP to detect subtle changes in the birth prevalence of these defects using Poisson and cumulative sum (CUSUM) techniques. The base rates for all limb deficiencies, for bilateral intercalary or preaxial deficiencies, and for all intercalary limb deficiencies, were 0.53, 0.035, and 0.022/1,000, and the estimated relative risks were 175, 4,570, and 8,180, respectively. We varied the assumed rate of exposure to thalidomide from 1/10,000 to 5/100. With a 1/1,000 exposure rate, both Poisson and CUSUM techniques will detect a rate change in intercalary limb deficiency in about 6 months of monitoring, and a rate change in bilateral intercalary or preaxial deficiencies in about 12 months of monitoring. When monitoring all limb deficiencies, a pregnancy exposure rate of 3.5% or less would go unnoticed by the Poisson method and would take more than 50 years for the CUSUM method to signal an alarm with a 1/1,000 exposure rate. However, for rates of exposure less than 1/1,000, a progressively longer period of time or larger sample are needed to detect a rate change by both methods. Our findings highlight the importance of enlarging the monitored population and correct case classification in birth defects surveillance.

Epidemiological Surveillance of Birth Defects Compatible with Thalidomide Embryopathy in Brazil

“…They support the notion that an impracticable surveillance time would be necessary when the rate of exposure to thalidomide is very low, even when monitoring bilateral intercalary and preaxial defects (or only intercalary, which are the defects most frequently associated with TE). In the present study, however, local accessibility to thalidomide was high, and we proposed the cumulative sum methodology (CUSUM) for the detection of increases in the frequency of alarms, since it is a method which is faster at detecting changes in prevalences than the Poisson methodology [22]. The TE surveillance system presented herein is highly sensitive because all the LRD described in the syndrome are included, but the system has low specificity because it groups different types of LRD not related to TE.…”

“…Yang et al [22] evaluated the ability of monitoring systems to detect TE alarms and suggested that the surveillance of all LRD is insufficient for the detection of this type of embryopathy. They support the notion that an impracticable surveillance time would be necessary when the rate of exposure to thalidomide is very low, even when monitoring bilateral intercalary and preaxial defects (or only intercalary, which are the defects most frequently associated with TE).…”

“…CUSUM has already been widely used for birth defects surveillance [22], [23], [24], being able to detect variations of TEP from the BPR of the baseline period by the sum of differences between the number of cases occurring during the surveillance period and a reference value obtained from the baseline period. The false alarm rate was set to one in 500 months (average run length (ARL)  = 500).…”

“…Newborns with preaxial and bilateral intercalary LRD came into this category, as these are already well established in the literature as TE sentinel phenotypes [15], [22]. Also, individuals that presented amelia were included, since it is a defect frequently observed in TE [25].…”

EUROCAT: 25 years of European surveillance of congenital anomalies

“…frequency, the surveillance system can provide a rapid population based response to the observations of the ''alert clinician'', or it can be used to assess how well the use of known teratogenic drugs is avoided in pregnancy. 16 We are fortunate not to have experienced any further event of the scale of thalidomide, but it is likely that drugs remain on the market with less dramatic population effects, where the drug is less widely used and the teratogenic risks are lower, or restricted to smaller genetically or otherwise susceptible subpopulations. This is an area on the borderline between surveillance and research where we need to graft on to ongoing surveillance a variety of methods, including casecontrol approaches with accurate data on women's medication history during pregnancy, linkages between congenital anomaly registries and clinical databases of women with specific diseases (epilepsy, diabetes) or having undergone specific treatments (assisted conception), and linkages between registers and prescription databases.…”