The Antiretroviral Pregnancy Registry: individual drug safety reports on health of infants exposed to ARVs during pregnancy
Polly Clayden, HIV i-Base
In an oral presentation Karen Beckerman described the role of the Antiretroviral Pregnancy Registry (APR) and presented the latest analysis of compiled data. [1, 3]
The APR is an international registry, started in 1989, to prospectively monitor potential birth defects in infants exposed to antiretrovirals in utero. It is one of the largest ongoing pregnancy registries in the world.
The objectives of the registry are to provide early warning of major teratogenicity; estimate risk of birth defects and collect supplementary data from animal, clinical and epidemiological studies. Data collection is through voluntary enrollment by healthcare providers of pregnant women exposed to antiretrovirals, and in turn infant follow up.
This analysis looked at the ability to detect, at 80% power with Type I error rate of 5%, potential increases in birth defect prevalence in infants following first trimester exposure (during which organogenesis occurs), vs. second and third trimester exposures.
The registry has sufficient numbers of reports to detect a 2-fold increase in overall anomalies following exposure to abacavir, atazanavir, efavirenz, FTC, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, d4T and tenofovir. For AZT and 3TC there are sufficient numbers of reports to detect a 1.5-fold increase in such anomalies.
Dr Beckerman presented data from 1989 to 31 July 2008. The majority of reports (88.2%) are from the US, with small numbers from elsewhere (eg UK 3.1%, SA 1%). One of the current goals of the registry is to increase non-US reporting.
During this period 11,950 pregnancies were enrolled. Of these 494 (4.1%) were awaiting outcome and 985 (8.2%) were lost to follow up. There were 10471 evaluable pregnancies; 47% were exposed to antiretrovirals during the first trimester.
9,948 (93%) live birth outcomes were available for analysis. Among this group Dr Beckerman reported an overall prevalence of defects of 2.7% (271/9,948) 2.9% (126/4329) from pregnancies with earliest antiretroviral exposure in the first trimester vs. 2.6% (145/5618) with second and third trimester exposures.
APR continues to monitor two drugs that in the past met criteria for evaluation and further monitoring: AZT was associated with an increased risk of hypospadias among infants in the Women and Infants Transmission Study (WITS), and the registry found a higher than expected, 4.4% (94/3068), defect prevalence following first trimester of ddI exposure that has no apparent pattern and is not statistically significant. Notably, defect prevalence for efavirenz exposures were, 3.2% (13/407) ie not elevated above background population risk, and were no different from first and second/third trimester exposure to any other antiretroviral.
A major recent change in the APR has been the inclusion of data from the Women and Infants Transmission Study (WITS). A higher than expected incidence of hypospadias in babies exposed in utero to AZT is reported in these data, and, when added to the individual prospective reports to the register, AZT is associated with an increased risk of hypospadias. However, this association is not found when the WITS data are excluded. It is difficult to explain this discrepancy. Data from the European Collaborative Study, which are summarised in the APR reports, but not included in the analysis, do not suggest any association between AZT and hypospadias.
The higher rate of congenital anomalies with ddI has been documented in the APR for a number of years without attracting much attention, in part due to the lack of association with a specific defect (as compared with efavirenz). However, the overall rate has steadily reduced over several years; there have been fewer reports of congenital malformations associated with ddI in recent years. It should be noted that the APR has not examined rates of congenital malformations with specific combinations (which are legion) but one explanation of the trend is that ddI is no longer prescribed with other ARVs that increase the risk of congenital malformations.
As in all previous reports from the APR the overall risk of congenital malformation in babies exposed during the first trimester to efavirenz is not increased. One case of spina bifida has been reported in the prospective arm of the study but it is not possible to know whether this reflects an increased risk or is a chance observation.
Finally, it is important to note the paucity of data on all newly licensed antiretroviral therapies. These should be prescribed with caution in all women of child-bearing potential, regardless of stated family planning intent.
- KP Beckerman, D Covington, K Dominguez et al. Antiretroviral Pregnancy Registry (APR) at 10,000 prospective reports. 9th International Congress on Drug Therapy in HIV Infection. 9-13 November 2008, Glasgow. Abstract 0223.
- Watts DH, et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. Journal of Acquired Immune Deficiency Syndromes: JAIDS 2007, 44(3):299-305.
- Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2008 Wilmington, NC: Registry Coordinating Center; 2008.