As described by Leviton and Gilles, UTI was also associated with an increased risk for death. In both the NCPP and Medicaid data sets, more than 1.9% of the pregnancies resulted in a fetal death. For the NCPP analysis of death, the second trimester results are made on the basis of maternal UTI in the second trimester and fetal death in the second or third trimester. The third trimester results include some live-born infants, because the 35-day critical period following UTI occasionally extended into the postnatal period for some of the infants. Thus, for the infants who had postnatal deaths, prematurity and low birth weight could be an intermediate variable, since the relationship between UTI and prematurity has been established.16-18 The biologic explanation of fetal death associated with maternal UTI implicated endotoxins from gram-negative bacteria. It is likely that a similar mechanism is responsible for the brain damage (mental retardation or developmental delay) associated with maternal UTI.
Limitations
Our analyses and the comparison with the Medicaid data have several important limitations. First, there were issues related to the exposure variable. The case definition for UTI from the 2 data sources differed, since the NCPP data relied on a physician diagnosis and a date of occurrence and the Medicaid data relied on a physician diagnosis or a urine culture followed by a prescription for antibiotics within 14 days of diagnosis. The UTI rate was 20.9% for the Medicaid group and 15.6% for the NCPP group. Also, we did not have data on the specific symptoms or reason for the urine culture and the organism identified on culture. It is possible that only febrile cases of bacteriuria or specific bacterial species were associated with the adverse outcomes, but this could not be identified in these data sets. We could not determine how long the symptoms, if any, were present before treatment or the efficacy of treatment as measured by test-of-cure follow-up cultures later in pregnancy. Women with a positive urine culture or urine analysis who did not fill an antibiotic claim within 14 days following the laboratory test were not cases in the Medicaid analysis. This misclassification would result in some women with an untreated bacteriuria remaining in the comparison group and biasing the results toward the null hypothesis of not finding a difference between those in the case group and those in the control group.
Second, the case definition for mental retardation or developmental delay differed for the 2 data sets. For the NCPP we had actual scores on a test of cognitive functioning, and 4.5% scored in the mental retardation range (IQ 69). The Medicaid mental retardation or developmental delay diagnoses were identified for 7.0% using International Classification of Diseases-ninth revision-Clinical Modification codes 315 (specific delays in development), 317 (mild mental retardation), 318 (other specified mental retardation), or 319 (unspecified mental retardation).
We calculated the risk for death and mental retardation without regard to antibiotic prescription status for the NCPP, because the medication data were not coded with a date. The Medicaid data were useful in this regard, since we had the actual date the prescription was filled. Women with a filled prescription did not necessarily take the medication, and women without a filled prescription might have received samples of the antibiotic from their physicians. Thus, we do not know the actual compliance rate for treatment. It must be noted that there could be a difference in some other unidentified characteristic in these analyses of the women who filled their prescription compared with the women who did not. This could be referred to as a healthy patient effect. Finally, for the NCPP data set, children with mental retardation were more likely to be lost to follow-up before their fourth-year checkup than the children with normal cognitive functioning since out-of-home and institutional placement was still recommended for children with special needs before 1975. These factors, which could not be controlled for in this secondary data analysis, might bias the results toward the null hypothesis of no difference between the groups and therefore dilute the magnitude of our findings.
Further Research
Additional longitudinal studies are needed to evaluate the association of the time of infection with presenting symptoms and organisms. Also, animal models are needed to understand the mechanisms of injury to the fetal brain.
Conclusions
Our findings support an association between third trimester maternal UTI and fetal death, mental retardation, or developmental delay. Women with asymptomatic bacteriuria early in pregnancy may be at higher risk for UTI during the latter half of pregnancy,7 and more aggressive screening techniques may be appropriate for this population. The Medicaid data suggest there is no difference in mental retardation or developmental delay outcomes between the treated women and women without UTIs. Some physicians may want to advise women of the potential risks for infection of their fetus when a UTI is diagnosed, in an attempt to increase compliance with the medication regimen.