Perinatal infections

KEY POINTS

* Analyses of National Collaborative Perinatal Project (NCPP) data from the 1970s and Medicaid data from the 1990s support an association between third trimester maternal urinary tract infection (UTI) and mental retardation or developmental delay.

* The NCPP data support an association between third trimester maternal UTI and fetal death.

* OBJECTIVE We analyzed the relationship between fetal exposure to maternal urinary tract infections (UTIs) and mental retardation or developmental delay and fetal death.

* STUDY DESIGN A retrospective cohort design was used to explore the risk for fetal death and mental retardation or developmental delay associated with exposure to maternal UTI during pregnancy.

* POPULATION Matched maternal-child pairs from the National Collaborative Perinatal Project (NCPP) from the decades of 1960 and 1970 were compared with a previous analysis of the South Carolina Medicaid Reimbursement System (Medicaid) for 1995-1996. Both data sets are representative of poor women and their children.

* OUTCOMES MEASURED The outcomes measured were fetal death and mental retardation or developmental delay in the live-born children.

* RESULTS There was an increased relative risk (PR) for mental retardation or developmental delay in the third trimester of pregnancy (RR=1.40; 95% confidence interval [CI], 1.01-1.95) in the NCPP, and there was a similar risk in the Medicaid data. The third trimester relative hazard for fetal death associated with maternal UTI was 2.23 (95% CI, 1.40-3.55).

* CONCLUSIONS Our findings support an association between maternal UTI and fetal death and mental retardation or developmental delay. These results confirm the importance of diligent diagnosis and treatment of maternal UTI by prenatal care providers.

* KEY WORDS Urinary tract infections; mental retardation; infant mortality. (J Fam Pract 2001; 50:433-437)

Primary care providers know that the most common site of infection during pregnancy is the urinary tract.[1-6] Pregnant women at the highest risk for urinary tract infection (UTI) include those with a history of UTI, high frequency of sexual activity, high parity, functional urinary tract abnormalities, sickle cell trait, and diabetes mellitus.[1,3,5,7] The well-documented consequences of UTIs include pyelonephritis in pregnant women and preterm labor and low birth weight in the infants.[4,8-14] Fetal death has also been associated with maternal UTI. Leviton and Gillesl[15-17] conducted autopsies on fetuses with clinical reports of maternal UTI and found endotoxin-damaged glial cells in the maturing forebrain. Glial cells (destined to become oligodendroglia and lay down myelin) are either destroyed (causing necrosis) or transformed (resulting in hypertrophic astrocytes and damaged glia). The end result of this process can be perinatal leukoencephalopathy and death.[17,18] The relationship between maternal UTI and deficits in child development has also been explored; there has not been a consensus, however, about this association. Researchers for the National Collaborative Perinatal Project (NCPP) reported a 2.38-point decrease in the intelligence quotient (IQ) score in white boys and no significant variation in IQ scores in girls or black boys.[19,20] There are reports of an association between UTI and delayed motor performance at the age of 8 months and an increased risk for cerebral palsy.[21,22] Others found no relationship between maternal UTI and subsequent psychomotor impairments.[23]

We analyzed the relative risk for mental retardation or developmental delay following UTI, taking into account the trimester of infection and the impact of treatment. Medicaid reimbursement files were used to analyze the association for more than 41,000 mother-child pairs for the period 1994 to 1996. The proportion of women with a presumably untreated UTI who had a child with mental retardation or developmental delay was 35% higher than the unexposed group and 24% higher than the group that had a UTI and had prescriptions filled.[24] To further elucidate the relationships between fetal exposure to UTI and subsequent mental retardation or developmental delay, we compared the analysis of the NCPP data set with our previous analysis of the Medicaid data. We also used survival analysis to explore the potential relationship between maternal UTI and intrauterine fetal demise. This was done since the maternal UTI and death associations reported by Leviton and Gilles,[15-17] was based on autopsy studies from the NCPP, and the comparison was between dead infants whose mothers did and did not have a reported UTI. We used the retrospective cohort design to compare the risk for fetal death for infants with and without maternal UTI exposure.

METHODS

The data used for these analyses were the research variables from the NCPP. Those women were recruited from 12 urban university medical centers throughout the United States between 1959 and 1974. The NCPP data for the outcome of mental retardation or developmental delay were compared with the South Carolina Medicaid data set from 1994 to 1996, using the methods previously described in the literature.[24]

The NCPP was a longitudinal study of the outcomes of pregnancies of primarily urban poor women. A total of 53,043 pregnancies (including 7522 repeat pregnancies) were followed up, with 64% of the participants residing in the Northeast. The data were collected on the pregnancies during the prenatal visits, at admission for delivery, and during scheduled follow-up visits for 8 years. Psychologic evaluations of the children were performed at 8 months, 4 years, and 7 years. It should be noted that not all children were evaluated, since there was a 25% loss to follow-up for the 4-year examination. Of these, 9.6% died before age 4 years; 2.3% were tested for IQ, but no scores were obtained. The remaining families were either not located or refused to return for testing and examination.[19,20,25]

We analyzed 41,692 NCPP mother-child pairs for whom information about prenatal care and child outcomes were available. The data on exposure to maternal UTIs were recorded in the medical record and coded (month and year). The clinical diagnosis was supported by laboratory tests and recorded by the attending physician. The diagnoses of mental retardation or developmental delay were based on standardized scores on the Stanford-Binet Intelligence Scale Form L-M, which was administered to children aged 4 years in the NCPP data set.[20] Children with scores lower than 70 were classified as having mental retardation.

Information about fetal deaths was available for the NCPP; however, these data were limited by the late entry into the study. Only a small number of women entered the NCPP study in the first trimester, so first trimester terminations were not available. The case definition for fetal death was death occurring before and up to birth. We included neonatal deaths (deaths during the first 28 days of life) in our analysis; some infections occurred late in pregnancy, and the deaths did not occur until the postnatal period. A 35-day Critical period following the date of infection was used to allow for detection of either a fetal death at the monthly prenatal examination or spontaneous fetal loss.

We analyzed the data with chi-square tests, logistic regression modeling, and survival analysis procedures using SAS software (SAS Institute, Cary, NC). Chi-square tests were used to compare the distribution of independent variables to the 2 outcome variables (death and mental retardation or developmental delay). The woman's age when the infant was born, infant birth weight, infant sex, maternal education, gestational age at study entry, and race were considered potential confounders. When the final logistic regression models were developed to measure the impact of exposure to maternal UTI on the relative risk for mental retardation or developmental delay compared with survivors without mental retardation or developmental delay, the control variables were woman's age at the time of the birth of the infant, infant birth weight, and race. This was based on standard data-based variable selection procedures. We conducted survival analysis using Cox proportional hazard models by applying Lifetest and PHreg Procedures from SAS.

RESULTS

Demographics and other baseline characteristics of the NCPP mother-child pairs are shown in Table 1. The mother and child characteristics reflect the study entry criteria of an equal proportion of black and white participants from poor economic environments. More than half the women had less than a high school education, and 13.4% of the infants were born weighing less than 2500 g. The fetal death rate was 1.9%, and the UTI rate was 15.6%.

The overall risk for mental retardation in the children of pregnant women with UTI was 16% higher than for women without a UTI (Table 2). The only trimester that indicated a statistically significant increased risk was the third trimester (relative risk [RR]=1.40; 95% confidence interval [CI], 1.01-1.95). Because of late entry into the NCPP study, there were only 8 mothers with UTI in the first trimester who had infants with MR; thus, this estimate of risk was unstable. Also, we did not have treatment data for the NCPP group.

Table 3 shows the death risk associated with UTI exposure. There was a two-fold increased overall risk for death (RR=2.02; 95% CI, 1.32-3.07) when the fetus was exposed to a maternal UTI. Survival analysis was used to predict the risk for death 35 days after exposure to maternal UTI when taking into account the interaction of time and the UTI exposure. When the actual time of exposure is taken into account, the relative hazard was 1.41 (95% CI, 1.07-1.76) in the second trimester and 2.23 (95% CI, 1.40-3.55) in the third trimester.

DISCUSSION

Our analyses suggest that maternal UTIs are associated with MR and fetal death in the third trimester. The NCPP study recruited poor women, and 56% had less than a high school education. The infant birth weight proportions are similar to those reported nationally in 1970, with the low birth weight proportion 7.9% for all races and 13.9% for blacks.[26] Analyses of more highly educated women with different access to care would be required to ascertain whether this result is reproducible in other population groups. Support for the observed associations are strengthened, however, by the consistency between these data and the more recent analysis of women and children funded by Medicaid in South Carolina during 1994 to 1996.[24]

We analyzed the relationship between maternal UTI and mental retardation or developmental delay using logistic regression models for both the NCPP and Medicaid. The Medicaid data included information about whether a prescription for antibiotics was filled following the diagnosis of a UTI. Thus, in the Medicaid data set we were able to identify women who probably did and did not have treatment following the diagnosis. In the NCPP and the Medicaid models we determined the risk for mental retardation or developmental delay in children after controlling for gestational age at entry into the study, maternal age, maternal race, and birth weight. These confounders control for the effect of factors already known to be associated with both the exposure and the outcome, and are not believed to be in the causal pathway. The Medicaid data revealed an increased relative risks for mental retardation or developmental delay of 1.47 (95% CI, 1.08-2.01) in the first trimester and an RR of 1.42 (95% CI, 1.121.81) in the third trimester, when there was no documentation of an antibiotic prescription being filled. When medication prescriptions were filled there were no increased risks for mental retardation or developmental delay.

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 [is less than or equal to] 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.

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[26.] Kiely JL, Brett KM, Yu S, Rowley DL. Low birth weight and intrauterine growth retardation. In: Wilcox LS, Marks JS. From data to action: CDC's public health surveillance for women, infants, and children. Washington, DC: US Department of Health & Human Services; 1994:185-202.

(*) Submitted, revised, February 1, 2001. From the Department of Family and Preventive Medicine, University of South Carolina School of Medicine (S.M., W.C.); Department of Epidemiology and Biostatistics, University of South Carolina School of Public Health (V.D.); and the Office of Research and Statistics, South Carolina Budget and Control Board (H.M., L.S.).

The findings, conclusions, and opinions contained in this manuscript are those of the authors and do not necessarily reflect the findings, conclusions, and opinions of the South Carolina Department of Health and Human Services.

Reprint requests should be addressed to Suzanne McDermott, Department of Family and Preventive Medicine, 6 Richland Medical Park, Columbia, SC 29203. E-marl: suzanne.mcdermott@palmettohealth.org.

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