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Vol. 183, No. 1 DOI: 10.1093/aje/kwv129 Advance Access publication: December 13, 2015
Original Contribution The Development of Extremely Preterm Infants Born to Women Who Had Genitourinary Infections During Pregnancy
Alan Leviton*, Elizabeth N. Allred, Karl C. K. Kuban, T. Michael O’Shea, Nigel Paneth, Andrew B. Onderdonk, Raina N. Fichorova, and Olaf Dammann, for the ELGAN Study Investigators * Correspondence to Dr. Alan Leviton, Boston Children’s Hospital, Au-414, 300 Longwood Avenue, Boston, MA 02115-5724 (e-mail: [email protected]).
Initially submitted March 3, 2015; accepted for publication May 7, 2015.
Gestational genitourinary infections, which have been associated with neurodevelopmental impairments among infants born near term, have not been studied among very preterm infants. The mothers of 989 infants born before 28 weeks of gestation were interviewed about urine, bladder, or kidney infections (UTIs) and cervical or vaginal infections (CVIs) during pregnancy, as well as other exposures and characteristics, and their charts were reviewed for the Extremely Low Gestational Age Newborns (ELGAN) Study (2002–2004). At 2 years of age, these infants underwent a neurodevelopmental assessment. Generalized estimating equation logistic regression models of developmental adversities were used to adjust for potential confounders. Infants born to women who reported a UTI were less likely than were others to have a very low Mental Development Index (adjusted odds ratio = 0.5; 95% confidence interval: 0.3, 0.8), whereas infants born to women who reported a CVI were more likely than others to have a low Psychomotor Development Index (adjusted odds ratio = 1.7; 95% confidence interval: 1.04, 2.7). In this highrisk sample, maternal gestational CVI, but not UTI, was associated with a higher risk of impaired motor development at 2 years of age. The apparent protective effect of UTI might be spurious, reflect confounding due to untreated asymptomatic bacteriuria among women who were not given a diagnosis of UTI, or reflect preconditioning. child development disorders; infant, extremely premature; urinary tract infection; uterine cervicitis; vaginitis
Abbreviations: BV, bacterial vaginosis; CVI, cervicovaginal infection; M-CHAT, Modified Checklist for Autism in Toddlers; MDI, Mental Development Index; PDI, Psychomotor Development Index; UTI, urinary tract infection.
dysfunctions identified as “unfavorable neurodevelopmental outcome” (7). Women with gestational genitourinary infections have a higher risk of delivering prematurely (8), and extremely preterm newborns are at higher risk of impaired development (9). It therefore seems reasonable to consider the possibility that maternal cervicovaginal infection (CVI) and UTI during pregnancy contribute to impaired development in children born extremely preterm. In addition, in 1 study (10), of the women who gave birth before 28 weeks of pregnancy, those who reported a genitourinary infection during the pregnancy were more likely than were others to have a newborn who had evidence of systemic inflammation during the first postnatal week, which is a risk factor for impaired development (11), cerebral palsy (12), and microcephaly (13).
Maternal urinary tract infection (UTI) during pregnancy, especially if accompanied by fever, has been associated with a higher risk of histologic indicators of brain damage among children born at term (1, 2). Maternal UTI has also been associated with a higher risk of a low intelligence quotient at 7 years of age (3) and sometimes with cerebral palsy (4), although not invariably (5). Although the possibility that children whose mothers had bacterial vaginosis (BV) during the pregnancy were at higher risk of cerebral palsy was first raised more than 15 years ago (6), we are not aware of any study that has evaluated this hypothesis to date. In one study in which investigators evaluated the developmental correlates and consequences of BV, the population largely comprised children born near term, who were classified as having or not having an amalgam of 28
Am J Epidemiol. 2016;183(1):28–35
Maternal Genitourinary Infections: Child Development
Assessments of the risks of impaired development among children whose mothers had genitourinary infections during the pregnancy have been limited to children born at term. In the present study, we describe results from 989 children born before the 28th week of gestation who underwent a developmental assessment at 2 years of age. At an intake interview conducted close to the time of delivery, each child’s mother was asked if she had a UTI or a CVI during the current pregnancy. Our choice to rely on maternal report is supported by documentation that pregnant women provide valid information about exposures and pregnancy characteristics (14–17). In addition, in the present population, children of women who reported a UTI were more likely than were others to have systemic inflammation 1 week after birth, whereas children of women who reported a CVI were more likely than others to have systemic inflammation during the first few postnatal days (10). Thus, maternal report of UTI and CVI appears to convey information about the very preterm offspring’s likelihood of exposure to biologically important inflammatory stimuli. METHODS
During the years 2002–2004, women who delivered infants before 28 weeks of gestation at any 1 of 14 participating institutions were asked to enroll in the Extremely Low Gestational Age Newborns (ELGAN) Study (18). The enrollment and consent processes were approved by the individual institutional review boards. Of the 1,506 enrolled infants, 1,419 had mothers who provided information about genitourinary infections; 1,064 infants survived to 2 years of age, and 989 returned for a developmental assessment at that time. These 989 children comprise the sample for our assessments of the relationship between gestational genitourinary infection and neurodevelopmental abnormalities (Web Table 1, available at http:// aje.oxfordjournals.org/). After delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form and following procedures defined in a manual. Among the questions asked was, “During this pregnancy, did you have any of these conditions or disorders?” Among the 9 options were “urine, bladder, or kidney infection” and “vaginal or cervical infection.” Each woman was given the opportunity to provide more detail about the type of CVI. The types of infections included bacterial infection (n = 4), bacterial vaginosis (n = 30), mixed infection (n = 4), and yeast infection (n = 62). The remaining 43 women specified some other type of infection (e.g., chlamydia, trichomonas, or herpes) or did not provide the particular infection (n = 43). Estimation of gestational age at birth was based on a hierarchy ordered by the quality of available information. The preferred estimates were based on the dates of embryo retrieval or intrauterine insemination or on fetal ultrasound before the 14th week of gestation (62%). When these were not available, priority was placed sequentially on a fetal ultrasound at 14 weeks or later (29%), followed by date of last menstrual period (7%) and then gestational age recorded in the log of the neonatal intensive care unit (1%). The birth weight z score is the number of standard deviations that an infant’s birth weight is above or below the median weight Am J Epidemiol. 2016;183(1):28–35
29
of infants in a reference sample of children who were not delivered because of maternal or fetal indications (19, 20). Details about the handling of placentas, including microbiologic procedures (21, 22) and the assessment of histologic characteristics (23, 24) have been previously described in detail. Details about ultrasound scans of the brain have also been published previously (25). Families were invited to bring their children for a developmental assessment close to the time the children reached a corrected age of 24 months. The full evaluation included a neurological examination and use of the Bayley Scales of Infant Development–Second Edition (26), the Gross Motor Function Classification System (27), and the Modified Checklist for Autism in Toddlers (M-CHAT) (28). All evaluators who performed neurologic examinations were trained to minimize examiner variability, and their results demonstrated acceptably low variability (29). For each child, they were asked to perform a neurological examination and a separate evaluation using the Gross Motor Function Classification System. A child classified at level II or higher could not walk even when his or her hand was held. The topographic diagnosis of cerebral palsy (quadriparesis, diparesis, or hemiparesis) was based on an algorithm using data from the Extremely Low Gestational Age Newborns Study (25). Head circumference and body weight z scores were based on standards in the data sets from the Centers for Disease Control and Prevention (30, 31). For each child, certified examiners calculated the Mental Development Index (MDI) and the Psychomotor Development Index (PDI) based on the Bayley Scales of Infant Development–Second Edition, with adjustment for age as appropriate. An index of less than 55 placed the child more than 3 standard deviations below the expected mean, and an index between 55 and 69 placed the child between 2 and 3 standard deviations below the expected mean. The parent or caregiver who accompanied the child was asked to complete the M-CHAT. A child screened positive if the answers to any 3 of the 23 total items or 2 of the 6 “critical” items were affirmative. Of the 989 infants who were assessed at an approximate corrected age of 2 years using the Bayley Scales of Infant Development–Second Edition, 740 had a mother who had had neither a UTI nor a CVI, 33 infants had a mother who had both, 114 had a mother who had a UTI but not a CVI, and 102 had a mother who had had a CVI only. Because of the relatively small number of infants whose mothers reported both types of infection, we elected to evaluate any UTI (n = 147) and any CVI (n = 135) separately. We evaluated the generalized null hypotheses that a gestational UTI or CVI is not associated with indicators of brain damage, including ultrasound lesions indicative of cerebral white matter damage (ventriculomegaly and a hypoechoic lesion) when the infant was in the intensive care nursery, a diagnosis of cerebral palsy, a low MDI (
Vol. 183, No. 1 DOI: 10.1093/aje/kwv129 Advance Access publication: December 13, 2015
Original Contribution The Development of Extremely Preterm Infants Born to Women Who Had Genitourinary Infections During Pregnancy
Alan Leviton*, Elizabeth N. Allred, Karl C. K. Kuban, T. Michael O’Shea, Nigel Paneth, Andrew B. Onderdonk, Raina N. Fichorova, and Olaf Dammann, for the ELGAN Study Investigators * Correspondence to Dr. Alan Leviton, Boston Children’s Hospital, Au-414, 300 Longwood Avenue, Boston, MA 02115-5724 (e-mail: [email protected]).
Initially submitted March 3, 2015; accepted for publication May 7, 2015.
Gestational genitourinary infections, which have been associated with neurodevelopmental impairments among infants born near term, have not been studied among very preterm infants. The mothers of 989 infants born before 28 weeks of gestation were interviewed about urine, bladder, or kidney infections (UTIs) and cervical or vaginal infections (CVIs) during pregnancy, as well as other exposures and characteristics, and their charts were reviewed for the Extremely Low Gestational Age Newborns (ELGAN) Study (2002–2004). At 2 years of age, these infants underwent a neurodevelopmental assessment. Generalized estimating equation logistic regression models of developmental adversities were used to adjust for potential confounders. Infants born to women who reported a UTI were less likely than were others to have a very low Mental Development Index (adjusted odds ratio = 0.5; 95% confidence interval: 0.3, 0.8), whereas infants born to women who reported a CVI were more likely than others to have a low Psychomotor Development Index (adjusted odds ratio = 1.7; 95% confidence interval: 1.04, 2.7). In this highrisk sample, maternal gestational CVI, but not UTI, was associated with a higher risk of impaired motor development at 2 years of age. The apparent protective effect of UTI might be spurious, reflect confounding due to untreated asymptomatic bacteriuria among women who were not given a diagnosis of UTI, or reflect preconditioning. child development disorders; infant, extremely premature; urinary tract infection; uterine cervicitis; vaginitis
Abbreviations: BV, bacterial vaginosis; CVI, cervicovaginal infection; M-CHAT, Modified Checklist for Autism in Toddlers; MDI, Mental Development Index; PDI, Psychomotor Development Index; UTI, urinary tract infection.
dysfunctions identified as “unfavorable neurodevelopmental outcome” (7). Women with gestational genitourinary infections have a higher risk of delivering prematurely (8), and extremely preterm newborns are at higher risk of impaired development (9). It therefore seems reasonable to consider the possibility that maternal cervicovaginal infection (CVI) and UTI during pregnancy contribute to impaired development in children born extremely preterm. In addition, in 1 study (10), of the women who gave birth before 28 weeks of pregnancy, those who reported a genitourinary infection during the pregnancy were more likely than were others to have a newborn who had evidence of systemic inflammation during the first postnatal week, which is a risk factor for impaired development (11), cerebral palsy (12), and microcephaly (13).
Maternal urinary tract infection (UTI) during pregnancy, especially if accompanied by fever, has been associated with a higher risk of histologic indicators of brain damage among children born at term (1, 2). Maternal UTI has also been associated with a higher risk of a low intelligence quotient at 7 years of age (3) and sometimes with cerebral palsy (4), although not invariably (5). Although the possibility that children whose mothers had bacterial vaginosis (BV) during the pregnancy were at higher risk of cerebral palsy was first raised more than 15 years ago (6), we are not aware of any study that has evaluated this hypothesis to date. In one study in which investigators evaluated the developmental correlates and consequences of BV, the population largely comprised children born near term, who were classified as having or not having an amalgam of 28
Am J Epidemiol. 2016;183(1):28–35
Maternal Genitourinary Infections: Child Development
Assessments of the risks of impaired development among children whose mothers had genitourinary infections during the pregnancy have been limited to children born at term. In the present study, we describe results from 989 children born before the 28th week of gestation who underwent a developmental assessment at 2 years of age. At an intake interview conducted close to the time of delivery, each child’s mother was asked if she had a UTI or a CVI during the current pregnancy. Our choice to rely on maternal report is supported by documentation that pregnant women provide valid information about exposures and pregnancy characteristics (14–17). In addition, in the present population, children of women who reported a UTI were more likely than were others to have systemic inflammation 1 week after birth, whereas children of women who reported a CVI were more likely than others to have systemic inflammation during the first few postnatal days (10). Thus, maternal report of UTI and CVI appears to convey information about the very preterm offspring’s likelihood of exposure to biologically important inflammatory stimuli. METHODS
During the years 2002–2004, women who delivered infants before 28 weeks of gestation at any 1 of 14 participating institutions were asked to enroll in the Extremely Low Gestational Age Newborns (ELGAN) Study (18). The enrollment and consent processes were approved by the individual institutional review boards. Of the 1,506 enrolled infants, 1,419 had mothers who provided information about genitourinary infections; 1,064 infants survived to 2 years of age, and 989 returned for a developmental assessment at that time. These 989 children comprise the sample for our assessments of the relationship between gestational genitourinary infection and neurodevelopmental abnormalities (Web Table 1, available at http:// aje.oxfordjournals.org/). After delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form and following procedures defined in a manual. Among the questions asked was, “During this pregnancy, did you have any of these conditions or disorders?” Among the 9 options were “urine, bladder, or kidney infection” and “vaginal or cervical infection.” Each woman was given the opportunity to provide more detail about the type of CVI. The types of infections included bacterial infection (n = 4), bacterial vaginosis (n = 30), mixed infection (n = 4), and yeast infection (n = 62). The remaining 43 women specified some other type of infection (e.g., chlamydia, trichomonas, or herpes) or did not provide the particular infection (n = 43). Estimation of gestational age at birth was based on a hierarchy ordered by the quality of available information. The preferred estimates were based on the dates of embryo retrieval or intrauterine insemination or on fetal ultrasound before the 14th week of gestation (62%). When these were not available, priority was placed sequentially on a fetal ultrasound at 14 weeks or later (29%), followed by date of last menstrual period (7%) and then gestational age recorded in the log of the neonatal intensive care unit (1%). The birth weight z score is the number of standard deviations that an infant’s birth weight is above or below the median weight Am J Epidemiol. 2016;183(1):28–35
29
of infants in a reference sample of children who were not delivered because of maternal or fetal indications (19, 20). Details about the handling of placentas, including microbiologic procedures (21, 22) and the assessment of histologic characteristics (23, 24) have been previously described in detail. Details about ultrasound scans of the brain have also been published previously (25). Families were invited to bring their children for a developmental assessment close to the time the children reached a corrected age of 24 months. The full evaluation included a neurological examination and use of the Bayley Scales of Infant Development–Second Edition (26), the Gross Motor Function Classification System (27), and the Modified Checklist for Autism in Toddlers (M-CHAT) (28). All evaluators who performed neurologic examinations were trained to minimize examiner variability, and their results demonstrated acceptably low variability (29). For each child, they were asked to perform a neurological examination and a separate evaluation using the Gross Motor Function Classification System. A child classified at level II or higher could not walk even when his or her hand was held. The topographic diagnosis of cerebral palsy (quadriparesis, diparesis, or hemiparesis) was based on an algorithm using data from the Extremely Low Gestational Age Newborns Study (25). Head circumference and body weight z scores were based on standards in the data sets from the Centers for Disease Control and Prevention (30, 31). For each child, certified examiners calculated the Mental Development Index (MDI) and the Psychomotor Development Index (PDI) based on the Bayley Scales of Infant Development–Second Edition, with adjustment for age as appropriate. An index of less than 55 placed the child more than 3 standard deviations below the expected mean, and an index between 55 and 69 placed the child between 2 and 3 standard deviations below the expected mean. The parent or caregiver who accompanied the child was asked to complete the M-CHAT. A child screened positive if the answers to any 3 of the 23 total items or 2 of the 6 “critical” items were affirmative. Of the 989 infants who were assessed at an approximate corrected age of 2 years using the Bayley Scales of Infant Development–Second Edition, 740 had a mother who had had neither a UTI nor a CVI, 33 infants had a mother who had both, 114 had a mother who had a UTI but not a CVI, and 102 had a mother who had had a CVI only. Because of the relatively small number of infants whose mothers reported both types of infection, we elected to evaluate any UTI (n = 147) and any CVI (n = 135) separately. We evaluated the generalized null hypotheses that a gestational UTI or CVI is not associated with indicators of brain damage, including ultrasound lesions indicative of cerebral white matter damage (ventriculomegaly and a hypoechoic lesion) when the infant was in the intensive care nursery, a diagnosis of cerebral palsy, a low MDI (
