Background
Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental disorders in the offspring. However, findings on this topic have been inconsistent.
Objective
To examine the association between chorioamnionitis and neurodevelopmental disorders in offspring.
Study Design
This was a retrospective population-based cohort study in Sweden. A total of 2,228,280 singleton live births and stillbirths between 1998 and 2019 were included in our study population. Data on maternal characteristics and neurodevelopmental disorders in offspring were obtained by individual record-linkages of nationwide Swedish registries. Chorioamnionitis was identified using the National Medical Birth Register. Inpatient and outpatient diagnoses were obtained for cerebral palsy, autism, attention deficit hyperactivity disorder, epilepsy, and intellectual disability. Multivariable Cox proportional hazards regression was used to estimate the association between chorioamnionitis and each neurodevelopmental disorder with adjusted hazard ratios and 95% confidence intervals. A causal mediation analysis of the relationship between chorioamnionitis and neurodevelopmental disorders with preterm delivery (<37 weeks) was performed.
Results
A total of 5770 (0.26%) offspring were exposed to chorioamnionitis during pregnancy. During the study’s follow-up time there were 4752 (0.21%) cases of cerebral palsy, 17,897 (0.80 %) cases of epilepsy, 50,570 (2.27 %) cases of autism, 114,087 (5.12%) cases of attention deficit hyperactivity disorder, and 14,574 (0.65%) cases of intellectual disability. After adjusting for potential confounders, exposure to chorioamnionitis increased the hazard ratios of cerebral palsy (adjusted hazard ratio, 7.43; 95% confidence interval, 5.90–9.37), autism (adjusted hazard ratio, 1.43; 95% confidence interval, 1.21–1.68), attention deficit hyperactivity disorder (adjusted hazard ratio, 1.17; 95% confidence interval, 1.03–1.33), and intellectual disability (adjusted hazard ratio, 1.99; 95% confidence interval, 1.53–2.58), whereas chorioamnionitis was not significantly associated with higher rates of epilepsy in offspring. Mediation analysis revealed that these associations were mainly explained through preterm delivery; however, increased risk was also observed among term infants.
Conclusion
Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder, and intellectual disability. These associations were mainly mediated through preterm delivery. Efforts for timely identification and appropriate interventions to treat infections during pregnancy will have sustained benefits in reducing the burden of neurologic complications in children at the population level.
Introduction
Neurodevelopmental disorders represent a significant public health issue worldwide and are responsible for a considerable proportion of the global burden of disease. , Over the last decades, there has been a rise in the prevalence of neurodevelopmental disorders and an increase in the number of individuals acquiring such diagnosis. Many risk factors are likely to operate during fetal life and infancy, the earliest and most sensitive stages of brain development. ,
Why was this study conducted?
Evidence indicates that in utero exposure to chorioamnionitis might increase the risk of neurodevelopmental outcomes in the offspring. However, findings on this topic have been inconsistent. This study aimed to examine the association between chorioamnionitis and long-term neurodevelopmental disorders in the offspring.
Key findings
Chorioamnionitis increases the risk of neurodevelopmental disorders, particularly cerebral palsy, autism, attention deficit hyperactivity disorder (ADHD), and intellectual disability.
These associations were mainly mediated through preterm birth; however, increased risk was also observed among term infants.
What does this add to what is known?
Chorioamnionitis was associated with increased hazard ratios of 7.43 for cerebral palsy, 1.43 for autism, 1.17 for ADHD, and 1.99 for intellectual disability in the offspring (compared with offspring not exposed to chorioamnionitis), even after adjusting for several potential confounders. Preterm delivery accounted for a large proportion of the neurodevelopmental disorder risk associated with chorioamnionitis.
Evidence indicates that maternal infections, in particular chorioamnionitis, might negatively affect the sensitive fetal brain and lead to brain injury, adverse neurodevelopmental outcomes, and an increased lifetime risk of specific psychiatric diseases. Clinical chorioamnionitis is globally the most common infection-related complication in labor and delivery wards , and is estimated to have a prevalence of 1% to 6% in all pregnancies in the United States, whereas intraamniotic infection might be present in 10% of patients with preterm labor. , Clinical chorioamnionitis has been characterized as a syndrome rather than a single entity, linked with proven intraamniotic infection, sterile intraamniotic inflammation, or signs of a maternal systemic inflammatory process without intraamniotic inflammation. , The diagnostic criteria involve the presence of fever with 2 or more of the following: maternal or fetal tachycardia, maternal leukocytosis, tenderness of the uterus, and purulent or malodorous amniotic fluid. ,
Chorioamnionitis has been shown to be associated with long-term neonatal outcomes, such as cerebral palsy. , However, epidemiologic evidence about the association between chorioamnionitis and risks of other long-term neurologic disorders in offspring is limited. Therefore, in this Swedish nationwide population-based cohort study of >2 million singleton births, we aimed to investigate the association between chorioamnionitis and risk of long-term neurodevelopmental disorders in offspring, in particular cerebral palsy, autism, attention deficit hyperactivity disorder (ADHD), epilepsy, and intellectual disability. We also examined the extent to which preterm delivery mediates the effect of chorioamnionitis on neurodevelopmental disorders in offspring. We hypothesized that the exposure to chorioamnionitis is associated with increased risks of long-term neurodevelopmental disorders in offspring.
Materials and Methods
Using the Swedish Medical Birth Register, our cohort comprised all singleton births at ≥22 completed gestational weeks in Sweden from January 1, 1998, through December 31, 2019. Using the unique personal national registration numbers of mothers and their offspring the Medical Birth Register was cross-linked with the nation-wide National Patient, National Prescribed Drug, Total Population and Education Registers. Since 1997, diseases have been coded according to the Swedish version of the International Classification of Diseases, Tenth Revision (ICD-10). The Anatomical Therapeutic Chemical Classification System and the Drug Identification Numbers were used to retrieve the prescription medications for ADHD.
Exposure
Women with chorioamnionitis were identified from the Medical Birth Register with diagnosis records for the ICD-10 code O41.1 (including diagnoses of infection of amniotic sac and membranes, chorioamnionitis, and amnionitis) and their infants’ records including the ICD-10 code P02.7 (fetus or newborn affected by complications of placenta, cord, and membranes: chorioamnionitis). This case definition refers to clinical chorioamnionitis in the assessment of the clinician treating the mother and/or infant. Results of pathologic placental investigations were not available in our data sources.
Disorders
Adverse neurodevelopmental disorders included all clinically ascertained diagnoses of cerebral palsy, epilepsy, autism, ADHD, and intellectual disability. Children with epilepsy who had also cerebral palsy were not included in the epilepsy group. Diagnoses were identified from birth until December 31, 2020, in the National Patient Register and the prescription registry using ICD-10 codes ( Supplemental Table 1 shows specific codes). In Sweden, all infants and preschool children regularly undergo routine medical and developmental examinations. At 4 years of age, a mandatory assessment of motor, language, cognitive, and social development is conducted. Children who are suspected of having a developmental disorder are referred to a specialist team for further assessment, with any diagnostic information reported to the National Patient Register.
Covariates
We obtained maternal information about the country of birth, age at child’s birth, early-pregnancy body mass index (BMI), height, parity, years of education, smoking during pregnancy, cohabitation with a partner, history of psychiatric disorders, prepregnancy hypertension, and diabetes mellitus. Infant’s information included the calendar year of birth, sex, gestational age at birth, birthweight for gestational age, and major congenital malformation. The percentiles of birthweight for gestational age were based on the Swedish fetal growth reference obtained from the Medical Birth Register.
Maternal BMI (kg/m 2 ) was classified according to the World Health Organization as underweight (BMI <18.5), normal weight (18.5–24.9), overweight (25.0–29.9), obesity class I (30.0–34.9), and obesity class II and III (≥35.0). Mothers who reported daily smoking at the first antenatal visit and/or at 30 to 32 gestational weeks were classified as smokers. The mode of delivery was obtained from obstetrical records and categorized as vaginal noninstrumental, vaginal instrumental, elective cesarean delivery, and emergency cesarean delivery.
Statistical analysis
Baseline demographic characteristics of children born to mothers with and without chorioamnionitis were compared as presented in Table 1 . Summaries of categorical variables were presented in absolute numbers and proportions (%), whereas statistical significance was assessed by the Pearson chi-square test. Cumulative hazard curves were used to compare risks of each neurodevelopmental outcome over time according to chorioamnionitis status. The differences between the curves were assessed using the log-rank test. We calculated hazard ratios (HRs) and the corresponding 2-sided Wald-type 95% confidence intervals (CIs) using Cox proportional hazards regression models, which allowed detailed adjustment for censoring depending on the length of follow-up of each child. Each child was followed up from birth until the diagnosis of the outcome, death, emigration, or end of follow-up on December 31, 2020, whichever occurred first.
| Maternal characteristics | Total (n=2,228,280) | No chorioamnionitis (N=2,222,510) | Chorioamnionitis (N=5,770) | P value |
|---|---|---|---|---|
| No. (column %) | No. (row %) | No. (row %) | ||
| Maternal age (y) | <.001 | |||
| ≤19 | 32,245 (1.45) | 32,139 (99.67) | 106 (0.33) | |
| 20–24 | 278,510 (12.50) | 277,805 (99.75) | 705 (0.25) | |
| 25–29 | 689,567 (30.95) | 687,805 (99.74) | 1762 (0.26) | |
| 30–34 | 768,023 (34.47) | 766,201 (99.76) | 1822 (0.24) | |
| ≥35 | 459,935 (20.64) | 458,560 (99.70) | 1375 (0.30) | |
| Country of birth | <.001 | |||
| Nordic | 1,747,142 (78.41) | 1,742,965 (99.76) | 4177 (0.24) | |
| Non-Nordic | 478,948 (21.49) | 477,364 (99.67) | 1584 (0.33) | |
| Data missing | 2190 (0.10) | 2181 (99.59) | 9 (0.41) | |
| Education (y) | ||||
| ≤9 | 189,100 (8.49) | 188,507 (99.69) | 593 (0.31) | <.001 |
| 10–11 | 258,711 (11.61) | 257,923 (99.70) | 788 (0.30) | |
| 12 | 570,843 (25.62) | 569,403 (99.75) | 1440 (0.25) | |
| 13–14 | 320,862 (14.40) | 319,996 (99.73) | 866 (0.27) | |
| ≥15 | 867,879 (38.95) | 865,870 (99.77) | 2009 (0.23) | |
| Data missing | 20,885 (0.94) | 20,811 (99.65) | 74 (0.35) | |
| Mother cohabits with partner | ||||
| Yes | 1,986,484 (89.15) | 1,981,738 (99.76) | 4746 (0.24) | <.001 |
| No | 128,252 (5.76) | 127,729 (99.59) | 523 (0.41) | |
| Data missing | 113,544 (5.10) | 113,043 (99.56) | 501 (0.44) | |
| Parity | ||||
| 1 | 977,410 (43.86) | 973,492 (99.60) | 3918 (0.40) | <.001 |
| 2 | 823,667 (36.96) | 822,527 (99.86) | 1140 (0.14) | |
| 3 | 298,019 (13.37) | 297,579 (99.85) | 440 (0.15) | |
| ≥4 | 129,184 (5.80) | 128,912 (99.79) | 272 (0.21) | |
| Maternal height (cm) | ||||
| ≤159 | 307,412 (13.80) | 306,308 (99.64) | 1104 (0.36) | <.001 |
| 160–164 | 565,833 (25.39) | 564,220 (99.71) | 1613 (0.29) | |
| 165–169 | 635,203 (28.51) | 633,651 (99.76) | 1552 (0.24) | |
| ≥170 | 686,815 (30.82) | 685,488 (99.81) | 1327 (0.19) | |
| Data missing | 33,017 (1.48) | 32,843 (99.47) | 174 (0.53) | |
| Smoking | ||||
| No | 1,970,016 (88.41) | 1,965,174 (99.75) | 4842 (0.25) | <.001 |
| Yes | 169,202 (7.59) | 168,704 (99.71) | 498 (0.29) | |
| Data missing | 89,062 (4.00) | 88,632 (99.52) | 430 (0.48) | |
| Year of delivery | ||||
| 1998–1999 | 164,677 (7.39) | 164,345 (99.80) | 332 (0.20) | <.001 |
| 2000–2004 | 453,815 (20.37) | 452,897 (99.80) | 918 (0.20) | |
| 2005–2008 | 402,523 (18.06) | 401,727 (99.80) | 796 (0.20) | |
| 2009–2012 | 430,092 (19.30) | 429,119 (99.77) | 973 (0.23) | |
| 2013–2015 | 329,119 (14.77) | 328,094 (99.69) | 1025 (0.31) | |
| 2016–2019 | 448,054 (20.11) | 446,328 (99.61) | 1726 (0.39) | |
| Maternal body mass index | ||||
| <18.5 | 50,502 (2.27) | 50,409 (99.82) | 93 (0.18) | <.001 |
| 18.5–24.9 | 1,224,691 (54.96) | 1,222,204 (99.80) | 2487 (0.20) | |
| 25.0–29.9 | 514,705 (23.10) | 513,222 (99.71) | 1483 (0.29) | |
| 30.0–34.9 | 177,365 (7.96) | 176,693 (99.62) | 672 (0.38) | |
| ≥35.0 | 74,939 (3.36) | 74,557 (99.49) | 382 (0.51) | |
| Missing | 186,078 (8.35) | 185,425 (99.65) | 653 (0.35) | |
| Pregestational diabetes mellitus | ||||
| No | 2,188,462 (98.21) | 2,182,864 (99.74) | 5598 (0.26) | <.001 |
| Yes | 39,818 (1.79) | 39,646 (99.57) | 172 (0.43) | |
| Pregestational hypertension | ||||
| No | 2,213,181 (99.32) | 2,207,455 (99.74) | 5726 (0.26) | .431 |
| Yes | 15,099 (0.68) | 15,055 (99.71) | 44 (0.29) | |
| Any psychiatric diagnoses | ||||
| No | 1,987,049 (89.17) | 1,982,158 (99.75) | 4891 (0.25) | <.001 |
| Yes | 241,231 (10.83) | 240,352 (99.64) | 879 (0.36) | |
| Mode of delivery | ||||
| Vaginal noninstrumental | 1,704,444 (76.49) | 1,702,571 (99.89) | 1873 (0.11) | <.001 |
| Vaginal instrumental | 153,563 (6.89) | 153,123 (99.71) | 440 (0.29) | |
| Elective cesarean delivery | 182,067 (8.17) | 181,859 (99.89) | 208 (0.11) | |
| Emergency cesarean delivery | 173,621 (7.79) | 170,426 (98.16) | 3195 (1.84) | |
| Data missing | 14,585 (0.65) | 14,531 (99.63) | 54 (0.37) | |
| Gestational age at delivery (wk) | ||||
| ≥37 | 2,116,876 (95.00) | 2,113,213 (99.83) | 3663 (0.17) | <.001 |
| 32–36 | 93,085 (4.18) | 92,326 (99.18) | 759 (0.82) | |
| 28–31 | 10,770 (0.48) | 10,278 (95.43) | 492 (4.57) | |
| 22–27 | 6408 (0.29) | 5563 (86.81) | 845 (13.19) | |
| Data missing | 1141 (0.05) | 1130 (99.04) | 11 (0.96) | |
| Newborn’s sex | <.001 | |||
| Male | 1,146,581 (51.46) | 1,143,493 (99.73) | 3088 (0.27) | |
| Female | 1,081,685 (48.54) | 1,079,003 (99.75) | 2682 (0.25) | |
| Data missing | 14 (0.00) | 14 (100) | 0 (0.00) | |
| Birthweight for gestational age (percentiles) | ||||
| <3 | 37,241 (1.67) | 37,081 (99.57) | 160 (0.43) | <.001 |
| 3 to <10 | 108,073 (4.85) | 107,685 (99.64) | 388 (0.36) | |
| 10 to 90 | 1,807,702 (81.13) | 1,803,196 (99.75) | 4506 (0.25) | |
| >90 to 97 | 186,791 (8.38) | 186,364 (99.77) | 427 (0.23) | |
| >97 | 81,055 (3.64) | 80,825 (99.72) | 230 (0.28) | |
| Data missing | 7418 (0.33) | 7359 (99.20) | 59 (0.80) | |
| Premature rupture of membranes | ||||
| No | 2,197,724 (98.63) | 2,193,329 (99.80) | 4395 (0.20) | <.001 |
| Yes | 30,556 (1.37) | 29,181 (95.50) | 1375 (4.50) | |
| Preeclampsia | ||||
| No | 2,166,645 (97.23) | 2,161,076 (99.74) | 5569 (0.26) | .001 |
| Yes | 61,635 (2.77) | 61,434 (99.67) | 201 (0.33) | |
Adjusted HRs were obtained from multivariable Cox models in 3 steps, gradually adjusting for additional potential confounders. In model 1, we adjusted for maternal age at child’s birth, parity, maternal educational level, country of mother’s birth, smoking during pregnancy, maternal height, early-pregnancy BMI, any psychiatric disorders, child’s sex, calendar year of birth, and cohabitation with a partner. In model 2, we also adjusted for major congenital malformations, and in model 3, additional adjustment was made for the mode of delivery. The robust sandwich estimate of the covariance matrix was used to calculate 95% CIs in all Cox models to account for the sequential births to the same mother.
Causal mediation analysis
We considered preterm birth (<37 weeks) as a potential mediator for the effect of chorioamnionitis on cerebral palsy, autism, ADHD, and intellectual disability ( Supplemental Figure , Supplemental Table 2 , Supplemental Table 3 ). Therefore, we undertook causal mediation analyses based on a counterfactual framework to disentangle the association between chorioamnionitis and the outcomes (ie, total effect) into the natural direct effect (the association between chorioamnionitis and the outcomes [cerebral palsy, autism, ADHD, and intellectual disability] in the absence of preterm birth) and the natural indirect effect (the association operating through the mediators). We also estimated the controlled direct effect, which provided an estimate of the effect of chorioamnionitis on the outcomes that is not mediated through preterm birth (ie, among term births). We also assessed the proportion of the total effect (on the HR scale) between chorioamnionitis and the outcome(s) that was mediated through preterm delivery. Furthermore, we created a composite mediator of preterm delivery and neonatal infection, and preterm delivery and respiratory distress syndrome (RDS), diagnosed at 0 to 27 days of age, to examine the joint mediation effect of neonatal morbidity and preterm delivery on the association between chorioamnionitis and the disorders.
Sensitivity analyses
We performed several sensitivity analyses. First, because mediation methods were developed under a strict no-unmeasured-confounding assumption, we examined the robustness of causal effects to unmeasured confounders by estimating an E-value (defined as the maximal strength of association that an unmeasured confounder would need to have with the exposure and the outcome to fully explain away an observed exposure–outcome association). Second, given that death before the diagnosis of outcome would preclude a child from being diagnosed with such conditions in the future, we also quantified the adjusted association between chorioamnionitis and a composite outcome including any of the following: stillbirth, infant mortality (ie, death within the first year after birth), or any neurodevelopmental disorder (ie, stillbirth, infant death, or epilepsy). Logistic regression analyses were used to assess the association between chorioamnionitis and each composite outcome, adjusting for the same confounders noted in model 2.
Third, to focus only on potentially clinically relevant cases of neurodevelopmental disorders, we restricted the age at diagnosis: 3+ years of age for ADHD and intellectual disability, 1+ years of age for diagnoses of autism, and 26+ days of age for epilepsy. Fourth, to address missing values of covariates in our cohort and the possible bias that it could introduce, we performed multiple imputation with chained equations under the assumption of missing at random. All analyses were performed using Stata statistical software, version 16 (StataCorp, College Station, TX) and SAS, version 9.4 (SAS Institute, Cary, NC).
Results
Between January 1, 1998 and December 31, 2019, the Medical Birth Register recorded information of about 2,228,290 singleton live births and stillbirths with valid national registration numbers for mothers and children. After excluding 10 births with missing information on child’s sex and maternal age, the final study cohort included 2,228,280 singleton births.
Demographic and clinical characteristics
Overall, there were 5570 (0.26%) offspring of mothers with chorioamnionitis. During the study follow-up, cerebral palsy was diagnosed in 4752 (0.21%), epilepsy in 17,897 (0.80 %), autism in 50,570 (2.27 %), ADHD in 114,087 (5.12%), and intellectual disability in 14,574 (0.65%) children. The median age at diagnosis of cerebral palsy was 2.04 years (interquartile range [IQR], 1.10–3.95), 5.60 years (IQR, 2.20–9.82) for epilepsy, 10.49 years (IQR, 6.29–14.14) for autism, 11.04 years (IQR, 8.54–14.31) for ADHD, and 8.86 years (IQR, 6.24–12.56) for intellectual disability. Compared with women without chorioamnionitis, those with chorioamnionitis were more likely to be older (≥35 years), non-Nordic, to live without a partner, to smoke, to be obese (BMI>30.0), to be nulliparous, and to have a lower education. Women with chorioamnionitis were more likely to have a history of psychiatric disorders ( Table 1 ). Furthermore, women with chorioamnionitis had elevated rates of emergency ceasarean delivery, preterm birth, premature rupture of membranes, and small-for-gestational age (SGA<10th percentile) infants.
Univariable and multivariable analysis
Unadjusted cumulative hazard curves showed a significantly higher cumulative hazard of cerebral palsy, autism, ADHD, and intellectual disability among offspring born to mothers with chorioamnionitis than among those born to mothers without chorioamnionitis ( Figure ). After adjusting for potential confounders, compared with offspring of mothers without chorioamnionitis, the adjusted HRs were higher for cerebral palsy, autism, ADHD, and intellectual disability in offspring of mothers with chorioamnionitis ( Table 2 , Model 1), whereas chorioamnionitis was not significantly associated with epilepsy in offspring. Although slightly attenuated, the same pattern of associations remained after adjusting for major malformations and mode of delivery ( Table 2 , Model 2 and 3).
