Abstract
BACKGROUND:
Infants born less than 29 weeks, or extremely preterm (EPT), experience increased morbidity and mortality. We hypothesized that exposure to maternal infection might contribute to neurodevelopmental impairment (NDI) or death at 2 years of age.
METHODS:
We conducted a retrospective cohort study of EPT infants from January 2010 to December 2020. Maternal data extracted included maternal infections, classified as extrauterine or intrauterine. Placental pathologic and infant data were extracted. The primary outcome was NDI or death at 2 years of age.
RESULTS:
548 EPT infants were born to 496 pregnant people: 379 (69%) were not exposed to any documented maternal infection prenatally, 124 (23%) to extrauterine infection, and 45 (8%) to intrauterine infection. Neither diagnosis of maternal extrauterine nor intrauterine infection was associated with NDI or death at 2 years of age (p > 0.05). Acute histologic chorioamnionitis was associated with NDI or death at 2 years of age (p = 0.033).
CONCLUSIONS:
Maternal infection was not associated with NDI or death at 2 years of age in EPT infants. However, acute histologic chorioamnionitis was associated with this outcome. Further work should investigate the differential influence of infection and immune response with this pathology as relates to outcomes in EPT infants.
INTRODUCTION
Extremely premature infants (EPT), or infants born less than 29 weeks gestational age, experience increased morbidity and mortality.1 Only 74% of EPT infants survive to discharge of initial hospitalization.2,3 Respiratory distress syndrome (RDS) is a leading cause of morbidity, affecting 86 to 95% of EPT infants.2 Other neonatal sequelae include higher rates of bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH); neurodevelopmental outcomes include cognitive impairment, cerebral palsy and motor impairment.1
The etiology of these morbidities is likely multifactorial. While some can be attributed to prematurity, recent research has suggested that the fetal inflammatory response syndrome (FIRS) is an independent risk factor for neonatal morbidity.4,5 Moreover, there may be an association between maternal chorioamnionitis, FIRS, and cerebral palsy.6 Taken together this research suggests that maternal infection may result in FIRS and alter neonatal outcomes—including neurodevelopmental—in EPT infants. However, there is limited epidemiologic data examining the effect of maternal infection on outcomes in EPT infants, as most data examining the impact of maternal infection at older gestational ages.7–10
We sought to address in our research the impact of exposure to maternal infection on outcomes in EPT infants. Our primary outcome of interest was the impact of maternal infection on neurodevelopment impairment (NDI) and death at 2 years of age. Secondarily, we sought associations between exposure to maternal infection and other neonatal outcomes. We also examined the association of placental lesions with NDI and death at 2 years of age. We hypothesized that intrauterine as opposed to extrauterine infection was likely impact on the primary outcome of NDI or death due to generation of both systematic and local inflammation.
METHODS
This was a retrospective cohort study of all EPT infants born between 23 0/7 and 28 6/7 weeks gestational age at our tertiary-care institution between January 2010 and December 2020. Exclusion criteria included EPT infants receiving planned comfort care in the delivery room, experiencing a neonatal death within 48 hours, and those found to have major congenital and/or chromosomal abnormalities. EPT infants were also excluded if there was no prenatal care established prior to delivery, precluding the ability to assess for antepartum maternal infection, or if there was diagnosis of a maternal infection with known transplacental passage (e.g. cytomegalovirus, syphilis). Maternal data extracted included: maternal age, medical morbidities, obstetric complications, route of delivery, antepartum infections, presentation characteristics upon infection, and infection treatment.
Maternal infection status was categorized as no infection, extrauterine infection, or intrauterine infection. Extrauterine infections included: pyelonephritis, symptomatic COVID, influenza, meningitis, pneumonia, bacterial vaginosis, asymptomatic bacteriuria, cystitis, chlamydia, gonorrhea, trichomonas, and vulvovaginal candidiasis. Intrauterine infection was defined as clinical chorioamnionitis diagnosed in the intrapartum periods based on maternal fever of ≥38 degrees Celsius with associated maternal tachycardia and/or fetal tachycardia without another source of infection.
Infant demographics and outcomes were also extracted. Neurodevelopmental impairment was diagnosed based on the Bayley Scales of Infant and Toddler Development -Third edition (Bayley-III) at 18–24 months. Neonates born <29 weeks gestational age routinely undergo systemic standardized neurologic assessments and Bayley-III assessments at 18–24 months corrected age at our outpatient follow-up clinic.11,12 Neurodevelopment impairment (NDI) was defined as the presence of Bayley-III cognitive, language, or motor score <85 and severe NDI was defined as Bayley-III cognitive, language, or motor score <70.11
Secondary outcomes assessed for this study included: gestational age at delivery, birth weight, BPD, NEC, IVH, PDA, sepsis, congenital pneumonia, pneumothorax, pulmonary hypertension, pulmonary interstitial emphysema, ventilator days, days on continuous positive airway pressure, and maximum FiO2. Moderate to severe BPD was defined as the need for supplemental oxygen at 36 weeks postmenstrual age.13 NEC was defined as Stage ≥ 2 based on the modified Bell’s criteria.14 The study was approved by the Institutional Review Board.
Placental analysis
All available placentas associated with specific maternal-fetal complications—including extreme prematurity—are routinely collected at delivery for examination by a pathologist according to a standardized protocol as described.15–18 Initial gross examination includes removal of the umbilical cord, fetal membranes, and nonadherent blood clots followed by placental weight. The placental disc is then serially sectioned at 1- to 2-cm intervals and examined for intraparenchymal lesions. Representative sections of the umbilical cord, fetal membranes, normal placental parenchyma, and any abnormalities seen on gross exam are submitted for histological examination using the standardized classification and diagnostic terminology for major placental findings and lesions.15–18 Based on the Amsterdam criteria, the histopathologic abnormalities assessed were divided into the following subcategories: (1) acute histologic chorioamnionitis, as defined by maternal inflammatory response (MIR) with or without fetal inflammatory response (FIR). FIR was defined as funisitis, umbilical vasculitis, or chorionic plate vasculitis; (2) villitis of unknown etiology (VUE), further classified into low grade, high grade, and villitis with avascular villi; (3) maternal vascular malperfusion (MVM) including maternal vascular lesions; infarcts, hemorrhage or hematoma, thrombi (involving >5% of parenchyma); villous changes; and placental hypoplasia; (4) fetal vascular malperfusion (FVM); (5) other lesions including inflammatory lesions characterized by chronic deciduitis with plasma cells, massive chronic intervillositis, perivillous fibrin, and histiocytic intervillositis, delayed villous maturation, and villous edema; and (6) abnormalities in size of placentas were reported as either small for gestational age (<10th percentile, SGA) or large for gestational age (>90th percentile, LGA). All placental pathology reports were reviewed by INM.
Statistical analysis
Descriptive statistics of maternal demographics, obstetric outcomes, and infant outcomes were calculated and expressed as means and standard deviations, medians and interquartile ranges, and frequencies and percentages as appropriate for the data. Continuous variables were compared among the groups (no infection versus extrauterine versus intrauterine infection) using the Student’s t-test, the one-way analysis of variance, and the Kruskal-Wallis test. Categorical variables were compared among the groups using the χ2 and Fisher’s exact tests. Statistical significance was indicated by p < 0.05. All statistical analysis was conducted in R v3.6.1.
RESULTS
548 EPT infants met inclusion criteria for analysis with paired antepartum data available from 496 pregnant people (Fig. 1). Exposure to maternal infection was observed in 169 EPT infants, 124 extrauterine and 45 intrauterine. Maternal demographics and select obstetric and infant outcomes based on maternal infection status are shown in Table 1. Of note, no maternal infection required intensive care unit admission or met criteria for severe sepsis. There were a few observed differences among groups, including maternal age, gravidity, and race/ethnicity and gestational age at delivery (all p < 0.05). There were also lower observed rates of hypertensives disorders of pregnancy and cesarean section and higher rates of preterm prelabor rupture of membranes (PPROM) in those with pregnancies with intrauterine infection (all p < 0.05).
Fig. 1.
Study flow diagram. GA gestational age.
Table 1.
Maternal demographics and select obstetric and infant outcomes based maternal infection status.
| Maternal | All patients N = 496 |
Intrauterine infection N = 43 |
Extrauterine infection N = 110 |
No infection N = 343 |
P-value |
|---|---|---|---|---|---|
| Maternal age (years) | 28.8 (6.9) | 30.1 (6.7) | 27.4 (6.0) | 29.1 (6.8) | 0.031* |
| Gravidity | 3 (1–4) | 4 (2–5) | 2 (1–4) | 3 (2–4) | 0.028* |
| Parity | 1 (0–2) | 2 (0–3) | 1 (0–2) | 1 (0–2) | 0.124 |
| Race/ethnicity | 0.045* | ||||
| Non-Hispanic White | 17 (3) | 2 (5) | 6 (5) | 9 (3) | |
| Non-Hispanic Black | 124 (25) | 5 (12) | 31 (28) | 88 (26) | |
| Hispanic | 348 (70) | 36 (84) | 71 (65) | 241 (70) | |
| Asian | 5 (1) | 0 (0) | 0 (0) | 5 (1) | |
| Othera | 2 (<1) | 0 (0) | 2 (2) | 0 (0) | |
| Diabetes mellitusb | 72 (15) | 7 (16) | 21 (19) | 44 (13) | 0.253 |
| Hypertensive disorders of pregnancyc | 172 (35) | 2 (5) | 42 (38) | 128 (37) | <0.001* |
| Body mass index (BMI, kg/m2) | 31.1 (27.0–36.3) | 32.1 (26.0–36.7) | 30.1 (25.1–36.4) | 31.2 (27.4–36.1) | 0.45 |
| BMI class | 0.037* | ||||
| Underweight (<18.5) | 3 (1) | 0 (0) | 1 (1) | 2 (1) | |
| Normal (18.5–24.9) | 72 (15) | 8 (19) | 26 (24) | 38 (11) | |
| Overweight (25–29.9) | 138 (28) | 9 (21) | 27 (25) | 102 (30) | |
| Obese (≥30) | 281 (57) | 26 (60) | 54 (49) | 201 (59) | |
| Missingd | 2 (<1) | 0 (0) | 2 (2) | 0 (0) | |
| Substance abuse | 28 (6) | 0 (0) | 9 (8) | 19 (6) | 0.144 |
| Antenatal steroids | 296 (60) | 31 (72) | 68 (62) | 197 (57) | 0.159 |
| Antenatal magnesium | 325 (66) | 31 (72) | 74 (67) | 220 (64) | 0.532 |
| Preterm labor | 144 (29) | 12 (28) | 29 (26) | 103 (30) | 0.741 |
| Preterm prelabor rupture of membranes (PPROM) | 110 (22) | 29 (67) | 22 (20) | 59 (17) | < 0.001* |
| Placental abruption | 51 (10) | 3 (7) | 14 (13) | 34 (10) | 0.600 |
| Cesarean section | 338 (68) | 20 (47) | 77 (70) | 241 (70) | 0.006* |
| Infant | All patients N = 548 |
Intrauterine infection N = 45 |
Extrauterine infection N = 124 |
No infection N = 379 |
P-value |
| Female | 257 (47) | 28 (62) | 62 (50) | 167 (44) | 0.051 |
| Gestational age at delivery (weeks) | 26.9 (25.1–28) | 26 (25–27) | 26.9 (25–28) | 27 (25.9–28) | 0.024* |
| Birth weight (grams) | 900 (760–1130) | 870 (740–1135) | 878 (760–1050) | 920 (770–1148) | 0.211 |
| Multifetal gestation | 101 (18) | 7 (16) | 27 (22) | 67 (18) | 0.519 |
| Surfactant use | 408 (74) | 37 (82) | 92 (74) | 279 (74) | 0.469 |
| Apgar scores | |||||
| 1 min | 4 (2–6) | 3 (2–6) | 4 (2–6) | 4 (2–6) | 0.687 |
| 5 min | 7 (5–8) | 6 (4–7) | 7 (5–8) | 7 (6–8) | 0.068 |
Categorial data expressed as N (%). Quantitative variables expressed as median (interquartile range), except age which is reported as mean (standard deviation).
denotes p < 0.05.
Other includes individuals who identified as American Indian (1) and Bengali (1).
Diabetes mellitus indicates either gestational or overt diabetes mellitus.
Hypertensive disorders of pregnancy includes gestational hypertension, preeclampsia without severe features, and preeclampsia with severe features.
In two people BMI was not available due to missing height and/or weight.
Table 2 demonstrates infant outcomes based on maternal infection status. There was no difference in the primary outcome of neurodevelopmental outcome or death at 2 years of age based on maternal infection status (p > 0.05). For secondary outcomes, only patent ductus arteriosus was different among groups (p = 0.011), with higher rates observed in the intrauterine infection group. There was an association observed between acute histologic chorioamnionitis on placental pathology and the outcome of neurodevelopmental impairment or death at 2 years of age, (p = 0.033, Table 3).
Table 2.
Infant outcomes by maternal infection status.
| All patients N = 548 |
Intrauterine infection N = 45 |
Extrauterine infection N = 124 |
No infection N = 379 |
P-value | |
|---|---|---|---|---|---|
| Primary outcomes | |||||
| NDI or deatha | 448 (82) | 36 (80) | 102 (82) | 310 (82) | 0.944 |
| NDI | 378 (69) | 32 (71) | 90 (73) | 256 (68) | 0.546 |
| Death | 70 (13) | 4 (9) | 12 (10) | 54 (14) | 0.299 |
| Bayley-III cognitive scaleb | |||||
| Bayley-III cognitive <85 | 226 (47) | 15 (37) | 59 (53) | 152 (47) | 0.199 |
| Bayley-III cognitive 70 – <85 | 193 (40) | 13 (32) | 51 (46) | 129 (40) | 0.275 |
| Bayley-III cognitive <70 | 33 (7) | 2 (5) | 8 (7) | 23 (7) | >0.999 |
| Bayley-III motor scalec | |||||
| Bayley-III motor <85 | 337 (71) | 11 (28) | 33 (30) | 82 (26) | 0.658 |
| Bayley-III motor 70 – <85 | 216 (45) | 8 (20) | 25 (23) | 59 (19) | 0.610 |
| Bayley-III motor <70 | 121 (25) | 3 (8) | 8 (7) | 23 (7) | >0.999 |
| Bayley-III language scaled | |||||
| Bayley-III language <85 | 126 (27) | 30 (73) | 77 (69) | 230 (71) | 0.886 |
| Bayley-III language 70 – <85 | 92 (20) | 22 (54) | 44 (40) | 150 (46) | 0.253 |
| Bayley-III language <70 | 34 (7) | 8 (20) | 33 (30) | 80 (25) | 0.385 |
| Secondary Outcomes | |||||
| Moderate or severe bronchopulmonary dysplasia | 262 (48) | 27 (60) | 61 (49) | 174 (46) | 0.191 |
| Culture-proven necrotizing enterocolitis | 53 (10) | 4 (9) | 10 (8) | 39 (10) | 0.794 |
| Culture-proven sepsis proven | 100 (18) | 11 (24) | 18 (15) | 71 (19) | 0.305 |
| Interventricular hemorrhage (Grade 3 or 4) | 76 (14) | 7 (16) | 15 (12) | 54 (14) | 0.787 |
| Congenital pneumonia | 25 (5) | 1 (2) | 5 (4) | 19 (5) | 0.841 |
| Pneumothorax | 45 (8) | 4 (9) | 11 (9) | 30 (8) | 0.845 |
| Pulmonary hypertension | 44 (8) | 4 (9) | 11 (9) | 29 (8) | 0.841 |
| Pulmonary hemorrhage | 48 (9) | 1 (2) | 12 (10) | 35 (9) | 0.277 |
| Pulmonary interstitial emphysema | 167 (30) | 11 (24) | 46 (37) | 110 (29) | 0.144 |
| Patent ductus arteriosus | 150 (27) | 21 (47) | 32 (26) | 97 (26) | 0.011* |
| Ventilatory days | 6 (1–21) | 5 (1–26) | 8 (1–24) | 6 (2–18) | 0.584 |
| CPAP days | 29 (12–42) | 35 (20–49) | 30 (13–42) | 27 (12–41) | 0.121 |
| Max FiO2 | 100 (55–100) | 100 (60–100) | 100 (60–100) | 100 (55–100) | 0.312 |
Categorial data expressed as N (%). Quantitative variables expressed as median (interquartile range).
denotes p < 0.05.
NDI short for neurodevelopmental impairment, defined as <85 on Bayley-III cognitive, language, or motor scale. Death defined as occurring prior to 2 years of age.
70 missing (all infants who expired).
81 missing (all infants who expired and 11 additional).
73 missing (all infants who expired and 3 additional).
Table 3.
Placental pathologic lesions and neurodevelopmental impairment or death.
| All patients N = 548 |
NDI or deatha N = 448 |
No NDI or death N = 100 |
P-value | |
|---|---|---|---|---|
| Acute histologic chorioamnionitisb | 250 (46) | 214 (48) | 36 (36) | 0.033* |
| Villitis of unknown etiology (VUE) | ||||
| Low grade | 26 (5) | 20 (4) | 6 (6) | 0.601 |
| High grade | 31 (6) | 25 (6) | 6 (6) | 0.870 |
| With avascular villitis | 3 (1) | 2 (<1) | 1 (1) | 0.454 |
| Maternal vascular malperfusion (MVM) | ||||
| Maternal vascular lesions | 10 (2) | 10 (2) | 0 (0) | 0.221 |
| Infarcts | 66 (12) | 53 (12) | 13 (13) | 0.745 |
| Hemorrhage/hematoma | 42 (8) | 34 (8) | 8 (8) | 0.889 |
| Thrombi | 7 (1) | 5 (1) | 2 (2) | 0.617 |
| Villous changes | 48 (9) | 39 (9) | 9 (9) | 0.925 |
| Placental hypoplasia | 58 (11) | 48 (11) | 10 (10) | 0.834 |
| Fetal vascular malperfusion (FVM) | 22 (4) | 19 (4) | 3 (3) | 0.780 |
| Other lesions | ||||
| Other inflammatory lesions | 109 (20) | 92 (21) | 17 (17) | 0.407 |
| Villous edema | 7 (1) | 6 (1) | 1 (1) | >0.999 |
| Delayed villous maturation | 0 (0) | 0 (0) | 0 (0) | - |
| Multiple placental lesions | ||||
| Acute + chronic lesions | 33 (6) | 28 (6) | 5 (5) | 0.635 |
Categorical data expressed as N (%).
denotes p < 0.05.
NDI short for neurodevelopmental impairment, defined as <85 on Bayley-III cognitive, language, or motor scale. Death defined as occurring prior to 2 years of age.
Acute histologic chorioamnionitis as defined by maternal inflammatory response (MIR) with or without fetal inflammatory response (FIR). FIR was defined as funisitis, umbilical vasculitis, or chorionic plate vasculitis.
DISCUSSION
Neither maternal extrauterine nor intrauterine infection was found to be associated with NDI or death at 2 years of age in EPT infants. Exposure to maternal intrauterine infection was associated with PDA, but not other infant outcomes. Among the major placental pathologic lesions, only acute histologic chorioamnionitis was associated with NDI or death at 2 years of age.
Our data is consistent with what is previously known regarding differences observed in maternal demographics and obstetrics outcomes. We observed higher rates of PPROM in those people with intrauterine infection, consistent with the former being a risk factor for the latter.19 Outside of infection, hypertensive disorders of pregnancy would be another major cause of preterm birth and was more prevalent in pregnant people without intrauterine infection in our population.20 Intrauterine infection is the only mechanism that has been causally linked to spontaneous preterm birth with activation of the innate immune system and inflammatory cascades that stimulate the production of prostaglandins and matrix-degrading enzymes.19,21,22 This may explain the lower cesarean rate observed in the intrauterine infection group, as the processes of preterm labor may have already been prematurely activated.
Our study is additive to the existing literature as there is limited data on the association between maternal infection and outcomes in EPT infants. Bierstone et al. found that intrauterine infection was not associated with Bayley-III scores at 18–24 months in preterm infants born at 24–32 weeks of gestation.10 Taken together with our study, reassuring counseling can be provided that maternal infection alone does not appear to impact neurodevelopmental outcomes or death at 2 years of age in EPT infants.
We did find that intrauterine infection was associated with PDA. The finding of association between intrauterine infection with PDA is supported by previous study in preterm infants.23–26 Such phenomena is likely possible as the fetus may be more vulnerable to effects from ascending infection that are not possible with other infections that must pass through the maternal-fetal interface.27 Our findings collectively support that the EPT infant is likely protected from infection-mediated inflammation by interactions at the maternal-fetal interface, as the only significant associations are seen with ascending intrauterine infection.28,29 We found no association among other outcomes and maternal infection. In comparison to prior literature, bacterial vaginosis and pyelonephritis have not been shown to significantly impact short term outcomes in preterm infants.7,8 Contrary to our findings, Huang et al. found that antenatal infections increased the risk of developing intraventricular hemorrhage in the preterm infants <37 weeks, though evidence was based on low quality, pooled data and the need for well-designed studies was identified.9 Thus, given the association with PDA, pregnant people with intrauterine infection delivering an EPT infant should be counseled about this association. However, the lack of any additional impact should be reassuring to mother who experiences an infection and subsequently the birth of an EPT infant.
Acute histologic chorioamnionitis was associated with NDI and death in EPT infants in our study. This finding is consistent with prior literature.30–35 Our group and others have also demonstrated that children born extremely preterm with neurobehavioral impairments, including autism spectrum disorder, have >2-fold greater incidence of multiple placental pathologic lesions (i.e., acute histologic chorioamnionitis and chronic vascular placental lesions).36,37 Some recent studies also noted that acute histologic chorioamnionitis may be associated with some forms of neurodevelopmental impairments, including cerebral palsy, autism spectrum disorder, and epilepsy even at 10 years of age among extremely preterm infants.38 These findings suggest that placental pathology findings may be valuable in shedding light on prenatal pathologic processes underlying NDI or death in EPT infants.
Strengths of this study include correlation of maternal, obstetric, placental and infant outcomes among a large cohort at single institution. Limitations are largely based on the retrospective nature of the study and include lack of data due to lost-to follow-up for our primary outcome and potential bias due to either over or under-reporting NDI or death. Another limitation is that maternal infection status was based on access to prenatal care. As we excluded infants of pregnant people without documented prenatal care, it is possible the study has a selection bias for underestimating the number of people with an infection, particularly if their care was based on emergent or urgent care visits at outside facilities that were unavailable to us for analysis. None of our cohort had infections that required intensive care unit admission or met criteria for severe sepsis, so the impact of severe maternal illness is not fully demonstrated. Due to the limited number of infants with maternal infection exposure, we were also unable to look at the impact of timing of maternal infection on the primary outcome. As all patients were prescribed treatment at the times of diagnosis, we are also unable to comment on the impact of treatment of maternal infection (versus non-treatment). While we acknowledge there were differences in maternal demographics, a multivariate analysis was not performed as there were no new novel differences found in outcomes.
In conclusion, maternal infection was not associated with neurodevelopmental impairment (NDI) or death at 2 years of age in extremely preterm (EPT) infants. This is reassuring support that mechanisms at the maternal-fetal interface largely protect the EPT infant. However, placental pathologic findings of acute histologic chorioamnionitis did appear to correlate with NDI and death at 2 years of age. Further work should investigate the differential influence of infection and immune response with acute histologic chorioamnionitis on pathology as relates to outcomes in EPT infants.
IMPACT:
Maternal infection was not associated with neurodevelopmental impairment (NDI) or death at 2 years of age in extremely preterm (EPT) infants. This is reassuring support that mechanisms at the maternal-fetal interface largely protect the EPT infant.
However, pathologic findings of acute histologic chorioamnionitis were associated with NDI and death at 2 years of age.
Further work should investigate the differential influence of infection and immune response with acute histologic chorioamnionitis on pathology as relates to outcomes in EPT infants.
ACKNOWLEDGEMENTS
The authors thank Pollieanna Sepulveda for her assistance in data extraction, and Dr. Catherine Spong for her overall guidance on the project. This research was made possible through internal funding. C.L.H. is supported by grants K23HD103876 and L30HD109864.
Footnotes
COMPETING INTERESTS
The authors declare no competing interests.
DATA AVAILABILITY
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
REFERENCES
- 1.Patel RM Short- and Long-Term Outcomes for Extremely Preterm Infants. Am. J. Perinatol 33, 318–328 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stoll BJ et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 126, 443–456 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Patel RM et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N. Engl. J. Med 372, 331–340 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tang Q, Zhang L, Li H & Shao Y The fetal inflammation response syndrome and adverse neonatal outcomes: a meta-analysis. J. Matern Fetal Neonatal Med 34, 3902–3914 (2021). [DOI] [PubMed] [Google Scholar]
- 5.Francis F et al. Fetal inflammatory response syndrome (FIRS) and outcome of preterm neonates - a prospective analytical study. J. Matern Fetal Neonatal Med 32, 488–492 (2019). [DOI] [PubMed] [Google Scholar]
- 6.Yoon BH et al. Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am. J. Obstet. Gynecol 182, 675–681 (2000). [DOI] [PubMed] [Google Scholar]
- 7.Hill JB, Sheffield JS, McIntire DD & Wendel GD Jr. Acute Pyelonephritis in Pregnancy. Obstet. Gynecol 105, 18–23 (2005). [DOI] [PubMed] [Google Scholar]
- 8.Dingens AS, Fairfortune TS, Reed S & Mitchell C Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study. BMC Pregnancy Childbirth 16, 278 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Huang J et al. Antenatal infection and intraventricular hemorrhage in preterm infants: A meta-analysis. Medicine. 98, e16665 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bierstone D et al. Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates. JAMA Pediatr. 172, 534–541 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vohr BR et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J. Pediatr 161, 222–8.e3 (2012). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mir IN et al. Impact of multiple placental pathologies on neonatal death, bronchopulmonary dysplasia, and neurodevelopmental impairment in preterm infants. Pediatr. Res 87, 885–891 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Stoll BJ et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993–2012. Jama 314, 1039–1051 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bell MJ et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg 187, 1–7 (1978). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Redline RW, Heller D, Keating S & Kingdom J Placental diagnostic criteria and clinical correlation-a workshop report. Placenta 26, S114–S117 (2005). [DOI] [PubMed] [Google Scholar]
- 16.Greer LG et al. An immunologic basis for placental insufficiency in fetal growth restriction. Am. J. Perinatol 29, 533–538 (2012). [DOI] [PubMed] [Google Scholar]
- 17.Mir IN et al. Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia. Am. J. Obstet. Gynecol 213, 849.e1–7 (2015). [DOI] [PubMed] [Google Scholar]
- 18.Khong TY et al. Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch. Pathol. Lab Med 140, 698–713 (2016). [DOI] [PubMed] [Google Scholar]
- 19.Goldenberg RL, Hauth JC & Andrews WW Intrauterine infection and preterm delivery. N. Engl. J. Med 342, 1500–1507 (2000). [DOI] [PubMed] [Google Scholar]
- 20.Goldenberg RL, Culhane JF, Iams JD & Romero R Epidemiology and causes of preterm birth. Lancet 371, 75–84 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Romero R et al. The preterm parturition syndrome. Bjog 113, 17–42 (2006). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Romero R et al. The role of infection in preterm labour and delivery. Paediatr. Perinat. Epidemiol 15, 41–56 (2001). [DOI] [PubMed] [Google Scholar]
- 23.Watterberg KL, Demers LM, Scott SM & Murphy S Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97, 210–215 (1996). [PubMed] [Google Scholar]
- 24.Been JV et al. Chorioamnionitis alters the response to surfactant in preterm infants. J. Pediatr 156, 10–15.e1 (2010). [DOI] [PubMed] [Google Scholar]
- 25.Green CA et al. Association of chorioamnionitis and patent ductus arteriosus in a national U.S. cohort. J. Perinatol 41, 119–125 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Park HW, Choi YS, Kim KS & Kim SN Chorioamnionitis and Patent Ductus Arteriosus: A Systematic Review and Meta-Analysis. PLoS One 10, e0138114 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kim CJ et al. Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. Am. J. Obstet. Gynecol 213, S29–S52 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Megli CJ & Coyne CB Infections at the maternal-fetal interface: an overview of pathogenesis and defence. Nat. Rev. Microbiol 20, 67–82 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ander SE, Diamond MS, Coyne CB Immune responses at the maternal-fetal interface. Sci Immunol. 4 10.1126/sciimmunol.aat6114 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Clark EA et al. Association of fetal inflammation and coagulation pathway gene polymorphisms with neurodevelopmental delay at age 2 years. Am. J. Obstet. Gynecol 203, 83.e1–83.e10 (2010). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.García-Muñoz Rodrigo F, Galán Henríquez GM & Ospina CG Morbidity and mortality among very-low-birth-weight infants born to mothers with clinical chorioamnionitis. Pediatr. Neonatol 55, 381–386 (2014). [DOI] [PubMed] [Google Scholar]
- 32.Rees S, Harding R & Walker D The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int. J. Dev. Neurosci 29, 551–563 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Schlapbach LJ et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 128, e348–e357 (2011). [DOI] [PubMed] [Google Scholar]
- 34.Shi Z, et al. Chorioamnionitis in the Development of Cerebral Palsy: A Metaanalysis and Systematic Review. Pediatrics. 139 10.1542/peds.2016-3781 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ylijoki MK, Ekholm E, Ekblad M & Lehtonen L Prenatal Risk Factors for Adverse Developmental Outcome in Preterm Infants-Systematic Review. Front Psychol. 10, 595 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Mir IN et al. Autism spectrum disorders in extremely preterm infants and placental pathology findings: a matched case-control study. Pediatr. Res 89, 1825–1831 (2021). [DOI] [PubMed] [Google Scholar]
- 37.Raghavan R et al. Preterm birth subtypes, placental pathology findings, and risk of neurodevelopmental disabilities during childhood. Placenta 83, 17–25 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Venkatesh KK et al. Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation. Am. J. Obstet. Gynecol 223, 745.e1–745.e10 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.