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The fetal systemic inflammatory response associated with intra-amniotic inflammation may play a key role in the pathogenesis of complications of preterm birth. Funisitis is the histologic equivalent of the fetal inflammatory response, whereas chorioamnionitis represents a maternal inflammatory response. We conducted a frequentist and Bayesian model average (BMA) meta-analysis of studies investigating the effects of funisitis on short-term outcomes of prematurity. Thirty-three studies (12,237 infants with gestational age ≤ 34 weeks) were included. Frequentist meta-analysis showed that funisitis was associated with an increased risk of any bronchopulmonary dysplasia (BPD), moderate/severe BPD, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), any sepsis, early-onset sepsis (EOS), and mortality. However, Bayesian meta-analysis showed that the evidence in favor of the alternative hypothesis (i.e., funisitis is associated with an increased risk of developing the outcome) was strong for any IVH, moderate for severe IVH and EOS, and weak for the other outcomes. When the control group was restricted to infants having chorioamnionitis without funisitis, the only outcome associated with funisitis was any IVH. In conclusion, our data suggest that the presence of funisitis does not add an additional risk to preterm birth when compared to chorioamnionitis in the absence of fetal inflammatory response.

Introduction: Preterm birth represents the leading cause of neonatal mortality. Pathophysiological pathways, or endotypes, leading to prematurity can be clustered into infection/inflammation and dysfunctional placentation. We aimed to perform a systematic review and meta-analysis exploring the association between these endotypes and risk of mortality during first hospital admission Methods: PROSPERO ID: CRD42020184843. PubMed and Embase were searched for observational studies examining infants with gestational age (GA) ≤34 weeks. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for GA (SGA)/intrauterine growth restriction (IUGR). A random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals. Heterogeneity was studied using random-effects meta-regression analysis., Results: Of 4,322 potentially relevant studies, 150 (612,580 infants) were included. Meta-analysis showed positive mortality odds for chorioamnionitis (OR: 1.43, 95% confidence interval: 1.25-1.62) and SGA/IUGR (OR: 1.68, 95% confidence interval: 1.38-2.04) but negative mortality odds for HDP (OR 0.74, 95% confidence interval: 0.64-0.86). Chorioamnionitis was associated with a lower GA, while HDP and SGA/IUGR were associated with a higher GA. Meta-regression showed a significant correlation between these differences in GA and mortality odds., Conclusion: Our data suggest that the infectious/inflammatory endotype of prematurity has a greater overall impact on mortality risk as it is the most frequent endotype in the lower GAs. However, when the endotype of placental dysfunction is severe enough to induce growth restriction, it is strongly associated with higher mortality rates even though newborns are more mature., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Antenatal pathological conditions are key in the pathogenesis of bronchopulmonary dysplasia (BPD). Pathophysiological pathways or endotypes leading to prematurity and perinatal lung injury can be clustered into two groups: infection and dysfunctional placentation, which include hypertensive disorders of pregnancy (HDP) and intrauterine growth restriction (IUGR). We conducted a systematic review of observational studies exploring the association between the dysfunctional placentation endotype and BPD., Methods: MEDLINE, Embase and Web of Science databases were searched up to February 2020 for studies reporting data on the diagnosis of HDP, IUGR or small for gestational age (SGA) and BPD risk. BPD was classified as BPD28 (supplemental oxygen on day 28), BPD36 (oxygen at 36 weeks postmenstrual age), severe BPD (≥ 30% oxygen or mechanical ventilation), BPD36/death and BPD-associated pulmonary hypertension., Results: Of 6319 studies screened, 211 (347 963 infants) were included. Meta-analysis showed an association between SGA/IUGR and BPD36 (OR 1.56, 95% CI 1.37 to 1.79), severe BPD (OR 1.82, 95% CI 1.36 to 2.29) and BPD/death (OR 1.91, 95% CI 1.55 to 2.37). Exposure to HDP was not associated with BPD but was associated with decreased odds of BPD/death (OR 0.77, 95% CI 0.64 to 0.94). Both HDP (OR 1.41, 95% CI 1.10 to 1.80) and SGA/IUGR (OR 2.37, 95% CI 1.86 to 3.02) were associated with BPD-associated pulmonary hypertension., Conclusion: When placental vascular dysfunction is accompanied by fetal growth restriction or being born SGA, it is associated with an increased risk of developing BPD and pulmonary hypertension. The placental dysfunction endotype of prematurity is strongly associated with the vascular phenotype of BPD., Prospero Registration Number: Review protocol was registered in PROSPERO database (ID=CRD42018086877)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal condition among very and extremely preterm infants. Stem cell therapy has shown some promising protective effects in animal models of intestinal injury, including NEC, but no systematic review has yet evaluated the preclinical evidence of stem cell therapy for NEC prevention or treatment. Methods: PubMed and EMBASE databases were searched for studies using an animal model of NEC with stem cells or their products. The SYRCLE tool was used for the assessment of risk of bias. A random-effects model was used to pool odds ratios (ORs) and 95% confidence interval (CI). Results: We screened 953 studies, of which nine (eight rat and one mouse models) met the inclusion criteria. All animal models induced NEC by a combination of hypothermia, hypoxia, and formula feeding. Risk of bias was evaluated as unclear on most items for all studies included. Meta-analysis found that both mesenchymal and neural stem cells and stem cell-derived exosomes reduced the incidence of all NEC (OR 0.22, 95% CI 0.16-0.32, k = 16), grade 2 NEC (OR 0.41, 95% CI 0.24-0.70, k = 16), and grade 3-4 NEC (OR 0.28, 95% CI 0.19-0.42, k = 16). k represents the number of independent effect sizes included in each meta-analysis. The effect of the exosomes was similar to that of the stem cells. Stem cells and exosomes also improved 4-day survival (OR 2.89 95% CI 2.07-4.04, k = 9) and 7-day survival (OR 3.96 95% CI 2.39-6.55, k = 5) after experimental NEC. Meta-analysis also found that stem cells reduced other indicators of intestinal injury. Conclusion: The data from this meta-analysis suggest that both stem cells and stem cell-derived exosomes prevented NEC in rodent experimental models. However, unclear risk of bias and incomplete reporting underline that poor reporting standards are common and hamper the reliable interpretation of preclinical evidence for stem cell therapy for NEC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Villamor-Martinez, Hundscheid, Kramer, Hooijmans and Villamor.)

Chorioamnionitis (CA) is considered a key risk factor for very preterm birth and for developing early onset sepsis (EOS) in preterm infants, but recent data suggest that CA might be protective against late onset sepsis (LOS). We performed a systematic review and meta-analysis of studies exploring the association between CA and sepsis. A comprehensive literature search was performed in PubMed/MEDLINE and EMBASE, from their inception to December 1, 2018. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Sources of heterogeneity were analyzed by subgroup and meta-regression analyses. The following categories of sepsis were analyzed: EOS, LOS, unspecified onset sepsis (UOS), culture-proven, and clinical sepsis. CA was subdivided into clinical and histological chorioamnionitis. Funisitis was also analyzed. We found 3,768 potentially relevant studies, of which 107 met the inclusion criteria (387,321 infants; 44,414 cases of CA). Meta-analysis showed an association between any CA and any EOS (OR 4.29, CI 3.63-5.06), any LOS (OR 1.29, CI 1.11-1.54), and any UOS (OR 1.59, CI 1.11-1.54). Subgroup analysis showed that CA was associated with culture-proven EOS (OR 4.69, CI 3.91-5.56), clinical EOS (OR 3.58, CI 1.90-6.76), and culture-proven LOS (OR 1.31, CI 1.12-1.53), but not with clinical LOS (OR 1.52, CI 0.78-2.96). The presence of funisitis did not increase the risk of either EOS or LOS when compared with CA without funisitis. CA-exposed infants had lower gestational age (-1.11 weeks, CI -1.37 to -0.84) than the infants not exposed to CA. Meta-regression analysis showed that the lower gestational age of the CA group correlated with the association between CA and LOS but not with the association between CA and EOS. In conclusion, our data suggest that the positive association between chorioamnionitis and LOS may be modulated by the effect of chorioamnionitis on gestational age., (Copyright © 2020 Villamor-Martinez, Lubach, Rahim, Degraeuwe, Zimmermann, Kramer and Villamor.)

Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Epidemiological evidence and animal studies support that intrauterine exposure to tobacco smoke disturbs lung development and has a negative effect in the pulmonary health of the offspring. Individual studies suggest an association between fetal exposure to maternal smoking and risk of developing bronchopulmonary dysplasia (BPD). However, this association has not yet been systematically investigated. We aimed to conduct a systematic review of studies reporting on tobacco smoking during pregnancy as potential risk factor for BPD. PubMed/MEDLINE and EMBASE databases were searched. BPD was defined as requirement of supplemental oxygen on postnatal day 28 (BPD28; all BPD), at the postmenstrual age (PMA) of 36 weeks (BPD36; moderate/severe BPD), or as requirement of more than 30% oxygen and/or positive pressure at 36 weeks PMA (severe BPD). Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effects model. Of 2,894 potentially relevant studies, 33 met the inclusion criteria. The included studies evaluated 171,772 infants and included 30,445 cases of exposure to maternal smoking and 25,340 cases of BPD of any severity. Meta-analysis showed a significant association between tobacco smoking during pregnancy and BPD36 (17 studies, RR 1.126, 95% CI 1.008-1.259, p = 0.036), but could not demonstrate a significant association between tobacco smoking during pregnancy and BPD28 (16 studies, RR 1.021, 95% CI 0.924-1.129, p = 0.681), or severe BPD (3 studies, RR 1.143, 95% CI 0.528-2.478, p = 0.734). In conclusion, our data suggest that tobacco smoking during pregnancy increases the risk of moderate/severe BPD. Our results highlight the detrimental effects of tobacco smoking and reinforce the hypothesis of the involvement of prenatal insults in the etiopathogenesis of BPD., (Copyright © 2020 González-Luis, van Westering-Kroon, Villamor-Martinez, Huizing, Kilani, Kramer and Villamor.)

Prepregnancy overweight and obesity are associated with higher risk of perinatal complications. However, the effect of weight change prior to pregnancy on perinatal outcome is largely unknown. Therefore, it is aimed to examine the impact on perinatal outcomes of interpregnancy BMI change in women of different BMI categories. The MEDLINE, EMBASE, LILACS, and CINAHL databases were searched (1990-August 2019). Observational studies on interpregnancy BMI change were selected. Outcomes evaluated were gestational diabetes mellitus (GDM), preeclampsia, gestational hypertension (GH), cesarean section, preterm birth, and newborns being large (LGA) or small (SGA) for gestational age. Meta-analyses and meta-regression analyses were executed. Thirty studies were included (n > 1 million). Interpregnancy BMI gain was associated with a higher risk of GDM (for BMI gain ≥3 kg/m 2 : OR 2.21; [95%CI 1.53-3.19]), preeclampsia (1.77 [1.53-2.04]), GH (1.78 [1.61-1.97]), cesarean section (1.32 [1.24-1.39]), and LGA (1.54 [1.28-1.86]). The effects of BMI gain were most pronounced in women with BMI <25 kg/m 2 before the first pregnancy regarding GDM, GH, and cesarean section. Except for LGA, interpregnancy BMI loss did not result in a decreased risk of perinatal complications. In this study, women of normal weight who gain weight before pregnancy were identified as a high-risk population for perinatal complications. This emphasizes that weight management is important for women of all BMI categories and a pregnancy wish., (© 2019 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Importance: Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, remains one of the major and most common complications of very preterm birth. Insight into factors associated with the pathogenesis of BPD is key to improving its prevention and treatment., Objective: To perform a systematic review, meta-analysis, and metaregression of clinical studies exploring the association between chorioamnionitis (CA) and BPD in preterm infants., Data Sources: PubMed and Embase were searched without language restriction (last search, October 1, 2018). Key search terms included bronchopulmonary dysplasia, chorioamnionitis, and risk factors., Study Selection: Included studies were peer-reviewed studies examining preterm (<37 weeks' gestation) or very low-birth-weight (<1500 g) infants and reporting primary data that could be used to measure the association between exposure to CA and the development of BPD., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. Data were independently extracted by 2 researchers. A random-effects model was used to calculate odds ratios (ORs) and 95% CIs. Heterogeneity in effect size across studies was studied using multivariate, random-effects metaregression analysis., Main Outcomes and Measures: The primary outcome was BPD, defined as supplemental oxygen requirement on postnatal day 28 (BPD28) or at the postmenstrual age of 36 weeks (BPD36). Covariates considered as potential confounders included differences between CA-exposed and CA-unexposed infants in gestational age, rates of respiratory distress syndrome (RDS), exposure to antenatal corticosteroids, and rates of early- and late-onset sepsis., Results: A total of 3170 potentially relevant studies were found, of which 158 met the inclusion criteria (244 096 preterm infants, 20 971 CA cases, and 24 335 BPD cases). Meta-analysis showed that CA exposure was significantly associated with BPD28 (65 studies; OR, 2.32; 95% CI, 1.88-2.86; P < .001; heterogeneity: I2 = 84%; P < .001) and BPD36 (108 studies; OR, 1.29; 95% CI, 1.17-1.42; P < .001; heterogeneity: I2 = 63%; P < .001). The association between CA and BPD remained significant for both clinical and histologic CA. In addition, significant differences were found between CA-exposed and CA-unexposed infants in gestational age, birth weight, odds of being small for gestational age, exposure to antenatal corticosteroids, and early- and late-onset sepsis. Chorioamnionitis was not significantly associated with RDS (48 studies; OR, 1.10; 95% CI, 0.92-1.34; P = .24; heterogeneity: I2 = 90%; P < .001), but multivariate metaregression analysis with backward elimination revealed that a model combining the difference in gestational age and the odds of RDS was associated with 64% of the variance in the association between CA and BPD36 across studies., Conclusions and Relevance: The results of this study confirm that among preterm infants, exposure to CA is associated with a higher risk of developing BPD, but this association may be modulated by gestational age and risk of RDS.

Cerebellar hemorrhage (CBH) represents the most commonly acquired lesion of the posterior fossa in the neonatal period. We aimed to perform a systematic review and meta-analysis of studies exploring the perinatal risk factors and neurological outcome of CBH in preterm infants. A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE. Studies were included if they examined preterm infants and reported primary data on maternal, obstetric, or perinatal characteristics, and/or outcomes of infants with and without CBH. A random-effects model was used to calculate mean differences (MD), odds ratios (OR), and 95% confidence intervals (CI). We found 231 potentially relevant studies, of which 15 met the inclusion criteria (4,236 infants, 347 CBH cases). Meta-analysis could not demonstrate a significant association between CBH and multiple gestation, chorioamnionitis, pre-eclampsia, placental abruption, use of antenatal corticosteroids, mode of delivery, or infant sex. Infants with CBH had a significantly lower gestational age (6 studies, MD -1.55 weeks, 95% CI -1.93 to -1.16) and birth weight (6 studies, MD -173 g, 95% CI -225 to -120), and significantly higher rates of intubation at birth, hypotension, patent ductus arteriosus, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. CBH was significantly associated with delayed mental (6 studies, OR 2.95, 95% CI 1.21 to 7.20) and psychomotor (6 studies, OR 3.62, 95% CI 1.34 to 9.76) development, and higher rates of cerebral palsy (4 studies, OR 3.09, 95% CI 1.55 to 6.19). In conclusion, the present meta-analysis shows that the youngest and sickest preterm infants are at higher risk of developing CBH. Our results highlight the multifactorial nature of CBH and reinforce the idea that cerebellar injury in very preterm newborns has important neurodevelopmental consequences among survivors.

[This corrects the article DOI: 10.3389/fphys.2018.01253.].

It is generally accepted that intrauterine growth restriction (IUGR) increases morbidity and mortality among very preterm neonates. However, evidence is hampered by the widespread practice of using the terms small for gestational age (SGA) and IUGR as synonyms. We conducted a systematic review of studies reporting on the association between IUGR/SGA and patent ductus arteriosus (PDA). PubMed/MEDLINE and EMBASE databases were searched. Of 993 studies reviewed, 47 (50,790 infants) were included. Studies were combined using a random effects model and sources of heterogeneity were determined by subgroup and meta-regression analyses. Meta-analysis of all included studies showed a significantly reduced risk of PDA in the SGA/IUGR group with an odds ratio (OR) of 0.82, and a 95% confidence interval (CI) of 0.70 to 0.96 ( p = 0.015). Of the 47 studies, only 7 used a definition for growth restriction that went beyond birth weight (BW) for gestational age (GA). When pooled, meta-analysis could not demonstrate a significant effect size (OR 1.31, 95% CI 0.75 to 2.27, p = 0.343). Moreover, the significantly reduced risk of PDA was found in the 25 studies defining SGA as BW <10th percentile (OR 0.81, 95% CI 0.66 to 0.98, p = 0.032), but not in the 6 studies defining SGA as BW <3rd (OR 1.09, 95% CI 0.70 to 1.71, p = 0.694), or in the 27 studies using a more refined definition of PDA (i.e., hemodynamically significant PDA or PDA requiring treatment, OR 0.87, 95% CI 0.72 to 1.04, p = 0.133). In addition, we found that GA was significantly higher in the SGA/IUGR group (18 studies, mean difference 0.63 weeks, 95% CI 0.24 to 1.03, p = 0.002). Meta-regression analysis confirmed the correlation between this difference in GA and PDA risk. In summary, we observed marked heterogeneity across studies in the definition of growth restriction and PDA, and we found differences between the control and growth-restricted groups in relevant baseline characteristics, such as GA. Therefore, our meta-analysis could not provide conclusive evidence on the association between growth restriction and PDA.

The role of chorioamnionitis (CA) in the development of retinopathy of prematurity (ROP) is difficult to establish, because CA-exposed and CA-unexposed infants frequently present different baseline characteristics. We performed an updated systematic review and meta-analysis of studies reporting on the association between CA and ROP. We searched PubMed and EMBASE for relevant articles. Studies were included if they examined preterm or very low birth weight (VLBW, <1500g) infants and reported primary data that could be used to measure the association between exposure to CA and the presence of ROP. Of 748 potentially relevant studies, 50 studies met the inclusion criteria (38,986 infants, 9,258 CA cases). Meta-analysis showed a significant positive association between CA and any stage ROP (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.11 to 1.74). CA was also associated with severe (stage ≥3) ROP (OR 1.63, 95% CI 1.41 to 1.89). Exposure to funisitis was associated with a higher risk of ROP than exposure to CA in the absence of funisitis. Additional meta-analyses showed that infants exposed to CA had lower gestational age (GA) and lower birth weight (BW). Meta-regression showed that lower GA and BW in the CA-exposed group was significantly associated with a higher risk of ROP. Meta-analyses of studies with data adjusted for confounders could not find a significant association between CA and ROP. In conclusion, our study confirms that CA is a risk factor for developing ROP. However, part of the effects of CA on the pathogenesis of ROP may be mediated by the role of CA as an etiological factor for very preterm birth., Competing Interests: The authors have declared that no competing interests exist.

Although chorioamnionitis (CA) is a well-known risk factor for white matter disease of prematurity, the association with intraventricular hemorrhage (IVH) is controversial and has not been yet systematically reviewed. We performed a systematic review and meta-analysis of studies exploring the association between CA and IVH. A comprehensive literature search was conducted using PubMed/MEDLINE and EMBASE, from their inception to 1 July 2017. Studies were included if they examined preterm infants and reported primary data that could be used to measure the association between exposure to CA and the presence of IVH. A random-effects model was used to calculate odds ratios (OR) and 95% confidence intervals (CI). We found 1,284 potentially relevant studies, of which 85 met the inclusion criteria (46,244 infants, 13,432 CA cases). Meta-analysis showed that CA exposure was significantly associated with all grades IVH (OR 1.88, 95% CI 1.61-2.19), with grades 1-2 IVH (OR 1.69, 95% CI 1.22-2.34), and with grades 3-4 IVH (OR 1.62, 95% CI 1.42-1.85). Both clinical and histological CA were associated with an increased risk for developing IVH in very preterm infants. In contrast, the presence of funisitis did not increase IVH risk when compared to CA in the absence of funisitis (OR 1.22, 95% CI 0.89-1.67). Further meta-analyses confirmed earlier findings that CA-exposed infants have significantly lower gestational age (GA; mean difference [MD] -1.20 weeks) and lower birth weight (BW; MD -55 g) than the infants not exposed to CA. However, meta-regression and subgroup analysis could not demonstrate an association between the lower GA and BW and the risk of IVH in the CA-exposed infants. In conclusion, our data show that CA is a risk factor for IVH, but also a risk factor for greater prematurity and more clinical instability. In contrast to other complications of prematurity, such as patent ductus arteriosus, retinopathy of prematurity, or bronchopulmonary dysplasia, the effect of CA on IVH appears to be independent of CA as causative factor for very preterm birth.