World Journal of Pediatrics
The association between hypertensive disorders in pregnancy and bronchopulmonary dysplasia: a systematic review Guang-Liang Bi, Fei-Li Chen,Wei-Min Huang Guangzhou, China
Systematic review
Background: Whether hypertensive disorders in pregnancy (HDP) are the risk factors of bronchopulmonary dysplasia (BPD) is controversial. A systematic review was made to determine the association between HDP and BPD in preterm infants. Methods: We searched PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, with no language limitation, and reviewed the reference lists of the selected articles to identify additional relevant publications and contacted the authors of relevant studies for further information. The data were extracted independently by 2 reviewers who used a predetermined data extraction form. Studies were combined with an odds ratio (OR) using a random-effects model. Meta-regression and subgroup analysis were used to explore potential confounders. Funnel plots, Egger's test and Begg's test were used to investigate the publication bias. The Trim and Fill method was used to control the publication bias. Results: A total of 787 studies were identified and only 15 studies (20 779 patients) were included. The pooled unadjusted OR showed that HDP was significantly associated with BPD (P=0.04; OR=1.29, 95% CI=1.011.65). Heterogeneity was substantial (I2=74%) and might be partially explained by different variables in maternal complications between the control groups across the studies. The pooled adjusted OR suggested the same conclusion that HDP was a risk factor for BPD (P=0.01; OR=1.59, 95% CI=1.11-2.26). Funnel plot and Egger's test showed that there were publication bias of unadjusted estimate of association between HDP and BPD.
Author Affiliations: Department of Neonatology (Bi GL, Huang WM) and Department of Hematology (Chen FL), Nanfang Hospital, Southern Medical University, Guangzhou 510515, China Corresponding Author: Wei-Min Huang, MD, Department of Neonatology, Nanfang Hospital, 1838 Guangzhou Avenue North, Guangzhou 510515, China (Tel: 86-20-61641923; Fax: 86-20-61641923; Email: [email protected]) doi: 10.1007/s12519-013-0439-8 ©Children's Hospital, Zhejiang University School of Medicine, China and Springer-Verlag Berlin Heidelberg 2013. All rights reserved.
300
Conclusions: Unadjusted analyses showed that the rate of BPD was slightly higher in the infants exposed to HDP, and adjusted analyses confirmed this finding. But this result should be interpreted cautiously because substantial heterogeneity and publication bias were identified in this review. World J Pediatr 2013;9(4):300-306 Key words: bronchopulmonary dysplasia; hypertensive disorders in pregnancy; preeclampsia; pregnancy induced hypertension
Introduction
B
ronchopulmonary dysplasia (BPD) was first described as a complication of prematurity by Northway et al in 1967. [1] It was considered that premature birth, respiratory failure, oxygen supplementation, and mechanical ventilation were the main causes of classic BPD.[2] Due to advances in perinatal care and new neonatal respiratory therapies, classic BPD has been replaced by a milder clinical form,[3] a new BPD which is more related to immaturity, perinatal infection and inflammation, persistent ductus arteriosus, and disrupts alveolar and capillary development. [4] The new BPD is due to the injury of the lung in the canalicular and saccular phases of lung development that alters subsequent alveolar and vascular development, resulting in simplified alveolar structures, dysmorphic capillary configuration, variable interstitial cellularity and fibroproliferation.[5] Hypertensive disorders in pregnancy (HDP) including pregnancy-induced hypertension (PIH), preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) could be seen in 7% of pregnancies and rank second as a cause of maternal mortality. The current literature showed that PE might be mediated by an altered angiogenic state such as high levels of several anti-angiogenic factors,[6] and this angiogenic state was due to decreased umbilical cord vascular endothelial growth factor (VEGF) in infants born to PE mothers. [7] It was reported that
World J Pediatr, Vol 9 No 4 . November 15, 2013 . www.wjpch.com
Association between hypertensive disorders in pregnancy and bronchopulmonary dysplasia
Methods
Search strategy We searched PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, up in February 2013 with no limitations of language or publication status. Search terms of MeSH were "maternal hypertension", "hypertensive disorders in pregnancy", "gestational hypertension", "preeclampsia", "pregnancy-induced hypertension", "bronchopulmonary dysplasia" and "chronic lung disease". We reviewed the lists of selected articles to identify additional relevant publications and contacted the authors of relevant studies. Inclusion criteria The inclusion criteria of the studies should be met: (i) a control group is necessary in the studies; (ii) participants should be preterm or low BW infants; (iii) primary data could be used to detect the association between exposure to HDP and the development of BPD. PIH is defined as blood pressure higher than 140/90 mmHg occurred after 20 weeks of postmenstrual age,[15] without evidence of PE or HELLP syndrome. PE is defined as the development of hypertension plus one of the following: proteinuria, thrombocytopenia, or pulmonary edema.[16] HELLP syndrome was defined as hemolysis, elevated serum concentration of aspartate aminotransferase (≥70 IU/L) and thrombocytopenia.[17] We classified BPD as either a need for oxygen at the first 28 days together with a compatible chest radiograph [18] or a need for additional oxygen at 36 weeks of postmenstrual age according to the criteria of Bancalari et al.[19] Two reviewers screened the results of the searches and applied inclusion criteria using a structured form independently to identify relevant studies.
Quality assessment The quality of the studies was independently assessed by 2 reviewers using Newcastle-Ottawa Scale (NOS)[20] for case-control or cohort studies as appropriate. The assessment considered such domains: selection bias, comparability bias, exposure bias (case-control studies) and outcome bias (cohort studies). Data extraction Data were extracted independently by 2 reviewers who used a predetermined data extraction forms. For each study, the following characteristics were extracted: study design; population characteristics including sample size, ethnicity, birth weight (BW), gestational age (GA), data years, definitions of BPD, type of HDP, and usage of antenatal corticosteroids. Differences were resolved by discussion and consensus of the two reviewers. Statistical analysis The extracted data were analyzed using RevMan 5 and STATA 11. The association was evaluated between HDP and BPD by combining the studies with an odds ratio (OR) using a random-effects model. Heterogeneity was quantified using the I2 statistical method and the value greater than 50% was considered substantial. We conducted meta-regressions to test the effect on confounders such as GA, BW and antenatal steroid's prevalence separately. We also investigated heterogeneity by subgroup analysis according to the type of HDP, which was also considered the severity of HDP. Since this could not adequately explain the heterogeneity, post hoc analyses were conducted to assess whether the different inclusion criteria of participants, whether the definition of BPD or whether the different expoure factors of the control group could explain the heterogeneity. Forest plots were used to illustrate results from meta analyses, and unadjusted OR analyses were based on raw data for HDP and BPD. But adjusted OR analyses were based on data from multiple logistic regression analyses within the studies that adjusted for potential confounders. Funnel plots, Egger's or Begg's tests were used to investigate publication bias. The Trim and Fill method was used to control the publication bias.
Results
Identifying studies The literature review identified 787 potentially relevant studies from PubMed, Embase, Cochrane Library, ScienceDirect, and Web of Science. Forty-three studies were identified as relevant to the review through titles or abstracts, and 15 studies[10-14,21-30] met the inclusion criteria finally (Fig. 1). Characteristics of the studies The 15 studies were published in the English language
World J Pediatr, Vol 9 No 4 . November 15, 2013 . www.wjpch.com
301
Systematic review
angiogenesis was necessary for alveolarization during normal lung development and that injury to the pulmonary circulation during a critical period of lung growth may contribute to lung hypoplasia. [8] It was suggested that VEGF receptor signaling is required for the maintenance of the alveolar that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema. [9] Whether HDP is the risk factor of BPD is controversial. Studies [10-13] found that HDP was associated with an increased incidence of BPD, but one [14] reported that those born to mothers with mild hypertension had a significantly lower incidence of BPD as compared with those with severe maternal hypertension or without maternal hypertension at all. This systematic review aimed to find the association between BPD and HDP so that we could control the risk factors and prevent BPD in the early stage.
World Journal of Pediatrics between 1996 and 2013. Six studies were prospective cohort studies, 6 retrospective cohort studies and 3 case-control studies. There was great variability in the study size, from very small (n=66) to large (n=12 139). These studies were performed in a variety of countries. Not only definitions of BPD and HDP, but also the inclusion criteria varied in the studies (Table 1). Data extracted from the studies were used to measure the association between BPD and HDP, but only 6 studies provided adjusted measures of the association between BPD and HDP (Table 2).
Systematic review
Association between HDP and BPD Pooled unadjusted OR showed that the rate of BPD was Table 1. Characteristics of the studies included in the meta-analysis First author, year Data year Inclusion Sample Study design criteria (site) size Akram, 2006 (USA)[21]
1993-2000 GA
The association between hypertensive disorders in pregnancy and bronchopulmonary dysplasia: a systematic review Guang-Liang Bi, Fei-Li Chen,Wei-Min Huang Guangzhou, China
Systematic review
Background: Whether hypertensive disorders in pregnancy (HDP) are the risk factors of bronchopulmonary dysplasia (BPD) is controversial. A systematic review was made to determine the association between HDP and BPD in preterm infants. Methods: We searched PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, with no language limitation, and reviewed the reference lists of the selected articles to identify additional relevant publications and contacted the authors of relevant studies for further information. The data were extracted independently by 2 reviewers who used a predetermined data extraction form. Studies were combined with an odds ratio (OR) using a random-effects model. Meta-regression and subgroup analysis were used to explore potential confounders. Funnel plots, Egger's test and Begg's test were used to investigate the publication bias. The Trim and Fill method was used to control the publication bias. Results: A total of 787 studies were identified and only 15 studies (20 779 patients) were included. The pooled unadjusted OR showed that HDP was significantly associated with BPD (P=0.04; OR=1.29, 95% CI=1.011.65). Heterogeneity was substantial (I2=74%) and might be partially explained by different variables in maternal complications between the control groups across the studies. The pooled adjusted OR suggested the same conclusion that HDP was a risk factor for BPD (P=0.01; OR=1.59, 95% CI=1.11-2.26). Funnel plot and Egger's test showed that there were publication bias of unadjusted estimate of association between HDP and BPD.
Author Affiliations: Department of Neonatology (Bi GL, Huang WM) and Department of Hematology (Chen FL), Nanfang Hospital, Southern Medical University, Guangzhou 510515, China Corresponding Author: Wei-Min Huang, MD, Department of Neonatology, Nanfang Hospital, 1838 Guangzhou Avenue North, Guangzhou 510515, China (Tel: 86-20-61641923; Fax: 86-20-61641923; Email: [email protected]) doi: 10.1007/s12519-013-0439-8 ©Children's Hospital, Zhejiang University School of Medicine, China and Springer-Verlag Berlin Heidelberg 2013. All rights reserved.
300
Conclusions: Unadjusted analyses showed that the rate of BPD was slightly higher in the infants exposed to HDP, and adjusted analyses confirmed this finding. But this result should be interpreted cautiously because substantial heterogeneity and publication bias were identified in this review. World J Pediatr 2013;9(4):300-306 Key words: bronchopulmonary dysplasia; hypertensive disorders in pregnancy; preeclampsia; pregnancy induced hypertension
Introduction
B
ronchopulmonary dysplasia (BPD) was first described as a complication of prematurity by Northway et al in 1967. [1] It was considered that premature birth, respiratory failure, oxygen supplementation, and mechanical ventilation were the main causes of classic BPD.[2] Due to advances in perinatal care and new neonatal respiratory therapies, classic BPD has been replaced by a milder clinical form,[3] a new BPD which is more related to immaturity, perinatal infection and inflammation, persistent ductus arteriosus, and disrupts alveolar and capillary development. [4] The new BPD is due to the injury of the lung in the canalicular and saccular phases of lung development that alters subsequent alveolar and vascular development, resulting in simplified alveolar structures, dysmorphic capillary configuration, variable interstitial cellularity and fibroproliferation.[5] Hypertensive disorders in pregnancy (HDP) including pregnancy-induced hypertension (PIH), preeclampsia (PE), hemolysis, elevated liver enzymes, and low platelet count (HELLP) could be seen in 7% of pregnancies and rank second as a cause of maternal mortality. The current literature showed that PE might be mediated by an altered angiogenic state such as high levels of several anti-angiogenic factors,[6] and this angiogenic state was due to decreased umbilical cord vascular endothelial growth factor (VEGF) in infants born to PE mothers. [7] It was reported that
World J Pediatr, Vol 9 No 4 . November 15, 2013 . www.wjpch.com
Association between hypertensive disorders in pregnancy and bronchopulmonary dysplasia
Methods
Search strategy We searched PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, up in February 2013 with no limitations of language or publication status. Search terms of MeSH were "maternal hypertension", "hypertensive disorders in pregnancy", "gestational hypertension", "preeclampsia", "pregnancy-induced hypertension", "bronchopulmonary dysplasia" and "chronic lung disease". We reviewed the lists of selected articles to identify additional relevant publications and contacted the authors of relevant studies. Inclusion criteria The inclusion criteria of the studies should be met: (i) a control group is necessary in the studies; (ii) participants should be preterm or low BW infants; (iii) primary data could be used to detect the association between exposure to HDP and the development of BPD. PIH is defined as blood pressure higher than 140/90 mmHg occurred after 20 weeks of postmenstrual age,[15] without evidence of PE or HELLP syndrome. PE is defined as the development of hypertension plus one of the following: proteinuria, thrombocytopenia, or pulmonary edema.[16] HELLP syndrome was defined as hemolysis, elevated serum concentration of aspartate aminotransferase (≥70 IU/L) and thrombocytopenia.[17] We classified BPD as either a need for oxygen at the first 28 days together with a compatible chest radiograph [18] or a need for additional oxygen at 36 weeks of postmenstrual age according to the criteria of Bancalari et al.[19] Two reviewers screened the results of the searches and applied inclusion criteria using a structured form independently to identify relevant studies.
Quality assessment The quality of the studies was independently assessed by 2 reviewers using Newcastle-Ottawa Scale (NOS)[20] for case-control or cohort studies as appropriate. The assessment considered such domains: selection bias, comparability bias, exposure bias (case-control studies) and outcome bias (cohort studies). Data extraction Data were extracted independently by 2 reviewers who used a predetermined data extraction forms. For each study, the following characteristics were extracted: study design; population characteristics including sample size, ethnicity, birth weight (BW), gestational age (GA), data years, definitions of BPD, type of HDP, and usage of antenatal corticosteroids. Differences were resolved by discussion and consensus of the two reviewers. Statistical analysis The extracted data were analyzed using RevMan 5 and STATA 11. The association was evaluated between HDP and BPD by combining the studies with an odds ratio (OR) using a random-effects model. Heterogeneity was quantified using the I2 statistical method and the value greater than 50% was considered substantial. We conducted meta-regressions to test the effect on confounders such as GA, BW and antenatal steroid's prevalence separately. We also investigated heterogeneity by subgroup analysis according to the type of HDP, which was also considered the severity of HDP. Since this could not adequately explain the heterogeneity, post hoc analyses were conducted to assess whether the different inclusion criteria of participants, whether the definition of BPD or whether the different expoure factors of the control group could explain the heterogeneity. Forest plots were used to illustrate results from meta analyses, and unadjusted OR analyses were based on raw data for HDP and BPD. But adjusted OR analyses were based on data from multiple logistic regression analyses within the studies that adjusted for potential confounders. Funnel plots, Egger's or Begg's tests were used to investigate publication bias. The Trim and Fill method was used to control the publication bias.
Results
Identifying studies The literature review identified 787 potentially relevant studies from PubMed, Embase, Cochrane Library, ScienceDirect, and Web of Science. Forty-three studies were identified as relevant to the review through titles or abstracts, and 15 studies[10-14,21-30] met the inclusion criteria finally (Fig. 1). Characteristics of the studies The 15 studies were published in the English language
World J Pediatr, Vol 9 No 4 . November 15, 2013 . www.wjpch.com
301
Systematic review
angiogenesis was necessary for alveolarization during normal lung development and that injury to the pulmonary circulation during a critical period of lung growth may contribute to lung hypoplasia. [8] It was suggested that VEGF receptor signaling is required for the maintenance of the alveolar that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema. [9] Whether HDP is the risk factor of BPD is controversial. Studies [10-13] found that HDP was associated with an increased incidence of BPD, but one [14] reported that those born to mothers with mild hypertension had a significantly lower incidence of BPD as compared with those with severe maternal hypertension or without maternal hypertension at all. This systematic review aimed to find the association between BPD and HDP so that we could control the risk factors and prevent BPD in the early stage.
World Journal of Pediatrics between 1996 and 2013. Six studies were prospective cohort studies, 6 retrospective cohort studies and 3 case-control studies. There was great variability in the study size, from very small (n=66) to large (n=12 139). These studies were performed in a variety of countries. Not only definitions of BPD and HDP, but also the inclusion criteria varied in the studies (Table 1). Data extracted from the studies were used to measure the association between BPD and HDP, but only 6 studies provided adjusted measures of the association between BPD and HDP (Table 2).
Systematic review
Association between HDP and BPD Pooled unadjusted OR showed that the rate of BPD was Table 1. Characteristics of the studies included in the meta-analysis First author, year Data year Inclusion Sample Study design criteria (site) size Akram, 2006 (USA)[21]
1993-2000 GA
