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Keywords:

  • Antenatal steroids;
  • chorioamnionitis;
  • meta-analysis;
  • outcome;
  • preterm infant

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

Please cite this paper as: Been J, Degraeuwe P, Kramer B, Zimmermann L. Antenatal steroids and neonatal outcome after chorioamnionitis: a meta-analysis. BJOG 2011;118:113–122.

Background  There is debate concerning the safety and efficacy of antenatal steroids in preterm labour with suspected intrauterine infection (chorioamnionitis).

Objectives  We performed a systematic literature review and meta-analysis aimed at evaluating the efficacy and safety of antenatal steroids in clinical and histological chorioamnionitis.

Search strategy  MEDLINE, EMBASE, BioMed Central and the Cochrane databases were searched using the terms ‘chorioamnionitis OR intrauterine infection’ and ‘*steroids OR *corticoids’.

Selection criteria  Studies that reported selected neonatal outcome measures in preterm infants with clinical or histological chorio-amnionitis, according to antenatal steroid exposure, were eligible.

Data collection and analysis  Study selection, data extraction and data analysis were performed by two independent investigators. The meta-analysis techniques used included: Mantel–Haenszel analysis; an assessment of study heterogeneity using the Q statistic; and Egger’s regression test and funnel plots, to assess publication bias.

Main results  Seven observational studies were included. In histological chorioamnionitis (five studies), antenatal steroids were associated with reduced mortality (OR = 0.45; 95% CI = 0.30–0.68; = 0.0001), respiratory distress syndrome (OR = 0.53; 95% CI = 0.40–0.71; < 0.0001), patent ductus arteriosus (OR = 0.56; 95% CI = 0.37–0.85; = 0.007), intraventricular haemorrhage (IVH; OR = 0.35; 95% CI = 0.18–0.66; = 0.001) and severe IVH (OR = 0.39; 95% CI = 0.19–0.82; = 0.01). In clinical chorioamnionitis (four studies), antenatal steroids were associated with reduced severe IVH (OR = 0.29; 95% CI = 0.10–0.89; = 0.03) and periventricular leucomalacia (OR = 0.35; 95% CI = 0.14–0.85; = 0.02).

Conclusions  Antenatal steroids may be safe and reduce adverse neonatal outcome after preterm birth associated with chorioamnionitis. There is a need for randomised clinical trials to address this issue.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

Maternal administration of corticosteroids is an effective therapy to reduce respiratory distress and improve neurological morbidity and mortality in the preterm newborn. This approach has become standard care in cases of imminent or anticipated preterm delivery.1 However, general concern exists regarding the administration of antenatal steroids in cases of suspected intrauterine infection,2–5 as confirmed by a recent survey among Dutch perinatologists.6 Many expressed their fear for adverse effects in mother or child, and acknowledged the lack of evidence available on the subject. Although the majority would support a randomised clinical trial (RCT) to resolve the issue, many fear the potential harm to mother and child.

Available guidelines delineate chorioamnionitis as a contraindication for antenatal steroids, although the scientific basis for this recommendation remains obscure.4,5 Accordingly, pregnant women exhibiting signs suggestive of intrauterine infection (clinical chorioamnionitis) have often been excluded from RCTs investigating the effect of antenatal steroids on neonatal outcome.1,2 As a consequence, there is an important lack of data regarding the effects of antenatal steroids on neonatal outcome in the setting of suspected intrauterine infection.2

Antenatal infection or inflammation can be diagnosed in various ways. The diagnosis of chorioamnionitis based on the histological examination of the placenta and associated tissues is probably the most reliable and valid marker of intrauterine infection/inflammation.7 Although accurate, this histological diagnosis can only be made after birth, which is why clinical criteria are often used to try to identify patients with intrauterine infection.8 However, numerous studies have shown that the agreement between this so-called clinical chorioamnionitis and the histological diagnosis to be poor.8,9 To the best of our knowledge, RCTs reporting the effect of antenatal steroids in the subgroup of patients with either clinical or histological chorioamnionitis are non-existent. Observational studies addressing this issue are available, and should represent the best evidence currently available on the efficacy of antenatal steroids in patients with chorioamnionitis. Contrary to the general reluctance regarding the use of steroids in pregnancy complicated by chorioamnionitis, the positive findings of single studies have led investigators to suggest that a more liberal use of antenatal steroids in these patients may be justified.2,3,10

We performed a systematic review and meta-analysis on antenatal steroid administration and neonatal outcome in preterm infants with chorioamnionitis, to aggregate the current best evidence on the subject. Results are reported separately for clinical and histological chorioamnionitis because of important diagnostic differences between the two.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

Sources

A systematic literature search was performed independently by two investigators (JVB and PLD) in August 2010 using online databases for medical literature from 1966 onwards [MEDLINE, EMBASE, BioMed Central, Cochrane Database of Systematic Reviews (CDSR)]. In order to maximise the probability of identifying potentially relevant articles, broad search terms were used [(chorioamnionitis OR intrauterine infection) AND (*steroids OR *corticoids)] without additional restrictions. Additional searches were made by screening reference lists from articles of interest, as well as citations of articles of interest, using the ISI Web of Knowledge. Furthermore, attempts were made to identify relevant unpublished studies by searching the Cochrane Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register (ISRCTN) and the International Clinical Trials Registry Platform (ICTRP).

Study selection

Articles in any language were eligible for inclusion in the meta-analysis if they reported one or more neonatal outcome measures of interest with regard to antenatal steroid status in preterm infants with either histological or clinical chorioamnionitis. The neonatal outcome measures of interest were the following: neonatal mortality, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), severe IVH (grade 3–4), periventricular leucomalacia (PVL), necrotising enterocolitis (NEC), patent ductus arteriosus (PDA), culture-proven early-onset sepsis (within 72 hours of birth) and any culture-proven sepsis during admission. Composite outcome measures were not included in the meta-analysis. Study characteristics and patient data were extracted separately by the two investigators, and were subsequently cross-referenced. Any disagreement was resolved by consensus. The corresponding author of an article of interest was contacted in order to clarify any ambiguities, if present.

Analyses

Aggregate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Mantel–Haenszel analysis (fixed-effects model). The heterogeneity of studies was examined using both qualitative and quantitative assessment (Q statistic). When important heterogeneity was present, a random-effects model was applied. Study quality was assessed independently by two investigators (JVB and PLD) using the Newcastle–Ottawa Scale (NOS) for cohort studies. Again, any disagreement was resolved by consensus. To further assess the effects of potential heterogeneity, fixed-effect and random-effect models were compared for each outcome, and subgroup analyses were performed where possible. Egger’s regression test and funnel plots were used to assess publication bias. An alpha level of 0.05 was applied in all analyses, except when testing study heterogeneity, where < 0.10 was considered to be significant. All calculations were performed using RevMan 5 (The Cochrane Library, http://www.thecochranelibrary.com). Results are presented according to the MOOSE (Meta-analysis of Observational Studies in Epidemiology) criteria.11

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

Study selection and characteristics

A summary of article handling during the search process is presented in Figure 1. Eight studies were identified that reported one or more outcome measures of interest for infants exposed to chorioamnionitis, with regard to antenatal steroid administration.3,9,12–17 All studies were observational cohort studies: no RCTs addressing the effect of antenatal steroids within chorioamnionitis-exposed infants were identified. Of the eight studies, one small study was excluded because it included a highly selected cohort and applied liberal exclusion criteria, thereby complicating extrapolation of the findings.17 The general characteristics of the studies included in the meta-analysis are shown in Table 1. Three studies report the effect of antenatal steroids in infants with histological chorioamnionitis only,12,14,16 two in infants with clinical chorioamnionitis only,13,15 and two in both groups.3,9 All studies accepted overlap between clinical and histological chorioamnionitis, except for one, in which infants with clinical chorioamnionitis were excluded.12 Variation exists in the diagnostic criteria used to define both clinical and histological chorioamnionitis and the outcome measures of interest (Table 2). The overall study quality was comparable between reports (Table S1). In all of the studies, consecutively born preterm infants were studied and essential maternal, perinatal and neonatal characteristics were documented, although data collection was retrospective in most studies. Only one study reported on the comparison of chorioamnionitis-exposed infants treated or not treated with antenatal steroids, with regard to baseline characteristics, showing no differences.9

image

Figure 1.  Search results and study selection.

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Table 1.   Study characteristics
Author (year)Study periodLocationInclusion criteriaExclusion criteriaData collectionCAAntenatal steroidsN (CA+)Antenatal steroid coverage (%)
DrugDose (mg)Interval (hours)AS+RepeatAS+AS−
  1. AS+, the number of antenatal steroid doses used as a cut-off to determine antenatal steroids administration as positive; –, no exclusion criteria used; ?, no data available; *rescue course in selected cases ≥1 week after initial full course.

  2. AS, antenatal steroids; Aus, Australia; Beta, betamethasone; CA, chorioamnionitis; CC, clinical chorioamnionitis; Dex, dexamethasone; DM, diabetes mellitus; Fra, France; HC, histological chorioamnionitis; NL, Netherlands; Pro, prospective; Retro, retrospective; US, United States.

Elimian et al.121990–1997US500–1750 gCCRetroHCBeta1224≥2×Yes16935832
Baud et al.131993–1997Fra<33 weeks singletonsSevere DM; multiple malformationsRetroCCBeta /Dex12   624 12≥1×Yes6011035
Dempsey et al.141989–1999US<30 weeks singletonsRetroHCBeta1224≥2×?884268
Foix-L’Helias et al.151993–1996Fra24–31 weeks singletonsRetroCCBeta /Dex12   624 12≥1×Yes455246
Kent et al.161996–2001Aus<30 weeksProHCDex1212≥2×Yes581481
Goldenberg et al.31996–2001US23–32 weeks singletonsRetroHC CCBeta1224≥1×Yes*1823680
Been et al.92001–2003NL<32 weeksCongenital anomaliesProHC CCBeta1224≥2×No893274
Table 2.   Diagnostic criteria from individual studies
DiagnosisElimian et al.12Baud et al.13Dempsey et al.14Foix-L’Helias et al.15Kent et al.16Goldenberg et al.3Been et al.9
  1. +ve, positive; –, outcome not reported.

  2. AF, amniotic fluid; BPD, bronchopulmonary dysplasia; CC, clinical chorioamnionitis; CPAP, continuous positive airway pressure; CRP, C-reactive protein; CSF, cerebrospinal fluid; EOS, early onset sepsis; FiO2, fraction of inspired oxygen; HC, histological chorioamnionitis; IVH, intraventricular haemorrhage; mat, maternal; MV, mechanical ventilation; NEC, necrotising enterocolitis; PDA, patent ductus arteriosus; PL, preterm labour; PMA, postmenstrual age; PMNs, polymorphonuclear leucocytes; PPROM, preterm premature rupture of membranes; PVL, periventricular leucomalacia; RDS, respiratory distress syndrome; TAF, tracheal aspirate fluid; WBC, white blood cell count.

Chorio-amnionitisHC: Salafia et al.26CC: PL + two or more of: ≥2 × mat. T > 38°C; mat. CRP > 40 mg/l or WBC > 18 e3/ml; +ve AF cultureHC: abundant PMNs in chorion + amnionCC: PL without PPROM plus two or more of: mat. T > 38°C; mat. CRP > 20 mg/l; +ve AF culture; EOSHC: Naeye27 and Lewis and Perrin28HC: Bendon et al.;29 Faye-Petersen et al.;30 and Redline.31 CC: diagnosed by obstetrician (usually fever + abdominal pain + elevated WBC)HC: Redline et al.32 CC: mat. T > 38°C + no other focus + two or more of: uterine tenderness; malodorous vaginal discharge; mat WBC > 15 e3/ml, raised CRP, mat./fetal tachycardia
RDSMV + O2 need for ≥48 hours + typical X-rayAt <24 hours, two or more of: clinical signs; typical X-ray; lung immaturity in TAFThree or more of: clinical signs; FiO2 > 30% at 12–72 hours; CPAP/MV; typical X-rayAt <48 hours, two or more of: MV + O2 need; surfactant; typical X-ray; lung immaturity in TAFO2 need at 6–24 hours or X-ray at <24 hours consistent with RDS or need for surfactantClinical signs + typical X-ray according to Giedion et al.33
BPDO2 at 36 weeks PMAO2 at 36 weeks PMAO2 at 36 weeks PMA
IVHPapile34Papile34Papile34Papile34 and De Vries and Groenendaal35Volpe36Volpe36
PVLEcholucency or persistent echogenicityCystic echolucency before death or 6 weeks of ageVolpe36Volpe36
NECClinical signs + X-ray, surgery/autopsy confirmedIntramural gas on X-ray or perforation or necrosis at surgery/autopsyBell et al.37 stage ≥ 2Bell et al.37 stage ≥ 2
PDARequiring medication or surgeryUltrasound criteria + requiring medication or surgery
Sepsis+ve blood or CSF culture+ve blood culture no contamination+ve blood or CSF culture + clinical signs
Early onset sepsis+ve blood culture at ≤72 hourssepsis at ≤72 hours

Corresponding authors were contacted to obtain crude data when percentages were used,3,5,14 and to obtain additional information on antenatal steroid administration (preparation, dose, dosing scheme).3,13,15,16 Several responded and supplied additional information.3,13,15,16 A 10% cohort overlap between the studies by Foix-L’Helias et al. and Baud et al. was reported.13,15 This was not accounted for in the meta-analysis, and thus may slightly affect the pooled estimate on RDS after clinical chorioamnionitis.

Meta-analysis: histological chorioamnionitis

Individual study data and the results of the meta-analysis of the effects of antenatal steroids in infants with histological chorioamnionitis are shown in Figure 2. For this purpose, results that were reported separately for chorioamnionitis with and without a fetal inflammatory response were pooled.9,16 Administration of antenatal steroids was associated with significant reductions in neonatal mortality, RDS, PDA, IVH and severe IVH after histological chorioamnionitis. No significantly increased risk for any adverse outcome was detected after antenatal steroids. For early-onset sepsis, a random-effects model was applied because of study heterogeneity (= 0.04). No statistical indications for publication bias were present for any outcome measure.

imageimage

Figure 2.  Histological chorioamnionitis: meta-analysis of the effect of antenatal steroids on selected neonatal outcome measures.

Meta-analysis: clinical chorioamnionitis

Figure 3 shows individual study data and results of meta-analysis of the effects of antenatal steroids in infants with clinical chorioamnionitis. In these infants, antenatal steroids were associated with significant reductions in severe IVH and PVL. Again, no significant association between antenatal steroid administration and any adverse outcome measure was observed. In meta-analyses that included at least three studies, no indications for publication bias were present.

imageimage

Figure 3.   Clinical chorioamnionitis: meta-analysis of the effect of antenatal steroids on selected neonatal outcome measures. Data from Been et al.9 include unpublished data.

Meta-analysis: sensitivity analysis

The low number of studies and almost complete absence of subgroup-specific data reports did not allow for subgroup analyses to be performed. Application of a random-effects model did not importantly affect the effect size or significance level for most outcome measures. However, regarding the effect of antenatal steroids on severe IVH and PVL in infants with clinical chorioamnionitis, the random-effects model resulted in a loss of significance, although the point estimate remained essentially the same (OR = 0.32; 95% CI = 0.03–3.29; = 0.32; and OR = 0.38; 95% CI = 0.07–2.02; = 0.25; respectively).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

The current meta-analysis of observational studies indicates that in patients with chorioamnionitis antenatal steroids may be safe and effective in reducing adverse neonatal outcome. In patients with histological chorioamnionitis, antenatal steroid administration was associated with important reductions in mortality, RDS, PDA, total IVH and severe IVH. Antenatal steroids therapy in patients with clinical chorioamnionitis was associated with reductions in IVH and PVL. To our knowledge, no previous attempt was made to systematically review the available evidence on the efficacy and safety of antenatal steroids in chorioamnionitis. All included studies specifically addressed the research question, although only observational studies were identified. Yet, given the lack of RCTs on the issue, the present aggregation of observational studies provides the current best evidence on this subject.

The broad search strategy used and the multitude of databases searched minimised bias during the search process, although we cannot exclude having missed unpublished observational evidence. The MOOSE statement underlines the value of meta-analyses of observational studies when assessing the efficacy and effectiveness of therapies, as long as potential sources of bias are considered and discussed.11 We believe the relative uniformity of inclusion criteria and outcome parameters used, and the separation of analyses for histological and clinical chorioamnionitis, justify performing a meta-analysis by statistically aggregating the data. The absence of statistical indications for publication bias and study heterogeneity (except for early-onset sepsis after clinical chorioamnionitis) further supports the validity of the results; however, as noted, although a meta-analysis may substantiate the conclusions drawn from the available evidence, several important limitations should be acknowledged.

Overall the number of studies suitable for inclusion was low. Although individual cohorts were of considerable size, this may introduce bias mainly through differences in the inclusion and exclusion criteria between studies. An important example is the exclusion of infants with clinical chorioamnionitis by Elimian et al.12 Given the association between clinical chorioamnionitis and the severity of histological chorioamnionitis, this may have led to the exclusion of more severely affected infants with histological chorioamnionitis.18 Since antenatal steroids seem to improve outcome predominantly in infants with less severe chorioamnionitis,9 an overestimation of their positive effect on neonatal outcome may result. The resultant bias could be important because of the large cohort size of this particular study. Another consequence of the small number of studies is that results from a single study may sometimes largely explain the overall meta-analysis outcome. An example is the association between antenatal steroids and improved neurological outcome in infants with clinical chorioamnionitis, which is largely explained by results from the study by Baud et al.13

Aspects regarding the administration of antenatal steroids need additional consideration. Differences between studies are present in the type of drug used, in drug dosing and timing, and whether or not multiple courses were allowed. The latter may be a confounding factor, as repeat courses are less likely to have been given to mothers with chorioamnionitis.2 In some instances, steroids may not have been given because delivery ensued quickly after admission, leading to potential bias. Moreover, antenatal steroid administration was scored as positive by some authors only when a full course was administered, whereas others also included infants that received incomplete courses. Incomplete courses of antenatal steroids have been shown to have some effect on outcome. Thus, differences between studies may arise from whether infants who received an incomplete course were assigned to the treatment group or the control group. Another source of variation between studies is introduced by differences in diagnostic criteria related to both chorioamnionitis and outcome definitions. Comparison of random-effects and fixed-effects models suggests that the effect of heterogeneity is limited for most outcomes. However, in infants with clinical chorioamnionitis, the random-effects model resulted in the loss of significance of the beneficial effect of antenatal steroids, suggesting that study heterogeneity could account for part of the observed effect. In summary, although the meta-analysis clearly suggests that antenatal steroids may be beneficial in both histological and clinical chorioamnionitis, the results should be interpreted with great care given these methodological considerations.

Certain additional issues should be taken into account when interpreting the data. Most importantly, there is a lack of information on the timing of steroid administration relative to the emergence of signs suggestive of intrauterine infection. As stressed by Goldenberg et al.,3 steroids may have been administered before the occurrence of clinical chorioamnionitis in the majority of cases. Outcome measures of these infants obviously are not very helpful in guiding the use of antenatal steroids when intrauterine infection is clinically apparent. Thus, although antenatal steroids are associated with improved short-term neurological outcome in infants with clinical chorioamnionitis in the current meta-analysis, one should be prudent in extrapolating these findings to the clinical situation directly. Also, the identification of potential maternal adverse effects of steroid administration in the setting of suspected intrauterine infection was beyond the scope of this review, although none were reported in the studies included in this meta-analysis. In this respect it is important to note that antenatal steroid administration in itself has been shown not to increase the risk of developing clinical chorioamnionitis.1

From one standpoint, the efficacy of antenatal steroids in histological chorioamnionitis may not seem clinically relevant, as placental histology is not available to the obstetrician when deciding whether or not to give antenatal steroids. However, the beneficial effect of antenatal steroids after histological chorioamnionitis indicates that treatment may indeed be safe and effective, regardless of whether subclinical inflammation is present. Moreover, a meta-analysis of RCTs showing particular benefit of antenatal steroids in pregnant women with preterm prelabour rupture of membranes supports their therapeutic potential when intrauterine infection is imminent.1

Despite these potential sources of bias, the absence of any association between antenatal steroid treatment and adverse outcome in chorioamnionitis-exposed infants is reassuring. Moreover, the highly significant differences in several outcome measures between treated and non-treated infants suggest that at least some of these effects are genuine. Animal experimental data further support some of these associations. Antenatal steroids enhance lung maturation after experimental chorioamnionitis in preterm sheep, corresponding to the reduction in RDS observed in this meta-analysis.19–21 Data from the same model show that antenatal steroids and chorioamnionitis modulate the fetal innate immune response, both solitary and combined.22–24 Immunological effects may well mediate some of the associations between chorioamnionitis, antenatal steroids and outcome after preterm birth.25

Finally, the current meta-analysis provides information on steroid effects regarding neonatal outcome only. Data concerning the effects of antenatal steroids on outcome beyond the neonatal period in infants exposed to chorioamnionitis are virtually absent. We are aware of only one small study that was unable to show any difference in neurodevelopmental outcome at the ages of 1 and 3 years.16 Moreover, although not specifically designed to address this issue, no data were found on the association between antenatal steroids and maternal outcome in chorioamnionitis. Additional research is needed to evaluate the maternal and long-term offspring effects of antenatal steroids in chorioamnionitis.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

In conclusion, the current meta-analysis of observational studies suggests that antenatal steroids are safe and effective in preterm infants born before 33 weeks of gestation with subclinical chorioamnionitis. However, when chorioamnionitis is clinically apparent, the evidence is less obvious and more sensitive to bias. Retrospective subgroup analysis of observational studies and RCTs in which data on chorioamnionitis and antenatal steroid exposure are available, may further increase our knowledge on this important topic. We would favour an RCT to assess the efficacy and safety of antenatal steroids in clinical chorioamnionitis. Both maternal and neonatal outcome must be evaluated, and should include long-term follow-up. Until such a trial has been carried out, one should be cautious to make any clinical recommendation regarding this issue.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

JVB conceived the idea for the systematic literature review and meta-analysis, and wrote the article. PLD co-performed the systematic literature review and meta-analysis, and aided in manuscript preparation. BWK aided in manuscript preparation. LJZ supervised the literature review, meta-analysis and manuscript preparation.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

JVB is supported by a ‘Profileringsfonds’ grant and a Kootstra Talent Fellowship from Maastricht University Medical Centre. BWK is supported by a VENI grant and a grant from Research School GROW.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

We are grateful to Drs Andrews, Lacaze and Kent for supplying additional information on original studies included in the meta-analysis. The Maastricht University Medical Centre, School for Oncology and Developmental Biology, and School for Mental Health and Neuroscience are acknowledged for their financial support.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interests
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
  14. Supporting Information

Table S1. Quality assessment of the included studies using the Newcastle–Ottawa Scale (the fact that this study adjusted for potential confounding factors is not incorporated in the meta-analysis).

FilenameFormatSizeDescription
BJO_2751_sm_TableS1.doc31KSupporting info item

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