Defining Very Preterm Populations for Systematic Reviews With Meta-analyses

Abstract

This review compares the selection criteria, findings, and heterogeneity of systematic reviews with meta-analyses of cognitive outcomes among children considered very preterm at birth.

Survival of very preterm (VPT) infants (ie, those born at <32 weeks’ gestation) has improved markedly over recent decades, raising concerns about levels of impairment among survivors. Numerous studies have been conducted on the association between VPT birth and long-term neurodevelopment and health, and this voluminous literature is increasingly synthesized in systematic reviews with meta-analyses. This methodology is considered to provide the highest level of evidence, but its validity depends on appropriate selection of primary studies and management of heterogeneity. Heterogeneity is pervasive in the literature about VPT birth because of differences in criteria for defining preterm populations, study designs, follow-up periods, follow-up rates, and clinical assessments. Furthermore, medical practices, survival, and morbidities vary markedly across countries and hospitals and can affect long-term prognosis. This study aimed to compare the selection criteria, findings, and heterogeneity of systematic reviews with meta-analyses of cognitive outcomes after VPT birth, which are of major concern in this population and measured in most studies.

Methods

We searched for systematic reviews with meta-analyses published between January 2000 and August 2019 that were based on observational studies with cohort designs investigating general cognition (IQ) for VPT children compared with a control group. We defined search terms to identify studies (1) on preterm birth (premature OR preterm OR infant, Premature [Medical Subject Headings (MeSH)]), (2) the outcome [Developmental disabilities [MeSH] OR cognition disorders [MeSH] OR intellectual disability [MeSH] OR cognition [MeSH] OR cognit* OR intelligence OR IQ, and (3) the type of study (Meta-analysis OR meta analys* OR metaanaly* OR [systematic AND review* OR overview*] OR Review Literature as Topic [MeSH]). Two of us (M.S. and J.Z.) independently abstracted methods and results related to study selection, pooled analyses, and heterogeneity. We compiled primary studies and identified unique cohorts when several studies originated from the same cohort based on the country, birth year(s), and research group. For analyses, we used R statistical software, version 3.5.0 (The R Foundation).

Results

Five reviews were identified: 1 was published in 2012¹ and 4 were published in 2018 or 2019.^2,3,4,5 All investigated the association of birth at less than 32 weeks’ gestation with childhood IQ, although some also considered other outcomes or subgroups. Eligibility criteria varied for birth weight, assessment ages, and study period (Table). We searched MEDLINE,^1,2,3,4,5 Embase,^1,2 PsychInfo,^1,3,4,5 and Web of Science^3,4 using different search terms.

Table. Inclusion Criteria, Search Terms, and Principal Results in Systematic Reviews With Meta-analyses of Cognitive Outcome After VPT Birth.

	Study
	Kerr-Wilson et al,1 2012	Allotey et al,2 2018	Brydges et al,3 2018	Twilhaar et al,4 2018	Arpi et al,5 2019
Inclusion criteria for GA and/or BW	GA <37 wk (groups, <28 wk and 28 to 31 wk); BW not mentioned	GA <37 wk (groups, <28 wk and 28 to 33 wk); BW not mentioned	GA <32 wk; exclusion of studies was based on BW only	GA <32 wk and/or BW <1000 g or <1500 g	GA <32 wk and/or BW <1500 g
Assessment age	≥4 y	≥2 y	Mean age, 4 to 17 y	≥5 y	3-5 y
Time period	Published 1980-2009	Published 1980-2016	Published before July 2017	Published before March 2017; birth occurred during or after 1990a	Published 2000-2017; birth after 1994
Other criteria	No	Yesb	Yesc	No	No
Search terms for preterm population	Preterm, low BW, GA, date of delivery, prematur*, baby or babies, or infan*	(Preterm, pre-term, pre term, premature, near-term, prematurity, AND birth, infant, delivery, baby or babies) OR exp prematurityd	Low BW, premature*, preterm, AND child*	Prematur*, preterm, low birth weight, ELBW, VLBW	Preterm birth, premature, low BW, AND preschool* or preschool age
No. of studies/cohorts of VPT childrene	21/21	50/44	44/37	71/69	7/7
Pooled estimate for difference in IQ scores between VPT and FT children, SMD (95% CI)f	GA <28 wk: −0.95 (−1.09 to −0.80); GA 28 to 31 wk: −0.84 (−0.97 to −0.71)g	GA <28 wk: −0.78 (−0.85 to −0.72); GA 28 to 33 wk: −0.73 (−0.78 to −0.67)	GA <32 wk: −0.82 (−0.90 to −0.74)	GA <32 wk: −0.86 (−0.94 to −0.78)	GA <32 wk: −0.77 (−0.88 to −0.66)
Heterogeneity, I2	GA <28 wk: 66.5%; GA 28 to 31 wk: 48.4%	GA <28 wk: 35.3%; GA 28 to 33 wk: 63.7%	62.9%	74.1%	0%

Abbreviations: BW, birth weight; ELBW, extremely low birth weight; GA, gestational age; SMD, standardized mean difference; VLBW, very low birth weight; VPT, very preterm.

^aOr if birth occurred before 1990 with antenatal corticosteroid or surfactant therapy.

^bStudies were excluded if correction was made for chronological age at the assessment.

^cStudies were excluded if restrictions were placed on participants based on task performance.

^dThe search term exp indicates that the subject heading prematurity was exploded to include narrower subject headings included in its tree structure.

^eVery preterm was defined as having a GA of less than 32 weeks^1,3,4,5 or GA of less than 34 weeks (3 of the 44 cohorts had a GA of 32 or 33 weeks).²

^fData represent the SMD in IQ scores (VPT children – FT children) and 95% CI.

^gThe SMD was computed from the weighted mean difference reported by the authors: for children born at less than 28 weeks’ gestation: weighted mean difference, 13.9 (95% CI, 11.5-16.2); for those born at 28 to 31 weeks’ gestation: weighted mean difference, 11.4 (95% CI, 9.7-13.2).

A total of 156 primary studies reporting results from 114 VPT cohorts were included in all reviews. Among 107 cohorts included in the 3 reviews published in 2018 that did not have upper limits on assessment age, only 8 were included in all 3 reviews (Figure). When these were limited to the 58 cohorts covered by studies published before 2009 to permit comparison with the 2012 review, none was included in all 4 reviews and 35 (60%) were included in only 1 review. All 7 cohorts included in the review on assessments at ages 3 to 5 years⁵ were included in at least 1 other review, but none was included in all 3 reviews.

Figure. Overlap of 107 Cohorts Included in Three 2018 Systematic Reviews With Meta-analyses of the Association of Very Preterm Birth With Cognitive Outcome.

All reviews reported a lower IQ among VPT children compared with full-term children (pooled effects ranged from −0.77 [95% CI, −0.88 to −0.66] to −0.86 [95% CI, −0.94 to −0.78] for the standardized mean difference or 11.6-12.9 IQ points for results relating to all children born at <32 weeks’ gestation). Most of the reviews reported a moderate to high heterogeneity overall or in at least 1 gestational age subgroup (I², >60%).

Discussion

Investigators’ methodological choices appeared to affect the primary study selection in systematic reviews with meta-analyses on VPT birth and cognition despite shared objectives. These differences in study selection represent a missed opportunity to synthesize all available information and raise questions about appropriate criteria for selecting studies in this population. Nonetheless, similar pooled estimates affirmed the robust conclusion that VPT birth is associated with a lower IQ, although with substantial interstudy heterogeneity. A limitation of this study is that we could not attribute differences in study selection to specific methodological choices (ie, inclusion criteria, definitions, search terms), which would require reviewing all primary studies.

The exponential increase in systematic reviews with meta-analyses has called attention to the need to organize research efforts to avoid both redundant and contradictory results when evidence is synthesized.⁶ Continued investigation of the long-term consequences of VPT is essential to address concerns about high, stable impairment rates among VPT survivors and to investigate variation related to perinatal management, follow-up services, and the sociocultural environment. Establishing common guidelines to select primary studies, along with open-access repositories of studies from previous reviews, would ensure that future reviews use all relevant information and optimize the analysis of interstudy heterogeneity.