Elsevier

The Lancet

Volume 379, Issue 9814, 4–10 February 2012, Pages 445-452
The Lancet

Articles
Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review

https://doi.org/10.1016/S0140-6736(11)61577-8Get rights and content

Summary

Background

Neonatal interventions are largely focused on reduction of mortality and progression towards Millennium Development Goal 4 (child survival). However, little is known about the global burden of long-term consequences of intrauterine and neonatal insults. We did a systematic review to estimate risks of long-term neurocognitive and other sequelae after intrauterine and neonatal insults, especially in low-income and middle-income countries.

Methods

We searched Medline, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and Embase for studies published between Jan 1, 1966, and June 30, 2011, that reported neurodevelopmental sequelae after preterm or neonatal insult. For unpublished studies and grey literature, we searched Dissertation Abstracts International and the WHO library. We reviewed publications that had data for long-term outcome after defined neonatal insults. We summarised the results with medians and IQRs, and calculated the risk of at least one sequela after insult.

Findings

Of 28 212 studies identified by our search, 153 studies were suitable for inclusion, documenting 22 161 survivors of intrauterine or neonatal insults. The overall median risk of at least one sequela in any domain was 39·4% (IQR 20·0–54·8), with a risk of at least one severe impairment in any insult domain of 18·5% (7·7–33·3), of at least one moderate impairment of 5·0% (0·0–13·3%), and of at least one mild impairment of 10·0% (1·4–17·9%). The pooled risk estimate of at least one sequela (weighted mean) associated with one or more of the insults studied (excluding HIV) was 37·0% (95% CI 27·0–48·0%) and this risk was not significantly affected by region, duration of the follow-up, study design, or period of data collection. The most common sequelae were learning difficulties, cognition, or developmental delay (n=4032; 59%); cerebral palsy (n=1472; 21%); hearing impairment (n=1340; 20%); and visual impairment (n=1228; 18%). Only 40 (26%) studies included data for multidomain impairments. These studies included 2815 individuals, of whom 1048 (37%) had impairments, with 334 (32%) having multiple impairments.

Interpretation

Intrauterine and neonatal insults have a high risk of causing substantial long-term neurological morbidity. Comparable cohort studies in resource-poor regions should be done to properly assess the burden of these conditions, and long-term outcomes, such as chronic disease, and to inform policy and programme investments.

Funding

The Bill & Melinda Gates Foundation, Saving Newborn Lives, and the Wellcome Trust.

Introduction

Nearly 140 million children per year are born worldwide, with 3·6 million neonatal deaths and 2·6 million stillbirths.1, 2, 3 More than 90% of neonatal deaths occur in resource-poor countries, mostly in rural areas.4 Worldwide, an increasing proportion (currently more than 40%) of mortality in children younger than 5 years occurs in the neonatal period (aged 0–28 days), which has led to increased attention to neonatal mortality. The common causes of neonatal mortality include preterm birth complications, intrapartum-related factors such as hypoxic ischaemic encephalopathy, infections (notably sepsis, meningitis, and neonatal tetanus), and other conditions such as jaundice and congenital infections (cytomegalovirus, toxoplasma, syphilis, and rubella).4, 5, 6 However, the prevalences of these insults and the long-term consequences for neonates who survive, particularly in resource-poor regions, are unclear.4

Many neonates survive major insults without any evidence of impairment because of the plasticity of the developing brain and improvements in medical care. However, in some newborn babies, insults can cause varying degrees of long-term neurodevelopmental impairment.5, 6, 7, 8 These impairments cause a major socioeconomic burden, especially in resource-poor countries. Intrauterine and neonatal insults substantially affect the global burden of disease, measured in disability-adjusted life-years, because they contribute to both premature mortality and long-term disability.9 However, little is known about the severity and distribution of long-term impairments after intrauterine or neonatal insults. As a result, sequelae from intrauterine and neonatal insults have not been adequately captured in estimates of the global burden of disease.10

We reviewed published data for the long-term consequences of intrauterine and neonatal insults. The questions addressed were: what are the long-term outcomes after intrauterine and neonatal insults (neonatal sepsis, neonatal meningitis, hypoxic ischaemic neonatal encephalopathy, neonatal jaundice, preterm birth, neonatal tetanus, congenital infections [cytomegalovirus, toxoplasma, syphilis, rubella], and HIV)? What is the risk and severity of at least one sequela and of multiple sequelae reported after these insults? And what is the risk and severity of sequelae after multiple insults for one infant?

Section snippets

Search strategy and selection criteria

We included studies that reported neurological outcomes after an identifiable and well defined neonatal insult (webappendix). We searched Medline, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and Embase for studies published between Jan 1, 1966, and June 30, 2011. For unpublished studies and grey literature, we searched Dissertation Abstracts International and WHO library. The initial search strategy used the words “neonate” and “outcome”, and each of the

Results

Our search identified 28 212 publications. From the titles we selected 1330 (5%) for review of the abstract and finally selected 949 studies for detailed review (figure 1). We excluded 796 (84%) after assessment of full text because they did not meet the inclusion criteria. The main reasons for exclusion were that numbers of survivors with sequelae could not be extracted; no clear description or diagnosis of the neonatal insult was provided; less than 80% of survivors were followed up after

Discussion

In our study, the median overall risk of sequelae in survivors of intrauterine and neonatal insults was very high. Our Article provides supportive evidence that intrauterine and neonatal insults result in significant long-term neurological morbidity and that these insults have a high risk of affecting more than one domain (eg, cognitive impairment, motor impairment and hearing and vision loss). Despite the fact that we initially identified many studies, few had data that were suitable for

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