Neonatal hypothermia and its associated factors in East Africa: a systematic review and meta-analysis

Background : Neonatal hypothermia is a global health problem and a major contributing factor for neonatal morbidity, mortality, and for new-born survival, especially in low and middle-income countries. High prevalence of hypothermia has been reported from countries with the highest burden of neonatal mortality. Therefore, the aim of this systematic review and meta-analysis was to assess the prevalence of neonatal hypothermia and its associated factors in Eastern Africa. Methods: Using PRISMA guideline, we systematically reviewed and meta-analyzed studies that examined the prevalence and associated factors of neonatal hypothermia from PubMed, Cochrane library, and Google Scholar. Heterogeneity across the studies was evaluated using the Q and the I 2 test. A weighted inverse variance random-effects model was applied to estimate the national prevalence and the effect size of associated factors. The subgroup analysis was conducted by country, study design, and year of publication. A funnel plot and Egger’s regression test were used to see publication bias. Result: A total of 12 potential studies with 20,911 participants were used for analysis. The pooled prevalence of neonatal hypothermia in East Africa was found to be 57.22% (95%CI; 39.48–74.95).Delay in initiation of breastfeeding (AOR=2.83; 95%CI: 1.398-4.259; I 2 = 49.2%; P=0.097), having neonatal health problem (AOR=2.68; 95%CI: 1.21-4.15; I 2 = 0.0%; P=0.98), being low birth weight (AOR =2.16; 95%CI: 1.03-3.29; I 2 =3.3%; P=0.005), being preterm(AOR=4.01; 95%CI: 3.02-5.00; I 2 = 0.0%; P=0.457), and night time delivery (AOR=4.01; 95%CI:3.02-5.00; I 2 =0.0%; P=0.457) were identi�ed associated factors which signi�cantly increase the risk of neonatal hypothermia. Conclusions : The prevalence of neonatal hypothermia in Eastern Africa remains high. Delay in initiation of breastfeeding, having neonatal health problem, being low birth weight, preterm, and nighttime delivery were identi�ed associated factors which signi�cantly increase the risk of neonatal hypothermia. It is recommended that early initiation of breast feeding should be promoted and emphasis should be given towards low birth weight, preterm and neonates with neonatal problems to prevent burdens of hypothermia in East Africa.


Introduction
According to World Health Organization(WHO), neonatal hypothermia is an abnormal thermal state in which the newborn's body temperature is below 36.5°C[1].It is a global health problem with higher rate in countries with low resource settings [3].In sub-Saharan countries, hypothermia increases neonatal death by 80% for every 1 degree Celsius decrease of body temperature [3].
Hypothermia occurs usually with severe infections,prematurity, and asphyxia paying much for the least drop in neonatal death rate of the African regions [6].It leads to diverse neonatal health consequences, and its prevalence in hospitals varies from 32 to 85% and at homes from 11 to 92%, including in the tropical environments [4].Hypothermia is one of the important causes for neonatal death and morbidity in developing countries, which rises neonatal mortality by ve times.Previous studies had revealed that every 1°c reduction of neonate's body temperature raises the mortality by 80% [3,7,8].The prevalence is high among countries with the highest burden of neonatal morbidity and mortality.Hence, increasingly, it is documented as a contributor for newborn survival [9,10].
In developed countries neonatal hypothermia takes for 28% of the world burden.More than 98% of yearly neonatal mortality occur in developing countries [11].Despite this fact only limited progress has been made towards risk for neonatal mortality [11].To solve the major neonatal problems secondary to hypothermia, identifying its determinants is needed; which have greater input to attain sustainable development goal (SDG) 3 of ensuring healthy lives and promote well-being for all at all age.Indeed, approaches that can prevent and treat neonates with hypothermia are vital to hasten the advancement of newborn survival.In East Africa, variety of studies was conducted to estimate the prevalence of neonatal hypothermia.However, prevalence of neonatal sepsis ranges from 1.3% [14] to 79% [15] which indicated a great inconsistencies across different geographical settings and different time periods.In addition, there are some opposing or inconsistent ndings on risk factors and mortality predictors of neonates due to hypothermia.Moreover, there is no regionally denoted pooled data of neonatal hypothermia in East Africa.Therefore, this systematic review and meta-analysis was aimed; to estimate the pooled prevalence of neonatal hypothermia and the effect size of its associated factors in East Africa context.

Reporting
The results of this review were reported based on the Preferred Reporting Items for Systematic Review and Meta-Analysis statement (PRISMA) guideline (Supplementary le 1: PRISMA checklist) and, it is registered in the Prospero database: (PROSPERO 2019: CRD42019131654) Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID = CRD42019131654.

Searching strategy and selection criteria
We identi ed studies providing data on the prevalence and/or potential risk factors for neonatal hypothermia with the search focused on Eastern Africa.PubMed, Google Scholar, and Cochrane library were retrieved.The search included keywords and MeSH terms, combinations, and snowball searching in references of relevant papers for linked articles.The core search terms and phrases were "newborn", "neonate", "infant", "hypothermia", "low body temperature", "thermoregulation", Body Temperature Regulation, and Eastern Africa.The search strategies were developed using different Boolean operators.
Notably, to t advanced PubMed database, the following search strategy was applied: (prevalence OR magnitude) AND (causes OR determinants OR associated factors OR predictors) AND (newborn [MeSH Terms] OR neonate OR infant OR child OR children)AND (hypothermia [MeSH Terms] OR low body temperature OR thermoregulation OR Body Temperature Regulation)AND (Eastern Africa).We also screened at the reference lists of the remaining papers to identify additional relevant studies to this review.

Study selection / Eligibility criteria
Retrieved studies were exported to Endnote version 8 reference manager software, to remove duplicate studies.Two investigators (BBA and AMK) independently screened the selected studies using article titles and abstracts before retrieval of full-text papers.We used pre-speci ed inclusion criteria to further screen the full-text articles.Disagreements were discussed during a consensus meeting with other reviewers (MWK and MAR) for the nal selection of studies to be included in the systematic review and metaanalysis.

Inclusion and exclusion criteria
Cross-sectional, case-control, and cohort studies were included.Those studies had reported the prevalence and/or at least one associated factor for neonatal hypothermia and published in English language from 2000 up to 2019 were considered.Citations without abstract and/or full-text, anonymous reports, editorials, and qualitative studies were excluded from the analysis.

Quality assessment
Three authors independently appraised the quality of the studies by using the Joanna Briggs Institute (JBI) quality appraisal checklist was used [16].The disagreement was resolved by the interference of the fourth reviewer.The following items were used to appraise cohort studies: (1) similarity of groups, (2) similarity of exposure measurement, (3) validity and reliability of measurement, (4) identi cation of confounder,(5) strategies to deal with confounder, (6) appropriateness of groups/participants at the start of the study (7) validity and reliability of outcome measured, (8) su ciency of follow-up time, (9) completeness of follow-up or descriptions of reason to loss to follow-up, (10) strategies to address incomplete follow-up, and (11) appropriateness of statistical analysis.The items used to appraise casecontrol studies were: (1) comparable groups, (2) appropriateness of cases and controls, (3) criteria to identify cases and controls, (4) standard measurement of exposure, (5) similarity in measurement of exposure for cases and controls, (6) handling of confounder (7), strategies to handle confounder, (8) standard assessment of outcome, (9) appropriateness of duration for exposure, and (10) appropriateness of statistical analysis.Studies got 50% and above of the quality scale were considered low risk.The following items were used to appraise cross-sectional studies: (1) inclusion criteria, (2) description of study subject and setting, (3) valid and reliable measurement of exposure, (4) objective and standard criteria used,(5)identi cation of confounder, (6) strategies to handle confounder, (7) outcome measurement, and (8)appropriate statistical analysis.Studies were considered low risk when it scored 50% and above of the quality assessment indicators.

Data extraction
Two reviewers independently extracted the data using a structured data extraction form.Whenever variations of extracted data observed, the phrase was repeated.If discrepancies between data extractors continued, the third and fourth reviewer was involved.The name of the rst author and year of publication, tstudy country, study design, the target population, tsample size, prevalence of neonatal hypothermia, and AOR of associated factors were extracted

Outcome measurement
Neonatal hypothermia was considered, when neonate's body temperature was less than 36.5 degree centigrade or neonates who are diagnosed as hypothermia by attending physician and ful ll hypothermia criteria within 0-28 days of life.

Statistical analysis
We pooled the overall prevalence estimates of neonatal hypothermia by a random effect meta-analysis model [17].We examined the heterogeneity of effect size using Q statistic and the I 2 statistics [17].In this study, the I 2 statistic value of zero indicates true homogeneity, whereas the value 25, 50, and 75% represented low, moderate and high heterogeneity respectively [18,19].
For the data identi ed as heterogeneous, we conducted our analysis by random-effects model analysis.Subgroup analysis was done by the study country, design, and year of publication.Sensitivity analysis was employed to see the effect of a single study on the overall estimation.
Publication bias was checked by funnel plot and more objectively through Egger's regression test.

Results
A total of 3496 studies were identi ed; 2252 from PubMed, 12 from Cochrane Library, 1210 from Google Scholar and 22 from other sources.After duplication removed, a total of 1034 articles remained.Finally, 201 studies were screened for full-text review and , only 12 articles with (n=20,911 patients) were selected for the prevalence and/ or associated factors analysis (Fig. 1)

Subgroup analysis of the prevalence of neonatal hypothermia in Eastern Africa
The subgroup analysis was done through strati ed by country, study design, and year of publication.Based on this, the prevalence of neonatal hypothermia was found to be 55.3% in Ethiopia, 62.6% in Uganda, and 60.0% in Kenya (Fig 3 and Table 2).Based on the study design, the prevalence of neonatal hypothermia was found to be 63.5% in cross-sectional studies and 32.98% in cohort studies (Fig 4 and Table 2).Based on the year of publication, the prevalence of neonatal hypothermia was found to be 65.06% from 2000-2015, while it was 57.90% from studies conducted from 2016-2019(Fig 5 , Table 2).

Publication bias
A funnel plot showed asymmetrical distribution.Egger's regression test p-value was 0.019, which indicated the presence of publication bias.Due to presence of publication bias we employed a leave-oneout sensitivity analysis to identify the potential source of heterogeneity in the analysis of the prevalence of neonatal hypothermia in Eastern Africa.The results of this sensitivity analysis showed that our ndings were not dependent on a single study.Our pooled estimated prevalence of neonatal hypothermia varied between 54.79(36.47-73.12)and 62.26(55.22-69.30)after deletion of a single study.Byaruhanga R, 2005(23), Mekonnen Tilahun, 2018(34) had shown an impact on the overall estimation.

Factors associated with neonatal hypothermia in East Africa
See Table 3.

Delayed initiation of breast feeding
Five studies found signi cant association between delayed initiation of breast feeding and neonatal hypothermia.Birhanu etal (2017) revealed that neonates with delayed initiation of breast feeding were 4.39 times at risk of having neonatal hypothermia compared to neonates with timely initiation of breast feeding.G/silasea etal revealed that neonates with delayed initiation of breast feeding were 2.42 times at risk of having neonatal hypothermia (95% CI: 1.45, 4.02) compared to neonates with timely initiation of breast feeding.Tewodros et al revealed that neonates with delayed initiation of breast feeding were 7.58 times at risk of having neonatal hypothermia compared to neonates with timely initiation of breast feeding.Hagos et alrevealed that neonates with delayed initiation of breast feeding were 7.23 times at risk of having neonatal hypothermia compared to neonates with timely initiation of breast feeding.Wubet revealed that neonates with delayed initiation of breast feeding were 1.63 times at risk of having neonatal hypothermia (95% CI: 0.88, 2.99) compared to neonates with timely initiation of breast feeding.
Regarding heterogeneity test, galbraith plot showed homogeneity and combining the result of ve studies, the forest plot showed the overall estimate of AOR of home delivery was 2.83( 95%C I: 1.398-4.26;I 2 = 49.2%;P=0.097).I-Squared (I 2 )and P-value also showed homogeneity ( g 6).
Regarding publication bias, a funnel plot showed an asymmetrical distribution.During the Egger's regression test, the p-value was 0.016, which indicated the presence of publication bias.Due to presence of publication bias trim and ll analysis was done and 2 studies were added, and the total number of studies becomes 7.The pooled estimate of AOR of home delivery was found to be 2.463.

Neonatal health problems
Five studies (G/silasea etal 2019, Tewodros S etal 2015, Hagos T 2018, Wubet A etal 2019 and ANNA BM etal 2005) found signi cant association between neonatal health problems and neonatal hypothermia.G/silasea et al revealed that neonates with health problem were 2.46 times at risk of having neonatal hypothermia (95% CI: 1.07, 5.66) compared to neonates without health problems.Tewodros et al revealed that neonates with health problem were 3.1 times at risk of having neonatal hypothermia compared to neonates without health problem.Hagos revealed that neonates with health problem were 2.282 times at risk of having neonatal hypothermia compared to neonates without health problem.Wubet A revealed that neonates with health problems were 4.24 times at risk of having neonatal hypothermia (95% CI: 1.92, 9.34) compared to neonates without neonatal health problems.ANNA BM etal revealed that neonates with health problems were 4.24 times at risk of having neonatal hypothermia compared to neonates without health problems(table 3) Regarding heterogeneity test for neonatal health problems, galbraith plot showed homogeneity and combining the result of ve studies the forest plot showed the overall estimate of AOR of home delivery was 2.68( 95%CI: 1.21-4.15;I 2 = 0.0%;P=0.98).I-Squared (I 2 )and P-value also showed homogeneity ( g 7) Regarding publication of bias for neonatal health problems analysis, the funnel plot analysis showed asymmetrical distribution.During the Egger's regression test, the p-value was 0.068, which indicated the absence of publication bias.Trim and ll analysis was done, and 1 study were added and the total number of studies become 6 .thepooled estimate of AOR of preterm becomes 2.49.
We employed a leave-one-out sensitivity analysis to identify the potential source of heterogeneity in the analysis of the prevalence of neonatal hypothermia in Eastern Africa.The results of this sensitivity analysis showed that our ndings were not dependent on a single study.Our pooled estimate of neonatal health problems varied between 2.49(95%CI,0.88-4.09)and 2.75(95%CI, 1.15-4.34)after deletion of a single study.

Low birth weight
Five studies (Birhanu W etal 2017, G/silasea etal 2019, Tewodros S etal 2015, Hagos T 2018, Wubet A etal 2019) found signi cant association between low birth weight and neonatal hypothermia.Birhanu W etal revealed that neonates with low birth weight were 1.33 times at risk of having neonatal hypothermia compared to neonates with normal birth weight.G/silasea etal revealed that neonates with low birth weight were 3.61 times at risk of having neonatal hypothermia (95% CI: 2.1, 6.18) compared to neonates with normal birth weight.Tewodros S etal revealed that neonates with low birth weight were 3.75 times at risk of having neonatal hypothermia compared to neonates with normal birth weight.Hagos T revealed that neonates with low birth weight were 8.51 times at risk of having neonatal hypothermia compared to neonates with normal birth weight.Wubet A revealed that neonates with low birth weight were 1.2 times at risk of having neonatal hypothermia (95% CI: 0.51,2.82)compared to neonates with neonatal birth weight.
Regarding heterogeneity test, galbraith plot showed heterogeneity and combining the result of ve studies the forest plot showed the overall estimate of AOR of low birth weight was 2.16( 95%CI: 1.027-3.293;I 2 = 3.3%;P=0.005).I-Squared (I 2 )and P-value also showed heterogeneity( g 8).
Regarding publication bias a funnel plot showed a symmetrical distribution.Egger's regression test pvalue was 1.98, which indicated the absence of publication bias.
Trim and ll analysis was done, and 2 studies were added and the total number of studies become 7.The pooled estimate of AOR of low birth weight becomes 1.85.

Preterm
Five studies (Birhanu W etal 2017, G/silasea etal 2019, Tewodros S etal 2015, Hagos T 2018, Wubet A etal 2019) found signi cant association between preterm and neonatal hypothermia.Birhanu W etal revealed that preterm neonates were 4.39 times at risk of having neonatal hypothermia compared to term neonates.G/silasea etal revealed that preterm neonates were 4.61times at risk of having neonatal hypothermia (95% CI: 2.1, 8.18) compared to term neonates.Tewodros etal revealed that term neonates were 1.5 times at risk of having neonatal hypothermia compared to preterm neonates.Hagos revealed that term neonates were 3.689 times at risk of having neonatal hypothermia compared to preterm neonates.Wubet revealed that term neonates 3.37 times at risk of having neonatal hypothermia (95% CI: 1.53, 7.44) compared to preterm neonates (Table 3).
Regarding heterogeneity test, the galbraith plot analysis showed homogeneity and combining the result of ve studies the forest plot showed the overall estimate of AOR of home delivery was 4.01( 95%C I: 3.02,5.00;I 2 = 0.0%;P=0.457).I-Squared (I 2 )and P-value also showed homogeneity( gure 9) Regarding publication bias a funnel plot showed a symmetrical distribution.Egger's regression test pvalue was 0.131, which indicated the presence of publication bias.

Nighttime delivery
Five studies (Birhanu W etal 2017, G/silasea etal 2019, Tewodros S etal 2015, Hagos T 2018, Wubet A etal 2019) found signi cant association between night delivery and neonatal hypothermia.Birhanu W etal revealed that neonates delivered at night were 1.32 times at risk of having neonatal hypothermia compared to neonates who delivered at day.G/silasea etal revealed that neonates delivered at night 1.68 times at risk of having neonatal hypothermia (95% CI: 1.01, 2.83) compared to neonates who delivered at day.Tewodros etal revealed that neonates delivered at night 6.61 times at risk of having neonatal hypothermia compared to neonates who delivered at day.Hagos revealed that neonates delivered at night 6.25 times at risk of having neonatal hypothermia compared to neonates delivered at day.Wubet revealed that neonates delivered at night were 3.18 times at risk of having neonatal hypothermia (95% CI: 0.51, 2.82) compared to neonates delivered at day.Regarding heterogeneity test, the galbraith plot showed homogeneity and combining the result of ve studies the forest plot showed the overall estimate of AOR of low birth weight was 4.01( 95%C I: 3.018-5.002;I 2= 0.0%;P=0.457).I-Squared (I 2 )and P-value also showed homogeneity( gure 10).
Regarding publication bias, the funnel plot analysis showed a symmetrical distribution.During the Egger's regression test, the p-value was 0.131, which indicated the absence of publication bias.

Discussion
In this systematic review and meta-analysis, we explored the prevalence and determinants of neonatal hypothermia in Eastern Africa.14 studies were included in the nal analysis.Based on the meta-analysis a signi cant proportion (more than 1 in 2) of neonates had neonatal hypothermia in Eastern Africa.This shows that neonatal hypothermia is a signi cant public health problem in Eastern Africa.We also identi ed factors that were signi cantly associated with neonatal hypothermia in Eastern Africa.In this study, the pooled prevalence of neonatal hypothermia in Eastern Africa was 57.22 %( 95%CI; 39.48-74.95).The results of this meta-analysis were in line with other systematic review, prevalence of hypothermia ranges from 32% to 85% (33).
The results of this meta-analysis were higher than review conducted in Iran which was 7.48 to 53.3 percent (34).
Lower than a review in sub Saharan Africa, a prevalence rate of 62% (35).These differences might be due to the socioeconomic and cultural differences between the countries.Moreover, the other obvious reason for the various might be the sample size, a collection of data from different settings (community and institution setting) as well as different study periods.
Delay in initiation of breastfeeding, having neonatal health problem, being low birth weight, being preterm, and night time delivery were identi ed factors which signi cantly increase the risk of neonatal hypothermia.Similar nding was also reported from the meta-analysis [30][31][32].

Conclusion
The prevalence of neonatal hypothermia in Eastern Africa remains high.Delay in initiation of breastfeeding, having neonatal health problem, being low birth weight, being preterm, and nighttime delivery were identi ed factors which signi cantly increase the risk of neonatal hypothermia.It is recommended that early initiation of breast feeding should be promoted and emphasis should be given towards low birth weight, preterm and neonates with neonatal problems to prevent burdens of hypothermia in East Africa.This review may help policy-makers and program o cers to design neonatal sepsis preventive interventions.

Strength and limitations
This study has several strengths: First, we used a pre-speci ed protocol for search strategy and data abstraction and conducted quality assessment two independent investigators to lessen the possible assessor bias; second, we employed subgroup and sensitivity analysis based on study country, study design, and publication year to identify the small study effect and the risk of heterogeneity.Nevertheless, this review had some limitations: The result in this meta-analysis is derived from studies conducted in hospital settings, and this limits the generalizability of the review ndings.

Recommendations
Hypothermia prevention messages and interventions into evidence-based, cost-effective packages for maternal and newborn care should be introduced.Attention is needed for thermal care of newborn especially those preterm, low birth weight and newborns with health problems on early initiation of breastfeeding immediately after delivery.It is also important to give attention babies delivered during nighttime.Forest plot for pooled estimate of preterm

Figure 6 Forest
Figure 6

Figure 7 Forest
Figure 7

Figure 8 Forest
Figure 8

Table 2 :
Subgroup analysis of the prevalence of neonatal hypothermia Eastern Africa by country, year of publication

Table 3 :
Identified associated factors for neonatal hypothermia from studies in East Africa, January 2000 -2019.