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International Journal of Pediatrics & Adolescent Medicine logoLink to International Journal of Pediatrics & Adolescent Medicine
. 2020 Feb 18;7(1):2–8. doi: 10.1016/j.ijpam.2020.02.004

Review of the evidence for interventions to reduce perinatal mortality in low- and middle-income countries

Vivek V Shukla 1, Waldemar A Carlo 1,∗
PMCID: PMC7193071  PMID: 32373695

Abstract

Low- and middle-income countries contribute to the overwhelming majority of the global perinatal and neonatal mortality. There is a growing amount of literature focused on interventions aimed at reducing the healthcare gaps and thereby reducing perinatal and neonatal mortality in low- and middle-income countries. The current review synthesizes available evidence for interventions that have shown to improve perinatal and neonatal outcomes. Reduction in important gaps in the availability and utilization of perinatal care practices is needed to end preventable deaths of newborns.

Keywords: Stillbirth, Mortality, Fetal, Perinatal mortality, Developing countries

1. Introduction

The perinatal period in life has the highest risk for mortality [1]. Annually, there is an estimated 4 million perinatal and neonatal deaths [[2], [3], [4]]. Estimates show that low- and middle-income countries contribute to approximately 98% of all perinatal deaths [2,3,5,6]. Because of the suboptimal vital registry infrastructure in low- and middle-income countries, it is likely that the total perinatal and neonatal deaths in these countries are even higher [7,8]. The contribution of neonatal mortality to the under-five mortality has been steadily rising [9] because post neonatal child mortality is decreasing faster than neonatal mortality. Home births and lack of trained neonatal care providers at birth in low- and middle-income countries are the most likely factors responsible for high perinatal and neonatal deaths [6,[10], [11], [12]]. In 2009, 60 million deliveries were estimated to occur outside health facilities [13]. Out of those 60 million deliveries, approximately 52 million deliveries happen without the presence of a trained birth attendant [11,14]. In low- and middle-income countries health facilities are inadequately equipped and lack trained neonatal care providers [6,15,16]. The limited quality of perinatal care and the neonates’ inherent low capacity to compensate in adverse conditions or diseases results in high rates of neonatal mortality in low- and middle-income countries [6,[17], [18], [19], [20], [21]]. The objective of this review is to synthesize and to evaluate the interventional and observational studies designed to assess antenatal, intrapartum, and neonatal interventions aimed to reduce perinatal and neonatal mortality in low- and middle-income countries. (see Table 1)

Table 1.

Meta-analyses focusing on interventions to reduce perinatal mortality.

Period of intervention Intervention n name Year of meta-analysis Publication year of included studies Number of studies included Types of trials included Number of participants Effects studied & size (95% CI)
Antenatal Antenatal care [25] 2018 2009–2017 18 Cross sectional & case-control studies 94,118 neonates NM RR = 0.66 (0.54–0.80)
Antenatal care, sub-Saharan Africa [26] 2019 2009–2019 12 Cohort & cross-sectional studies 79,990 neonates NM RR = 0.61 (0.43–0.86)
Birth interval < 18 months [28] 2013 1982–2004 5 Cohort studies 32,670 neonates SGA OR = 1.51 (1.31–1.75)
Prematurity OR = 1.58 (1.19–2.10)
NM OR = 1.49 (0.93–2.37)
IM OR = 1.83 (1.19–2.81)
Tetanus toxoid vaccination [29] 2010 1966–1998 2 RCT & cohort study 2146 neonates NM from tetanus infection RR = 0.06 (0.02–0.2)
Nutrition education [34] 2015 1973–2014 17 RCT 9030 women Prematurity RR = 0.46 (0.21–0.98)
LBW RR = 0.04 (0.01–0.14)
Iron supplementation [35] 2015 1947–2012 61 RCT & quasi-RCT 43,274 women LBW RR = 0.84 (0.69–1.03)
Prematurity RR = 0.93 (0.84–1.03)
NM RR = 0.91 (0.71–1.18)
Vitamin A supplementation [36] 2015 1993–2011 19 RCT, quasi-RCT, & cluster RCT 310,000 women PM RR = 1.01 (0.95–1.07)
NM RR = 0.98 (0.94–1.01)
Vitamin C supplementation [37] 2015 1966–2014 29 RCT & quasi-RCT 24,300 women SB RR = 1.15 (0.89–1.49)
PM RR = 1.07 (0.77–1.49)
NM RR = 0.79 (0.58–1.08)
Vitamin D supplementation [38] 2019 1980–2017 30 RCT, quasi-RCT, & cluster RCT 7033 women Prematurity RR = 0.66 (0.34–1.34)
LBW RR = 0.55 (0.35–0.87)
Multi-micronutrient supplementation [39] 2019 1975–2014 21 RCT 142,496 women Very preterm neonates RR = 0.81(0.71–0.93)
SGA RR = 0.92 (0.88–0.97)
LBW RR = 0.88 (0.85–0.91)
Prematurity RR = 0.95 (0.90–1.01)
SB RR = 0.95 (0.86–1.04)
PM RR = 1.00 (0.90–1.11)
NM RR = 1.00 (0.89–1.12)
Delivery Basic neonatal resuscitation [42] 2011 1985–2011 24 Observational, quasi-experimental, & cluster RCT 392,506 neonates Intrapartum-related deaths RR = 0.70 (0.59–0.84)
Basic neonatal resuscitation [43] 2017 1990–2016 20 RCT, quasi-RCT, interrupted time series, & before–after studies 1,653,805 neonates SB RR = 0.79 (0.44–1.41)
7-day NM RR = 0.53 (0.38–0.73)
28-day NM RR = 0.50 (0.37–0.68)
PM RR = 0.63 (0.42–0.94)
Skilled birth attendant [45] 2011 1989–2008 21 Pre-post cohort studies Not mentioned SB RR = 0.77 (0.69–0.85)
Clean delivery practices [46] 2011 1991–2010 38 Case-control & cohort studies Not mentioned Provider handwashing & NM RR = 0.19 (0.01–0.34)
Maternal handwashing
& NM RR = 0.44 (0.18–0.62)
Health facility delivery [59] 2013 1996–2012 19 Cohort & cross-sectional studies 1,606,805 neonates NM RR = 0.71 (0.54–0.87)
Health facility delivery [60] 2019 2010–2017 19 Cohort & cross-sectional studies 1,046,362 neonates NM OR = 0.48 (0.38–0.58)
Post Delivery & Neonatal Umbilical cord chlorhexidine application [61] 2016 2006–2013 6 RCT, quasi-RCT, & cluster RCT 59,179 neonates NM RR = 0.85 (0.76–0.95)
Omphalitis RR = 0.71 (0.62–0.81)
Exclusive breastfeeding [62] 2015 1982–2011 11 Observational studies 70,976 neonates NM OR = 3.67 (2.04–6.61)
Kangaroo mother care [63] 2016 1988–2016 21 RCT 3041 neonates NM RR = 0.60 (0.39–0.92)
Sepsis RR = 0.35 (0.22–0.54)
Hypothermia RR = 0.28 (0.16–0.49)
Kangaroo mother care [64] 2016 1988–2014 124 RCT & observational studies Not mentioned NM RR = 0.64 (0.46–0.89)
Sepsis RR = 0.53 (0.34–0.83)
Hypothermia RR = 0.22 (0.12–0.41)
Combined Antenatal &Postnatal Education [65] 2019 1995–2017 33 RCT, quasi-RCT, & cluster RCT Not mentioned NM RR = 0.87 (0.78–0.96)
Early NM RR = 0.74 (0.66–0.84)
Late NM RR = 0.54 (0.40–0.74)
PM RR = 0.83 (0.75–0.91)
Education [66] 2011 2008–2011 4 RCT 57270 neonates NM OR = 0.81 (0.75–0.88)
Early NM OR = 0.80 (0.70–0.91)
Late NM OR = 0.79 (0.63–0.99)
Education [67] 2017 2001–2017 17 Cluster-RCT Not mentioned NM RR = 0.75 (0.69–0.80)
Home based antenatal & neonatal care [69] 2016 2008–2012 5 Cluster-RCT 101,655 neonates NM RR = 0.75 (0.61–0.92)
PM RR = 0.78 (0.64–0.94)
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SGA = small for gestational age, LBW = low birth weight, SB = stillbirth, PM = perinatal mortality, NM = neonatal mortality, IM = infant mortality, OR = odds ratio, RR = risk ratio.

2. Antenatal interventions

2.1. Antenatal care

Antenatal care has been shown to be associated with improved perinatal outcomes in low- and middle-income countries [22,23]. In a study based on cross-sectional data from 57 low- and middle-income countries (N = 464,728), regular antenatal care was associated with a lower risk of neonatal mortality (HR = 0.45, 95% CI = 0.42–0.48) [24]. In a meta-analysis of cross sectional and case-control studies, antenatal care was found to be associated with a lower in neonatal mortality (RR = 0.66, 95% CI 0.54–0.80) [25]. In a meta-analysis of cohort and cross-sectional studies only from sub-Saharan Africa, antenatal care was found to be associated with a lower in neonatal mortality (RR = 0.61, 95% CI 0.43–0.86) [26], There has not been a meta-analysis of comprehensive antenatal care in low- and middle-income countries. However, improved antenatal care and a program of emergency obstetric and neonatal care did not reduce perinatal or neonatal mortality in a recent large and well-conducted randomized controlled trial [27].

2.2. Birth interval

Increasing the birth interval between pregnancies is associated with less adverse neonatal outcomes. In a meta-analysis assessing cohort studies of birth interval, birth interval <18 months was associated with a higher risk of small for gestational age (aOR = 1.51, 95% CI 1.31–1.75), prematurity (aOR = 1.58, 95% CI = 1.19–2.10), neonatal mortality (aOR = 1.49, 95% CI 0.93–2.37) and infant mortality (aOR = 1.83, 95% CI = 1.19–2.81) [28].

2.3. Tetanus toxoid vaccination

In a meta-analysis based on one randomized controlled trial and one cohort study to assess the effect of tetanus vaccination on neonatal mortality, two doses of tetanus vaccine administered to the mother before delivery reduced neonatal mortality from tetanus infection (RR = 0.06 95% CI 0.02–0.2) [29].

2.4. Antenatal corticosteroids

Evidence from many well-designed randomized controlled clinical trials conducted in higher-income countries and the respective meta-analyses indicate that antenatal corticosteroids reduce neonatal mortality and major morbidities [30]. Data on the effect of antenatal corticosteroids on preterm neonatal outcomes from low-income countries are limited. In a multi-country cluster randomized controlled trial of antenatal corticosteroids in women at high risk of preterm delivery (N = 98,137), 28-day neonatal mortality increased in the antenatal steroid group compared to the control group (RR 1.12, 1.02–1.22, P = .0127). Furthermore, there was an increased incidence of suspected maternal infection in the antenatal steroid group (OR = 1.45, 95% CI = 1.33–1.58, P < .0001) [31]. The ongoing trial of antenatal corticosteroid and its impact on perinatal outcomes from low-income countries will help in further understanding the role of antenatal corticosteroids on outcomes [32].

2.5. Antenatal ultrasound

A multi-country cluster-randomized controlled trial from low-income countries of two antenatal ultrasound assessments in addition to standard care showed no significant difference in antenatal care coverage, hospital delivery of complicated pregnancies, or composite outcome of adverse perinatal outcomes including stillbirth and neonatal mortality [33].

2.6. Antenatal nutrition

A meta-analysis of randomized controlled trials of antenatal nutritional education and perinatal outcomes showed that antenatal nutrition education decreased preterm birth (RR = 0.46, 95% CI = 0.21–0.98) and low birth weight (RR = 0.04, 95% CI = 0.01–0.14). Other perinatal outcomes did not differ between the two groups [34]. A meta-analysis of randomized controlled and quasi-randomized controlled trials assessing antenatal iron supplementation and pregnancy outcomes showed that antenatal iron supplementation was associated with a trend towards the decreased risk of low birth weight (RR = 0.84, 95% CI 0.69–1.03), prematurity (RR = 0.93, 95% CI 0.84–1.03), and neonatal mortality (RR = 0.91, 95% CI 0.71–1.18) [35]. A meta-analysis of randomized controlled, quasi-randomized controlled, and cluster randomized controlled trials showed that antenatal vitamin A supplementation did not impact perinatal (RR = 1.01, 95% CI 0.95–1.07) or neonatal mortality (RR = 0.98, 95% CI 0.94–1.01) [36]. In a meta-analysis of randomized controlled and quasi-randomized controlled trials of antenatal vitamin C supplementation and perinatal outcomes, vitamin C was not found to be associated with any significant impact on stillbirth (RR = 1.15, 95% CI 0.89–1.49), perinatal mortality (RR = 1.07, 95% CI 0.77–1.49), and neonatal mortality (RR = 0.79, 95% CI 0.58–1.08) [37]. A meta-analysis of randomized controlled, quasi-randomized controlled, and cluster randomized controlled trials showed that vitamin D supplementation had no effect on preterm birth (RR = 0.66, 95% CI 0.34–1.34) but was associated with decrease in low birth weight (RR = 0.55, 95% CI 0.35–0.87). However, vitamin D with calcium supplementation was associated with increased prematurity (RR = 1.57, 95% CI 1.01–2.28) [38]. In another meta-analysis of randomized controlled trials assessing the effect of multi-micro nutrient supplementation on pregnancy outcomes, multi-micro nutrient supplementation was associated with reduction in very preterm neonates (RR = 0.81, 95% CI 0.71–0.93), small for gestation age (RR = 0.92, 95% CI 0.88–0.97), and low birth weight (RR = 0.88, 95% CI 0.85–0.91). Multi-micro nutrient supplementation was associated with a trend of reduced prematurity (RR = 0.95, 95% CI 0.90–1.01) and stillbirth (RR = 0.95, 95% CI 0.86–1.04). Multi-micro nutrient supplementation did not decrease perinatal (RR = 1.00, 95% CI 0.90–1.11) and neonatal mortality (RR = 1.00, 95% CI 0.89–1.12) [39].

2.7. Genitourinary tract infection screening and treatment

Genitourinary tract infection screening is being widely adopted in developed countries. A meta-analysis of randomized controlled trials showed that treatment of asymptomatic genitourinary infection reduced low birth weight births (adjusted RR, aRR = 0.64, 95% CI 0.45–0.93) and prematurity (RR = 0.27, 95% CI 0.11–0.62) [40]. However, the quality of evidence in this meta-analysis was deemed low for both outcomes because all fourteen studies included in the meta-analysis were from 1960 to 1987. Furthermore, the description of the methods was not clear. All studies had high or unclear risk of bias [40]. However, a recent cluster-randomized controlled trial antenatal genitourinary tract infection screening from a low-income country reported no difference in prematurity (RR = 1.07, 95% CI 0.91–1.24) [41].

3. Labor and delivery intervention

3.1. Basic neonatal resuscitation

A meta-analysis of observational, quasi-experimental, and cluster randomized controlled trials in resource-limited settings showed that basic neonatal resuscitation decreased intrapartum-related deaths (RR = 0.70, 95% CI 0.59–0.84) [42]. Another meta-analysis of randomized, quasi-randomized controlled trials, interrupted time series studies, and before–after studies showed that basic neonatal resuscitation training decreased in stillbirths (RR = 0.79, 95% CI 0.44–1.41), 7-day neonatal mortality (RR = 0.53, 95% CI 0.38–0.73), 28-day neonatal mortality (RR = 0.50, 95% CI 0.37–0.68), and perinatal mortality (RR = 0.63, 95% CI 0.42–0.94). The meta-analysis of pre- and post-neonatal resuscitation training studies including an active baseline study showed that neonatal resuscitation training was associated with lower rates of stillbirths (RR = 0.88, 95% CI 0.83–0.94), fresh stillbirths (RR = 0.74, 95% CI 0.61–0.90), 1-day neonatal mortality (RR = 0.58, 95% CI 0.42–0.82), 7-day neonatal mortality (RR = 0.82, 95% CI 0.73–0.93), and perinatal mortality (RR = 0.82, 95% CI 0.74–0.91) [43].

A systematic review of cohort pre-post design trials showed that implementation of Helping Babies Breathe was associated with a significant decrease in perinatal mortality (RR = 0.75, p < 0.001), intrapartum-related stillbirths (RR 0.31–0.76), 1-day neonatal mortality (RR 0.37–0.67), and 7-day neonatal mortality (RR 0.32) [44].

3.2. Presence of skilled birth attendant at delivery

A meta-analysis of pre-post cohort design trials showed that the presence of a skilled birth attendant in the delivery was associated with a reduction in stillbirths (RR = 0.77, 95% CI 0.69–0.85) [45].

3.3. Clean delivery and resuscitation practice

A meta-analysis of case-control and cohort studies of clean delivery and neonatal care practice, resuscitation provider handwashing (19%, 95% CI 1–34%), maternal handwashing (44%, 95% CI 18–62%), clean delivery (at home (15%, IQR 10–20%) or in a facility (27%, IQR 24–36)), and clean after birth practices (40%, IQR 25–50%) were found to be associated with a lower neonatal mortality [46].

3.4. Delayed cord clamping

Delayed cord clamping is beneficial for both term (increased iron stores, decreased risk of anemia) and preterm neonates (reduction in mortality, reduction in the risk for anemia and blood transfusion requirement, improved hemodynamic stability, and reduction in the incidence of intraventricular hemorrhage and necrotizing enterocolitis) [[47], [48], [49], [50], [51], [52]]. Being a simple and effective intervention, delayed cord clamping has been recommended in all major basic neonatal resuscitation guidelines ([[53], [54], [55], [56], [57], [58]]).

3.5. Health facility delivery

Two meta-analyses of cohort and cross-sectional studies showed that health facility delivery was associated with a lower neonatal mortality as compared to home delivery (RR = 0.71, 95% CI 0.54–0.87) (59) and (OR = 0.48, 95% CI 0.38–0.58) [60].

4. Post-delivery and neonatal interventions

4.1. Umbilical cord chlorhexidine application

A meta-analysis based on randomized controlled, quasi-randomized controlled, and cluster randomized controlled trials showed that application of chlorhexidine on the umbilical cord decreased neonatal mortality (RR = 0.85, 95% CI 0.76–0.95) and omphalitis (RR = 0.71, 95% CI 0.62–0.81) [61].

4.2. Exclusive breastfeeding

A meta-analysis of observational studies of breastfeeding and perinatal outcomes showed that exclusive breastfeeding was associated with a lower neonatal mortality (OR for non-exclusively breastfeeding = 3.67, 95% CI 2.04–6.61) [62].

4.3. Kangaroo mother care

A meta-analysis of randomized controlled trials showed that kangaroo mother care decreased neonatal mortality (RR = 0.60, 95% CI 0.39–0.92), sepsis (RR = 0.35, 95% CI 0.22–0.54), and hypothermia (RR = 0.28, 95% CI 0.16–0.49) [63]. Another meta-analysis of randomized controlled trials and observational studies showed that kangaroo mother care in low birth weight neonates decreased neonatal mortality (RR = 0.64, 95% CI 0.46–0.89), sepsis (RR = 0.53, 95% CI 0.34–0.83), and hypothermia (RR = 0.22, 95% CI 0.12–0.41) [64].

5. Interventions focusing on antenatal and postnatal periods

5.1. Education

A meta-analysis of randomized controlled, quasi-randomized, and cluster-randomized controlled trials showed that community health educational interventions decreased neonatal mortality (RR = 0.87, 95% CI 0.78–0.96), early neonatal mortality (RR = 0.74, 95% CI 0.66–0.84), late neonatal mortality (RR = 0.54, 95% CI 0.40–0.74), and perinatal mortality (RR = 0.83, 95% CI 0.75–0.91) [65]. A meta-analysis of randomized controlled trials found that community-based behavioural interventions reduced neonatal mortality (aOR = 0.81, 95% CI 0.75–0.88), early neonatal mortality (aOR = 0.80, 95% CI 0.70–0.91), and late neonatal mortality (aOR = 0.79, 95% CI 0.63–0.99) [66]. In another meta-analysis of cluster-randomized trials, community-based interventions reduced neonatal mortality (RR = 0.75, 95% CI 0.69–0.80) [67].

5.2. mHealth interventions

A meta-analysis based on randomized controlled and quasi-experimental trials showed that mHealth interventions increased antenatal care (MD = 0.67, 95% CI = 0.35–0.99) and postnatal care (OR = 1.36, 95% CI = 1.00–1.85), but their effect on neonatal mortality was not adequately reported [68].

5.3. Home based antenatal and neonatal care

A meta-analysis of cluster-randomized trials showed that home-based antenatal and neonatal care reduced neonatal mortality (RR = 0.75, 95% CI 0.61–0.92) and perinatal mortality (RR = 0.78, 95% CI 0.64–0.94) [69]. 9 (Fig. 1).

Fig. 1.

Fig. 1

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Interventions and their effect on neonatal mortality. Not included in the Forest Plot are the meta-analysis that assessed individual cause specific mortality and those with unclear participant size. RR = risk ratio, OR = odds ratio.

6. Conclusion

Many effective interventions are associated with reduced neonatal mortality. Evidence-based interventions that improve neonatal survival should be scaled up to reduce preventable perinatal deaths. Given the magnitude of perinatal and neonatal mortality burden in low- and middle-income countries and existing gaps in healthcare availability and utilization, focused and quality interventional trials are needed to elucidate further interventions that might be of the highest benefit for improving neonatal survival. Packages of care focused on groups of interventions from pre-pregnancy to postnatal care with concurrent capacity building of local health infrastructure could identify the strategies to optimize the reduction of preventable deaths.

Footnotes

Peer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.

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