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4
inkages Among Reproductive Health,aternal Health, and Perinatal Outcomes
ulfiqar A. Bhutta,* Zohra S. Lassi,* Ann Blanc,† and France Donnay‡
Some interventions in women before and during pregnancy may reduce perinatal and neonataldeaths, and recent research has established linkages of reproductive health with maternal,perinatal, and early neonatal health outcomes. In this review, we attempted to analyze theimpact of biological, clinical, and epidemiologic aspects of reproductive and maternal healthinterventions on perinatal and neonatal outcomes through an elucidation of a biologicalframework for linking reproductive, maternal and newborn health (RHMNH); care strategiesand interventions for improved perinatal and neonatal health outcomes; public health implica-tions of these linkages and implementation strategies; and evidence gaps for scaling up suchstrategies. Approximately 1000 studies (up to June 15, 2010) were reviewed that have ad-dressed an impact of reproductive and maternal health interventions on perinatal and neonataloutcomes. These include systematic reviews, meta-analyses, and stand-alone experimentaland observational studies. Evidences were also drawn from recent work undertaken by theChild Health Epidemiology Reference Group (CHERG), the interconnections between maternaland newborn health reviews identified by the Global Alliance for Prevention of Prematurity andStillbirth (GAPPS), as well as relevant work by the Partnership for Maternal, Newborn and ChildHealth. Our review amply demonstrates that opportunities for assessing outcomes for bothmothers and newborns have been poorly realized and documented. Most of the interventionsreviewed will require more greater-quality evidence before solid programmatic recommenda-tions can be made. However, on the basis of our review, birth spacing, prevention of indoor airpollution, prevention of intimate partner violence before and during pregnancy, antenatal careduring pregnancy, Doppler ultrasound monitoring during pregnancy, insecticide-treated mos-quito nets, birth and newborn care preparedness via community-based intervention packages,emergency obstetrical care, elective induction for postterm delivery, Cesarean delivery forbreech presentation, and prophylactic corticosteroids in preterm labor reduce perinatal mor-tality; and early initiation of breastfeeding and birth and newborn care preparedness throughcommunity-based intervention packages reduce neonatal mortality. This review demonstratesthat RHMNH are inextricably linked, and that, therefore, health policies and programs shouldlink them together. Such potential integration of strategies would not only help improveoutcomes for millions of mothers and newborns but would also save scant resources. Thiswould also allow for greater efficiency in training, monitoring, and supervision of health careworkers and would also help families and communities to access and use services easily.Semin Perinatol 34:434-445 © 2010 Elsevier Inc. All rights reserved.
KEYWORDS reproductive health, maternal health, neonatal health, intrapartum, postpartum, perinatal
Epthsci
Division of Women and Child Health, the Aga Khan University, Karachi,Pakistan.
Engender Health, New York, NY.Division of Family Health, Bill & Melinda Gates Foundation, Seattle, WA.ddress reprint requests to Zulfiqar A. Bhutta, Division of Women and Child
Health, The Aga Khan University, Karachi, Pakistan. E-mail:
[email protected]34 0146-0005/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1053/j.semperi.2010.09.002
very year an estimated 3.6 million infants die in the first4 weeks of life.1,2 Of these deaths, maternal health com-
lications contribute to 1.5 million neonatal deaths duringhe first week of life and 1.4 million stillborn infants.3 Theighest neonatal mortality rates and rates of stillbirth occur inub-Saharan Africa, followed by Asia and Latin America. Inountries in which the mortality is greatest, almost 10% ofnfants do not survive longer than 1 month.
Globally, the main direct causes of neonatal death are es-
imated to be preterm birth, severe infections, and asphyxia.
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Reproductive health, maternal health, and perinatal outcomes 435
ow birth weight and maternal complications also carry aigh risk of neonatal death.4 Maternal reproductive healthnd nutrition are important for perinatal health, and mater-al infections contribute to adverse outcomes.Techniques for treating most critical medical problems
nd complications have been available for more than half aentury. The benefits are the greatest when there is a contin-um of care throughout prepregnancy, pregnancy, child-irth, and the postpartum period. Although care duringhildbirth is most crucial, antenatal care plays an importantole, primarily because it offers an important means of ad-ressing other health care needs, such as family planning,
mmunization against tetanus, and the prevention and treat-ent of human immunodeficiency virus (HIV) infection,
ther sexually transmitted infections (STIs), and malaria.Recent research has established linkages of reproductive
ealth with maternal, perinatal, and early neonatal healthutcomes. Children born 36 to 41 months after their nextlder sibling have a lower risk of neonatal and infant death asell as a lower risk of maternal death, third trimester bleed-
ng, and premature rupture of the membranes, puerperalndometritis, and anemia compared with births spaced 9 to4 months apart. Apart from birth spacing, preventing teen-ge pregnancy is also an important factor for reduced perina-al mortality. Young mothers often are not physically maturenough to deliver a baby, leaving her and her child at risk foreath or disabilities from obstructed labor, fistula, prematureirth, or low birth weight. At the same time, early childbirthegatively affects the educational and economic opportuni-ies of women and their children. Out-of-school girls areore likely to give birth than girls in school, and girls that
ecome pregnant while in school are more likely to drop outnd not complete their education. Women with lower edu-ational attainment have greater rates of maternal mortality,re less knowledgeable about health-prevention activities,nd are more likely to live a life of poverty. Their childrenave fewer options and are also more likely to die.On the basis of the potential health benefits of providing
ackaged interventions, focused and rapid actions areeeded if significant progress is to be made toward reachinghe Millennium Development Goal (MDG) targets related toaternal and child health. Reductions in perinatal mortality
an be achieved through various elements, such as the use ofvidence-based treatments and interventions, the use of aealth systems approach, the use of information technology,lobal and regional partnerships, and making pregnancyafer through initiatives that increase the focus on humanights.3 Although there have been several efforts at definingtrategies for maternal, newborn, and child survival and de-elopment in recent Lancet series and other publications,5-9
here have been relatively few efforts to identify synergies andntegrate these interventions across the continuum ofare.10,11 Some reviews in the past have evaluated the cost-ffectiveness of individual interventions12-14 and interventionackages, such as community-based newborn care packages,ntenatal care (tetanus toxoid, screening for pre-eclampsia,creening and treatment of asymptomatic bacteriuria and
yphilis), skilled attendance at birth, and emergency obstet- iical and neonatal care.13 However, only a few systematicfforts have been attempted to take advantage of potentialynergies in defining key interventions that integrate repro-uctive and maternal newborn health (RHMNH) with peri-atal outcomes.In this review, we attempt to define the linkages among
eproductive, maternal, and neonatal health. We have alsonalyzed the impact of biological, clinical, and epidemiologicspects of reproductive and maternal health interventions onerinatal outcomes through an elucidation of a biologicalramework for linking RHMNH; common risk factors under-coring the risks across RHMNH; care strategies and inter-entions for improved perinatal and neonatal health out-omes; public health implications of these linkages andmplementation strategies; and evidence gaps for scaling upuch strategies.
ethodshis review systematically evaluates reproductive and mater-al health interventions to prevent perinatal and neonatalortality. We identified all socially, epidemiologically, and
iologically plausible direct and indirect reproductive andaternal health interventions (Fig. 1) that have a potential
inkage with perinatal and neonatal mortality. Table 1 illus-rates the final interventions and reported perinatal and neo-atal mortality outcomes included in this review. We re-iewed approximately 1000 studies in which the authorsave addressed an impact of reproductive and maternalealth interventions on perinatal and neonatal outcomes, in-luding systematic reviews, meta-analyses, and stand-alonexperimental and observational studies. The search enginessed were PubMed and The Cochrane Library. Search terms
ncluded were “perinatal mortality,” “perinatal death*,” “neo-atal mortality,” “neonatal death*.” Targeted search termsere also used for each intervention (eg, “calcium” AND
supplementation” AND “pregnancy”; and “multiple micro-utrient” AND “pregnancy”). The last search date was June5, 2010. As much as possible, we have relied upon synthe-ized consensus statements and Cochrane reviews. We alsorew evidence from recent work undertaken by the Childealth Epidemiology Reference Group, the interconnectionsetween maternal and newborn health reviews identified byhe Global Alliance to Prevent Pregnancy and Stillbirth,15 asell as relevant work by the Partnership for Maternal, New-orn & Child Health.16,17
esultshe interventions reviewed in this section are classified ac-ording to service delivery strategies across the continuum ofare. The narrative is restricted to interventions for which aeasonable level of evidence is present. This review of thevidence indicates a remarkable paucity of data on perinatalnd neonatal mortality outcomes for many potentially rele-ant interventions. (Interventions estimates are summarized
n Table 2.)
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are Strategies and Interventionsor Improved Perinatal andeonatal Health Outcomes
repregnancyericonceptual Folic Acid Supplementationolic acid supplementation involves ingesting either foliccid tablets or eating foods that have been enriched with foliccid. Most women, especially those about to become preg-ant, need 0.4 mg (400 �g) of folic acid daily. Evidence fromhe Cochrane review, including 3 trials, by Lumley et al,18
howed that periconceptual folic acid supplementation has aignificant protective effect on neural tube defects (relative riskRR] � 0.28, 95% confidence interval [CI] � 0.13-0.58), but nompact on perinatal mortality; however, they reported a reducedut nonsignificant impact on stillbirths (RR � 0.78, 95% CI �.34-1.78). Rumbold et al19 also reported a nonsignificant re-uction in the rates of perinatal mortality (RR � 0.51, 95% CI �.05-5.54) when folic acid and multivitamin supplementationas compared with no supplementation.
irth Spacing/Family Planningamily planning involves choice of when to have childrennd the use of birth control to delay or avoid pregnancy.amily planning services are defined as “educational, com-rehensive medical or social activities which enable individ-als, including minors, to determine freely the number andpacing of their children and to select the means by which
Figure 1 Framework of linkages between reproductive(Color version of figure is available online.)
his may be achieved.” u
The relationship of birth spacing with improved neonatalnd infant outcomes is well described. In an analysis of De-ographic Health Surveys from 17 countries, Rutstein20
oted increasing risk of neonatal mortality with short birthntervals and recommended that the optimal birth intervalas 36 months. Stephansson, et al,21 by using a logistic re-ression analysis on the Swedish registry data, showed thatompared with interpregnancy intervals of 12-35 months,nterpregnancy intervals of �72 months were linked to anncreased and significant risk of stillbirths (adjusted oddsatio [aOR] � 1.5, 95% CI � 1.1-2.1) and increased thoughonsignificant risk of early neonatal deaths (aOR � 1.3, 95%I � 0.9-2.1).
uring Pregnancyntenatal Carentenatal Care During Pregnancy. Antenatal care includes
ecording medical history, assessment of individual needs,dvice and guidance on pregnancy and delivery, screeningests, education on self-care during pregnancy, identificationf conditions detrimental to health during pregnancy, first-ine management, and referral if necessary. Humphrey et al22
eported a significant increase in the risk of perinatal mortal-ty (OR � 6.3, 95% CI � 3.72-10.69) when antenatal careas not accessed.
ardiotocographic Monitoring. Cardiotocography (CTG) istechnical means of recording the fetal heartbeat and the
aternal health with perinatal and neonatal outcomes.
and mterine contractions during pregnancy, typically in the third
Table 1 Strategies and Interventions Reviewed for Linkages
Reproductive Health
Maternal Health
During Pregnancy Intrapartum PostpartumHealth SystemsStrengthening
Periconceptual folicacid supplementationbirth spacing/familyplanning
Antenatal care● Cardiotocographic monitoring● Doppler and ultrasound
monitoringLifestyle modification● Smoking cessation● Indoor air pollution● Prevention of intimate partner
violenceNutritional interventions● Multiple micronutrient● Iron/folate supplementation● Zinc supplementation● Balance protein energyManagement of infection● Management of syphilis● Treatment of STIs● Treatment of HIV/AIDS● Prevention of malaria● Treatment of antihelminthic
infections
Management ofcomplications
● Management of diabetes● Antiplatelets for
prevention of pre-eclampsia
● Calciumsupplementation for PIH
● Antihypertensive for mildto moderatehypertension
● Magnesium suplhate forPIH
Birth and newborn carepreparedness
● Promotion of earlyinitiation ofbreastfeeding
● Community-basedinterventions
Prophylacticcorticosteroidtherapy forpreterm labor
Recognition and treatmentof mild postpartumdepression
Comprehensive emergencyobstetrical care
● Lower segment Cesareandelivery
● Instrumental delivery-postterm induction of labor
● Home delivery vs facilitybirths
Abbreviations: PIH, pregnancy-induced hypertension; STI, sexually transmitted infection.
Reproductivehealth,m
aternalhealth,andperinataloutcom
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rimester, and could potentially serve as an early indication ofn adverse environment and fetal distress. The Cochrane re-iew by Grivel et al23 included 6 studies regarding the impactf cardiotocography use on perinatal mortality in high- orntermediate-risk pregnancies. The review reported a trendoward increased, although nonsignificant, perinatal mortal-ty in the cardiotocography group versus controls receivingo monitoring (RR � 2.05, 95% CI � 0.95-4.42) and couldepresent selection biases within the study subjects. Compar-son of computerized CTG versus traditional CTG in theforementioned review showed a significant reduction inerinatal mortality with computed CTG (RR � 0.20, 95%I � 0.04-0.88, 2 studies).
oppler and Late Ultrasound Monitoring. Doppler ultra-ound is a technique to study the fetoplacental and/or utero-lacental circulatory dynamics. A Cochrane review included6 randomized controlled trials (RCTs) and quasi-RCTs
able 2 Summary Estimates of Reproductive Health and Mate
Intervention
Prepregnancy
Perinatal Neon
ericonceptual folic acid (FA andMMN vs placebo)
(RR � 0.51; 95% CI �
0.05-5.54)19
irth spacing (IPIs of 12-35 m vsIPIs of 72 m)
(aOR � 1.5; 95% CI �
1.1-2.1)21
(aOR � 1.30.9-2.1)21
bbreviations: aRR, adjusted risk ratio; CI, confidence interval; CIntermittent preventive treatment; ITN, insecticide-treated net;OR, odds ratio; PIH, pregnancy-induced hypertension; RR, ris
omparing umbilical artery Doppler ultrasound in compli- c
ated pregnancies with no Doppler, and found a significant1% reduction in perinatal mortality (RR � 0.71, 95% CI � 0.52-.98) but no effect on neonatal mortality (RR � 1.04, 95%I � 0.58-1.85).24
ifestyle Modificationmoking Cessation During Pregnancy. Smoking-cessationtrategies in pregnancy include provision of advice and coun-eling via the use of various tools (written and electronicesources and telephone support), cognitive behavioral ther-py and motivational interviewing, advice and counselingased on feedback of fetal health status or measurement ofyproducts of tobacco smoking in the mother, provision ofharmacologic agents (such as nicotine replacement therapynd bupropion), social support and encouragement, includ-ng the use of rewards for cessation and other interventions,uch as hypnosis. The impact of smoking cessation on peri-atal and neonatal mortality has been assessed in the Co-
ealth Interventions
Intervention
Antenatal care (when no anaic)
I � CTG monitoring (vs no monitoring)
Doppler ultrasound monitoring (vs control)
Management of diabetes (any treatment) (subcutaneous insulin)
Multiple micronutrient supplementation
Iron and FA supplementation (daily iron alone) (daily iron/FA)
Prevention of malaria (IPT vs control) (insecticide treated bed nets)
Balanced protein energy supplementation
Management of syphilis (with 3 penicillin doses)Treatment of STIs (antibiotic vs placebo)
Treatment of HIV/AIDS (Zidovudine)Zinc supplementationTreatment with antihelminthicSmoking cessationAntiplatelets for high risk pregnancyCalcium for hypertensive disordersAntihypertensive for hypertensionMagnesium-sulfate for PIH
Early initiation of breastfeeding (those partially breastfed)Community-based intervention packagesIntimate partner violence (during or before pregnancy)Indoor Air pollution (among women exposed to smoke) (among
women exposed to biomass fuel)
ardiotocography; FA, folic acid; IPI, interpregnancy interval; IPT,lower segment cesarean section; MMN, multiple micro nutrients;; STI, sexually transmitted infection.
rnal H
atal
; 95% C
TG, cLSCS,
hrane review by Lumley et al.25 According to this review,
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Reproductive health, maternal health, and perinatal outcomes 439
moking-cessation programs in pregnancy did not reduceerinatal mortality (RR � 1.13, 95% CI � 0.72-1.77), andhere were no statistically significant differences in neonatalortality (RR � 1.17, 95% CI � 0.34-4.01), but these anal-
ses had very limited power. In the recent Global Alliance torevent Prematurity and Stillbirth consultation on stillbirths,his was highlighted as a potentially effective interventionnd, given the diversity of findings from the studies available,urther studies and analyses were needed on the subject areasing novel designs.
ndoor Air Pollution. Cooking is usually the domain ofomen, especially in developing countries even during preg-ancy. Their homes are often crowded and poorly ventilated,
eading to intense smoke exposure that could harm the grow-ng fetus as smoke metabolites cross the placental barrier.tudies on the impact of indoor air pollution on perinatalealth are restricted to south Asian countries. In India, Ma-alankar et al26 found a significant increase in early neonataleath risk in a case control study among women exposed tomoke (OR � 1.28, 95% CI � 1.04-1.58). In Pakistan, Sid-
able 2 Continued
Pregnancy
Perinatal Neonatal
OR � 6.3; 95% CI � 3.72-10.69)22
OR � 2.05; 95% CI � 0.95-4.42)23
RR � 0.71; 95% CI � 0.52-0.98)24 (RR � 1.04; 95% CI � 0.58-1.85)24
RR � 0.09; 95% CI � 0.01-1.70)42
RR � 2.0; 95% CI � 0.20-19.91)41
RR � 1.07; 95% CI � 0.92-1.25)29 RR � 1.05; 95% CI � 0.92-1.19)29
RR � 0.93; 95% CI � 0.67-1.29)30
RR � 0.83; 95% CI � 0.58-1.17)30
PT (RR � 1.02; 95% CI � 0.73-1.43)36
TN(RR � 0.67; 95% CI � 0.47-0.97)38
IPT (RR � 1.07; 95% CI � 0.52-2.22)36
(RR � 0.63; 95% CI: 0.37-1.06)32
RR � 0.37; 95% CI � 0.18-0.76)33
(RR � 7.43; 95% CI � 0.15-374.24)34
(RR � 2.0; 95% CI � 0.61-6.54)35
RR � 0.93; 95% CI � 0.24-3.65)31
RR � 1.10; 95% CI � 0.55-2.22)39
RR � 1.13; 95% CI � 0.72-1.77)25 (RR � 1.17; 95% CI � 0.34-4.01)25
(RR � 0.86; 95% CI � 0.76-0.98)43
RR � 0.70; 95% CI � O.56-0.88)44 (RR � 0.89; 95% CI � 0.73-1.09)53
RR � 0.96; 95% CI � 0.60-1.54)47 (RR � 0.79; 95% CI � 0.14-4.34)47
RR � 1.04; 95% CI � 0.80-1.36)48 (RR � 1.34; 95% CI � 0.84-2.14)48
(RR � 1.59; 95% CI � 0.42-6.05)49
(RR � 1.77; 95% CI � 1.32-2.39)50
RR � 0.80; 95% CI � 0.71-0.90)52 (RR � 0.73; 95% CI � 0.66-0.81)52
aRR � 2.1; 95% CI � 1.3-3.4)28
OR � 1.5; 95% CI � 1.0-2.1)26
OR � 1.90; 95% CI � 1.10-3.20)27
iqui et al27 reported nearly a 2-fold greater risk of stillbirths a
n pregnant women exposed to biomass fuel (aOR � 1.90,5% CI � 1.10-3.20).
revention of Intimate Partner Violence. The Centers forisease Control defines intimate partner violence as any typef physical, sexual, or psychological harm by a current orormer partner or spouse. There are 4 kinds of violence:hysical, sexual, psychological/emotional, and threats ofhysical or sexual violence. Perinatal intimate partner vio-
ence is violence inflicted before, during, and/or after preg-ancy, up to 1 year postpartum (the childbearing year) by an
ntimate partner (eg, spouse, ex-spouse, boyfriend).Available data show that intimate partner violence against
omen before or during pregnancy has adverse impacts onhe fetus/newborn, such as greater risk of growth retardationnd can also lead to perinatal death (adjusted RR � 2.1, 95%I � 1.3-3.4).28
utritional Interventionsultiple Micronutrient Supplementation During Preg-
ancy. Multiple micronutrient supplementation is defined
Intervention
Childbirth
Perinatal Neonatal
induction of labor vsctant management
(RR � 0.30; 95% CI �
0.09-0.99)55
egment casesarianon (LSCS vs plannedal)
(RR � 0.29; 95% CI �
0.10-0.86)53
ental delivery (OR � 0.80; 95%CI � 0.18-3.52)54
lactic corticosteroidpy
(OR � 0.60; 95%CI � 0.48-0.75)57
elivery vs facility births (RR � 1.83; 95% CI �
0.99-3.38)56
Postermexpe
Lower-ssectivagin
Instrum
Prophythera
Home d
s supplementation with at least 5 micronutrients, including
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he supplement (called UNIMAP, Multiple Micronutrientreparation) of 1 daily recommended allowance of majoricronutrients, or those with comparable composition. Ac-
ording to a recent Cochrane review, multiple micronutrientupplementation had no adverse effect on perinatal mortalityRR � 1.07, 95% CI � 0.92-1.25) and neonatal mortalityRR � 1.05, 95% CI � 0.92-1.19) but was associated with aeduction in intrauterine growth retardation.29
ron and Folic Acid Supplementation During Pregnancy. Mostomen are unable to meet the demands of expanding red cell-ass and fetal growth in pregnancy without depleting their
tores of iron, and diet typically contains insufficient foliccid to prevent a reduction in tissue folate concentrations. Asresult, some pregnant women become anemic. Supple-ents of iron and folic acid daily are effective in maintaining
ron stores and folate state and in raising the hemoglobinoncentration in healthy pregnant women.
The Cochrane review by Pena-Rosas and Viteri30 onntenatal iron supplementation found no impact on peri-atal mortality with a daily dose of iron alone (RR � 0.93,5% CI � 0.67-1.29) or with a daily dose of iron and foliccid supplementation (RR � 0.83, 95% CI � 0.58-1.17)ompared with placebo.
inc Supplementation in Pregnancy. Zinc plays an impor-ant role in many biological functions, including protein syn-hesis and nucleic acid metabolism. Mild-to-moderate zinceficiency is common in low-income settings, where preg-ant women tend to consume less than the daily recom-ended daily intake of 15 mg. The recent Cochrane review of
7 studies reported no effects of zinc supplementation onerinatal mortality (RR � 0.93, 95% CI � 0.24-3.65), andeonatal morbidity (sepsis; RR � 0.19, 95% CI �.02-1.66).31
alanced Protein Energy Supplementation During Preg-ancy. Balanced protein/energy supplementation is nutri-ional supplementation during pregnancy in women forhom protein intake provide less than 25% of the total daily
nergy consumption. Targeted women for this interventionnclude malnourished women with a body mass index
18.5. Pooled results from 6 studies in Kramer andakuma32 indicated that the risk of neonatal mortality was
ower with balanced protein energy supplementation duringregnancy (RR � 0.62, 95% CI � 0.37-1.05), but the resultsid not reach statistical significance.
anagement of Infectionsanagement of STIs in Pregnancy, Including HIV/AIDS,
yphilis, Chlamydia. Treatment of syphilis during preg-ancy according to the Centers for Disease Control and Pre-ention 2002 “Guidelines for Treatment of Sexually Trans-itted Diseases” should be with penicillin with dosesependent upon the stage of syphilis. Studies show that treat-
ng syphilis (complete or incomplete treatment with 3 peni-illin doses) as a part of antenatal care reduces perinatal mor-ality by 63% (RR � 0.37, 95% CI � 0.18-0.76).33 The
ochrane review of evidence for impact of any antibiotic qherapy versus placebo for treatment of chlamydia showedo effect on neonatal survival (RR � 7.43, 95% CI �.15-374.24).34
IV/AIDS. Use of highly active antiretroviral therapy inursing, HIV-infected women reduces disease transmissiono infants. The use of zidovudine in pregnancy did not yieldtatistically significant results for neonatal mortality (RR �.0, 95% CI � 0.61-6.54).35 However, the evidence of highlyctive antiretroviral therapy on pregnancy outcomes is onlyeginning to trickle in and preliminary data suggest that these of this therapy is associated with improved outcomes in
nfancy.
revention of Malaria in Pregnancyntermittent Preventive Treatment. Intermittent preventivereatment (IPT) involves giving women presumptive therapyt fixed times during pregnancy, usually with drugs having aong half-life like sulfadoxine-pyrimethamine.36 By contrast,rophylaxis is therapy administered daily (eg, Proguanil) oreekly (chloroquine).36 A meta-analysis of 2 studies showednonsignificant impact on perinatal mortality (RR � 0.66,5% CI � 0.41-1.07) when any antimalarial drug preventionas compared with no intervention in women during their firstr second pregnancy.37 Although benefits of intermittent pre-entive treatment have been reported on antenatal parasitemiand placental malaria, in a Cochrane review of 16 trials, Garnernd Gülmezoglu36 found no effect of antimalarial treatment onerinatal deaths (RR � 1.02, 95% CI � 0.73-1.43) or neonataleaths (RR � 1.07, 95% CI � 0.52-2.22).
nsecticide-Treated Bed Nets. An insecticide-treated bednets a mosquito net that repels, disables, and/or kills mosqui-oes coming into contact with insecticide on the netting ma-erial. All mosquito nets act as a physical barrier, preventingccess by vector mosquitoes and thus providing personalrotection against malaria to the individual(s) using the nets.he use of insecticide-treated bednets during pregnancy was
ound to be effective in reducing fetal loss (RR � 0.67, 95%I � 0.47-0.97).38
ntihelminthic Treatment. Hookworm infestation is associ-ted with anemia in women and children in endemic areas. Inuch areas, routine antenatal mebendazole therapy couldreatly reduce the prevalence of anemia in pregnancy. A Co-hrane review by Haider et al39 showed no impact of antihel-inthics during pregnancy on perinatal mortality (RR �
.10, 95% CI � 0.55-2.22). An observational study from Srianka on the effect of mebendazole therapy during preg-ancy on birth outcomes showed that stillbirths and perina-al deaths were significantly less common among womenho received mebendazole as part of antenatal care (RR �.55, 95% CI � 0.4-0.77).40
anagement of Complications During Pregnancyanagement of Diabetes in Pregnancy. The management of
iabetes includes glycemic control efforts through diet, exer-ise, and/or insulin therapy with glucose monitoring, fre-
uent fetal surveillance using tests of fetal well-being, and/or
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Reproductive health, maternal health, and perinatal outcomes 441
nduction at or before term. There are 2 main Cochrane re-iews41,42 that have discussed different aspects of manage-ent of maternal diabetes during pregnancy. In the Alwan
t al42 review, use of any specific treatment versus none didot have statistically significant impacts on the risk of peri-atal death (RR � 0.09, 95% CI � 0.01-1.70). The review byarrar et al41 showed a nonsignificant impact of continuousubcutaneous insulin infusion versus multiple daily injec-ions on perinatal mortality (RR � 2.0, 95% CI �.20-19.91).
ntiplatelets for Prevention of Pre-Eclampsia. Aspirin is annti-inflammatory agent at high doses but can have antiplate-et action at low doses. Aspirin acts as an antiplatelet agent byrreversible inhibition of the enzyme cyclooxygenase. Thisnzyme is needed for the production of thromboxane A2;herefore, decreased production of thromboxane A2 ishought to protect against vasoconstriction, which can leado ischemia and placental blood clots.
The evidence reviewed showed that the use of antiplateletgents was associated with reduced risk of pre-eclampsia andetal or neonatal deaths when used for primary preventionRR � 0.86, 95% CI � 0.76-0.98).43 However, in a compos-te analyses of the use of antiplatelet agents in pregnancy, webserved statistically insignificant effect on composite out-ome of maternal, neonatal, and fetal mortality (RR � 0.83,5% CI � 0.63-1.07). Antiplatelet agents used for gestationalypertension had a positive impact on the composite out-ome of gestational hypertension and preterm birth (RR �.50, 95% CI � 0.28-0.91) and gestational hypertension andmall-for-gestational age birth (RR � 0.56, 95% CI � 0.38-.82). The incidence of proteinuric pre-eclampsia and pre-erm birth was also reduced significantly by 12% (RR � 0.88,5% CI � 0.82-0.95), confirming the direction of effect.
alcium Supplementation for Hypertensive Disorders inomen During Pregnancy with Low or Inadequate Calcium
ntake. The recommended dosing schedule for calcium sup-lementation is at least 1 g of calcium per day, starting from4 weeks of gestation at the latest. Although a feasible, po-ential intervention, its safety profile needs to be establishedefore attempts to introduce it into public health practice areade. The use of calcium supplementation in women with
ow/inadequate calcium intake does reduce perinatal mortal-ty (RR � 0.70, 95% CI � 0.56-0.88).44,45 A recent meta-nalysis of calcium supplementation during pregnancy dem-nstrated that it also was associated with a significanteduction in neonatal mortality (RR � 0.70, 95% CI � 0.56-.88) and risk of preterm birth (RR � 0.88, 95% CI �.78-0.99).46
ntihypertensive Agents for Mild-to-Moderate Hyperten-ion. A range of antihypertensives may be used for the con-rol of hypertension during pregnancy. The review by Abalost al47 on antihypertensives for mild to moderate hyperten-ion during pregnancy reported no impact on perinatal mor-ality (RR � 0.96, 95% CI � 0.60-1.54)47 and neonatal mor-
ality (RR � 0.79, 95% CI � 0.14-4.34). aagnesium Sulfate for Treatment of Pregnancy Inducedypertension/eclampsia. Magnesium sulfate reduces uter-
ne contractility both in vivo and in vitro, indicating thisntervention may prevent stillbirth. When magnesium sulfateersus diazepam for eclampsia is compared, the evidenceuggests a nonsignificant impact on perinatal mortalityRR � 1.04, 95% CI � 0.80-1.36) and neonatal mortalityRR � 1.34, 95% CI � 0.84-2.14).48 The Cochrane review byakrides and Crowther49 in 2001 included 3 RCTs with
801 recipients and reported no impact on deaths beforeischarge among newborns (RR � 1.59, 95% CI �.42-6.05).
irth and Newborn Care Preparednessromotion of Early Initiation of Breastfeeding. In a studyy Mullany et al,50 it was seen that partially breastfed infantsere at a greater mortality risk (RR � 1.77, 95% CI � 1.32-.39) than those that were exclusively breastfed. Neonatalortality was increased with increasing delay in breastfeed-
ng initiation. Mortality was greater among late (�24 h) com-ared with early (�24 h) initiators (RR � 1.41, 95% CI �.08-1.86). This study is supported by results from Edmondt al,51 in which they observed that initiation of breastfeedingfter day 1 compared with earlier was associated with a 3-foldncrease in mortality risk (aOR � 3.23, 95% CI � 1.07-9.82)n neonates aged 2 to 28 days.
ommunity-Based Intervention Packages. A “community-ased intervention” is one that is delivered by any personithin the community, including health care personnel or
aypersons, and implemented locally at the woman’s home,illage, or defined community. In a recent review by Lassit al52 identified significant reduction in neonatal mortalityRR � 0.73, 95% CI � 0.66-0.81), and perinatal mortalityRR � 0.80, 95% CI � 0.71-0.90) because of the implemen-ation of community-based intervention care packages thatncluded a range of preventive and promotive interventionshat used community health workers as well as a variety ofpproaches to community mobilization and behaviorhange.
ntrapartumomprehensive Emergency Obstetrical Care. Emergencybstetrical care (EmOC) includes a package of medical inter-entions required to treat the major direct obstetrical com-lications. Basic emergency obstetrical care (BEmOC) is de-ned as administration of parenteral antibiotics, oxytocicrugs, and anticonvulsants, as well as manual removal oflacenta, removal of retained products, and assisted vaginalelivery. Comprehensive EmOC includes all the basic EmOCunctions as well as surgery (Cesarean delivery) and bloodransfusion. A Cochrane review of 3 RCTs comparinglanned Cesarean with planned vaginal delivery for breech
nfants showed a 71% reduction in perinatal or neonataleath, excluding fatal malformations (RR 0.29, 95% CI �.10-0.86).53
Forceps delivery is a delivery in which forceps are insertedhrough the vagina and used to grasp the head of the fetus
nd pull it through the birth canal. In vacuum delivery, a
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acuum extractor is applied to the fetal scalp and tractionpplied. No difference in perinatal mortality was found whenomparing vacuum versus forceps-assisted delivery (OR �.80, 95% CI � 0.18-3.52).54
ost-Term Induction of Labor Versus Expectant Manage-ent. Comparison of labor induction at a predetermined
estational age (41 completed weeks) with expectant man-gement until an indication for birth arises found that labornduction was associated with fewer perinatal deaths for theost-term group (41 and 42 completed weeks) (RR � 0.30,5% CI � 0.09-0.99).55
ome Delivery Versus Facility Births. In low- and, to aesser extent, middle-income countries, pregnant women of-en do not have a choice about where to deliver their infantsecause of limited access to hospital care. The evidence fromCTs of home versus institutional birth is therefore derived
rom high-income countries. A review found a near-signifi-ant increase in risk of perinatal mortality (RR � 1.83, 95%I � 0.99-3.38) in home-like settings, compared with hos-ital deliveries.56 There is emerging evidence from a review ofemographic Health Surveys on the potential impact of in-
acility births on reducing neonatal mortality (Lim et al, per-onal communication, 2010).
rophylactic Corticosteroid Therapy in Preterm Labor. Se-eral agencies recommend that women in preterm labor be-ore 34 weeks’ gestation and those with preterm rupture of
embranes before 32 weeks’ gestation should receive a sin-le dose of either betamethasone or dexamethasone. A Co-hrane review showed that the use of corticosteroids in pre-erm labor reduces neonatal mortality by 40% (OR � 0.60,5% CI � 0.48-0.75).57
ostpartumecognition and Treatment of Mild Postpartum Depres-ion. The most common perinatal mental disorders includeostpartum depression, anxiety disorders, and postnatal psy-hosis. The onset of depression in women increases during inregnancy and the postpartum period. There are 2 systematiceviews on pharmacologic methods to treat postnatal depres-ion,58,59 and one by Rahman et al60 on nonpharmacologicalherapy. None of these reviews reported perinatal or neonatalutcomes; however, these interventions were associated witheduction in infant outcome of diarrhea (diarrhea episodest 12 months: OR � 0.6, 95% CI � 0.39-0.98), and anncrease in complete immunization at 12 months (OR �.5, 95% CI � 0.79-3.18). Also, contraceptive use inothers at 12 months was also reported to increase (OR �
.6, 95% CI � 1.20-2.27).
iscussionur review amply demonstrates that opportunities for as-
essing outcomes for both mothers and newborns have beenoorly realized and documented and that the potential for
ntegration is enormous. Of nearly 1000 studies reviewed,
hich represented more than 50 interventions, in only 35 aid the authors report impacts on perinatal and/or neonatalutcomes in addition to maternal outcomes. Assessment ofutcomes along biologically plausible pathways, such as theontinuum between risk factors, morbidity and mortality,as rare. Most of the interventions reviewed will require
dditional greater-quality evidence before solid program-atic recommendations can be made. It must be noted thatany of these interventions do hold promise in relation toaternal and perinatal morbidity, even though mortality out-
omes are sparingly reported. Additional research on theost-effectiveness of many of these interventions is requiredefore they can be recommended for further scale-up.Although further evidence is needed, on the basis of our
eview, the following interventions with demonstrable bene-ts on perinatal and neonatal mortality outcomes can beecommended now for deployment and implementation ineveloping country programs.
● Interventions to prevent perinatal mortality: these in-clude birth spacing, prevention of indoor air pollution,prevention of intimate partner violence before and dur-ing pregnancy, antenatal care during pregnancy, Dopp-ler ultrasound monitoring during pregnancy, insecti-cide-treated mosquito nets, birth and newborn carepreparedness via community-based intervention pack-ages, emergency obstetrical care, elective induction forpost-term delivery, Cesarean delivery for breech presen-tation and prophylactic corticosteroids in preterm labor.
● Interventions to improve neonatal survival: these in-clude early initiation of breastfeeding, and birth andnewborn care preparedness through community-basedintervention packages.
Our premise of generating evidence from available dataere not only to show the impact of reproductive and mater-al health interventions on perinatal and neonatal outcomes,ut was also to underscore the importance of integratinghese interventions for maternal and newborn survival. Ef-orts to achieve the MDGs to improve perinatal and newbornealth can be accelerated by actively pursuing the integrationf reproductive, maternal and perinatal interventions.Reproductive and maternal and newborn health are inex-
ricably linked. When mothers are malnourished, ill, or re-eive inadequate care, their newborns face a greater risk ofisease and premature death.61 A recent study by Ronsmanst al62 in which they used the data from population surveil-ance during 1982-2005 in Matlab, Bangladesh, reported cu-
ulative probabilities of survival and rates of age-specificeath, according to the survival status of the mother duringhat period. These authors reported that the risk of death for
newborn whose mother has died increases up to 8-foldRR � 8.35, 95% CI � 5.73-12.18),62 whereas the risk of aeath increases up to 27-fold (RR � 27.61, 95% CI � 20.27-7.61)62 among both male and female infants ages 1 to 5onths. Almost a one-tenth (11%) of newborns in develop-
ng countries are born with low birth weight, largely becausef their mother’s poor health and nutritional status. Lowirth weight results in increased susceptibility to infection
nd a greater risk of health problems in later life. Many of
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Reproductive health, maternal health, and perinatal outcomes 443
hese deaths are preventable if the mother is able to care forer health right from the preconception period, to visit aealth facility for antenatal care, and to opt for institutionalelivery and receive visits from a health service provider inhe postpartum period.
Integration across time relates to continuity of carehrough the life cycle (Fig. 2), rather than disconnected careor women during reproductive age, during pregnancies, andor newborns. Health policies and programs in the fields ofHMNH have generally operated in isolation, although there isroad consensus among researchers and practitioners that inte-rated programs have both more impact and are more cost-ffective. Grouping interventions in one package can reduceosts by allowing greater efficiency in training, monitoring andupervision, and use of resources and in avoiding duplication ofork while enabling families and communities to access servicesore easily.Given the burden of maternal, newborn, and child mortal-
ty, no government, agency, or organization can addresshese challenges alone. RHMNH programs should join handso achieve the MDGs by strengthening and coordinating ac-ivities at all levels, promoting scale-up and promoting cost-ffective, proven interventions. Considering the close rela-ionship between maternal and newborn health, anntegrated approach appears to be the most pragmatic strat-gy to provide this interlinked care in low-resource settings.ntegrated services require functional linkages between vari-us levels of health systems and between service deliveryackages, so the care provided at each time and place con-ributes to the overall effectiveness.63 In many low-incomeountries, which have shortages in human and financial re-ources and have inadequate health-system infrastructure,are is neither continuous nor integrated.10 An effective con-inuum of care is especially important for mother and new-orn survival, and timely implementation of such packagesill be required to reduce maternal and child morbidity andortality.The creation of a continuum of care would require sus-
ained and concerted action, human and financial resources,nd a common vision. The continuum of care has been aecurrent theme, promoted in the World Health Report
Figure 2 Reproductive, maternal, and newborn interactiois available online.)
005,64 the Lancet Neonatal Survival Serie,s and subsequent b
eports.11,10,64 It involves integrating health interventions forewborn babies into maternal and child health programs thatan be delivered throughout the life cycle via outreach; fam-ly-community care; and facility-based clinical care. The
ain focus of this continuum is to promote access to repro-uctive and maternal health for women during their repro-uctive ages, particularly during pregnancy and childbirth sohat maternal and newborn survival can be maximized.65
Although there is evidence indicating how the continuumf care works to reduce perinatal and neonatal mortality,ore understanding is required on how we can innovate to
vercome implementation barriers. Working with familiesnd communities is a vital link for increasing access to andse of quality health services.66-71 This can be achievedhrough strategies of education, provision of care, and healthystem strengthening. Some interventions are especially suit-ble for delivery through community support groups andealth workers, whereas others can only be delivered by link-
ng community-based strategies with functional facilities orelivery of a combined bundle of care through community-ased intervention packages linked with facility-based care.Several recent studies in South Asia have suggested that
ommunity-based strategies with various outreach workers,articularly those that provide maternal and newborn care byrained village health workers, may have a substantial impactn reducing perinatal and neonatal mortality.51 On the basisf the quality of evidence, there is a strong recommendationor their implementation in settings in which the vast major-ty of deliveries occur at home. An outstanding feature of
any such programs is the training of a cadre of local resi-ents as community level health workers who make regularisits to women and their newborn infants. These workersive advice and identify and treat neonatal problems; theirkills in some places have been extended to resuscitate new-orns and administer antibiotics. They also work to empowerommunities to address maternal and newborn health issues,odify poor health behaviors, and provide linkages with the
ormal health system in their local communities.Although the effects of maternal health on fetal and neo-
atal outcomes are well defined, the converse is not the case.any gaps remain in our knowledge of how neonatal mor-
ifferent stages of the life cycle. (Color version of figure
ns at didity and mortality might affect maternal outcomes. Miscar-
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444 Z.A. Bhutta et al
iages, deaths in utero, neonatal deaths, and preterm birthsave a profound impact on maternal physical, mental, andocial well-being. There is evidence that immediate postnatalare can improve newborn survival72 but little informationn the benefits of such visits on maternal health, postnatalepression, and early detection of infections. This is an areahich merits much greater research in the next few years.
onclusionshis review has identified several effective interventions forreventing perinatal and neonatal mortality and morbidity ineveloping countries. The review also demonstrates thatHMNH are inextricably linked, and that, therefore, healtholicies and programs should link them together. Such po-ential integration of strategies would not only help improveutcomes for millions of mothers and newborns but wouldlso save scant resources. This would also allow for greaterfficiency in training, monitoring and supervision of healthare workers, and would also help families and communitieso access and use services easily.
Translating evidence to policy and ensuring that many ofhese interventions and packages of care are implementednd evaluated at scale is a difficult challenge. Such an ap-roach is critical to achieving MDGs 4 and 5 and ensuringhat we move beyond saving lives to also improving morbid-ties and developmental outcomes.
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