Born Too Soon: Care during pregnancy and childbirth to reduce preterm deliveries and improve health outcomes of the preterm baby

Antenatal care services for prevention of preterm birth for all women

Effective and culturally appropriate care during pregnancy is essential for increasing the likelihood of positive birth outcomes [19]. Antenatal care is a service delivery platform through which all women can be reached at multiple times during pregnancy with a package of interventions that can prolong a healthy pregnancy and improve maternal and perinatal health. Basic services that can be delivered during antenatal care with a potential impact on reducing preterm birth rates include identification of women at high risk of pretermbirth; screening for and treatment of sexually transmitted diseases including HIV and other infections (tuberculosis, malaria, bacterial vaginosis, bacteriuria); identification and correction of malnutrition and nutrition counselling including on multiple micro-nutrient supplementation; counselling on birth preparedness and complication readiness for identification of early labour and other risk factors; and behavioural and social support interventions such as smoking cessation programmes and programmes aimed at the prevention of violence against women [11, 19–25].

Infections during pregnancy can cross into the intra-amniotic cavity, establish intra-amniotic infection and result in preterm labour. In some women, such infections are associated with premature rupture of the membranes [6]. Screening for and treatment of infections such as asymptomatic bacteriuria and bacterial vaginosis during antenatal care may reduce preterm births, although study findings show inconsistent results. Systematic reviews and meta-analyses show that antibiotic treatment for infection and periodontal care does not reliably reduce the risk of preterm birth, and effectiveness may depend upon when during pregnancy the infection or periodontal disease is detected and treated. Three hypotheses have been proposed to explain the inconsistent findings of the effect of antibiotic treatment on reducing preterm delivery: 1) infections may be polymicrobial in nature and even broad spectrum antibiotics may not be sufficient to treat them all, 2) infections may not be the primary cause of preterm labour, and underlying [21, 22] immunosuppressive conditions may be responsible for inducing alternate biomolecular pathways leading to preterm labour. Therefore, treating the bacterial infection alone may not be sufficient, and 3) clinical signs of infection based on immune biomarkers are not true indicators of infection due to heterogeneity in inflammatory markers of various intra amniotic pathogens. More research is needed on the inter-relationships between infection, pregnant women's immune response, and the cascade of events resulting in preterm birth [26]. Such research can inform the development of optimal screening and treatment protocols based on underlying risk factors that will take into consideration when in pregnancy, or prior to pregnancy, screening and treatment for infections should occur to reduce the preterm birth rate [15].

The advantages of prophylactic treatment for malaria (intermittent presumptive treatment during pregnancy for malaria [IPTp]) and the use of bednets to prevent malaria transmission in malaria-endemic areas on reducing preterm birth similarly needs further investigation. More rigorous studies examining the impact of HIV infection and the use of antiretrovirals and TB medication during pregnancy on the risk of preterm birth that control for disease stage and other potential confounding factors are also needed [2].

Women's nutritional status during pregnancy has been linked to preterm birth, with underweight and obese pregnant women at elevated risk of preterm birth and other poor obstetrical outcomes [6, 27]. Malnutrition increases vulnerability to infection and predisposes pregnant women to adverse obstetrical outcomes including preterm delivery, although findings on obesity and the risk of preterm birth are mixed. Recent research suggests that the association between body mass index (BMI) and risk of preterm birth may differ by race or ethnic group, underscoring the complexity of the role nutrition plays in triggering preterm birth [28]. Providers can administer nutritional supplements and counselling services during routine antenatal visits. Evidence from clinical trials to date does not, in general, show a clear beneficial effect of nutritional counselling, or protein and calorie supplements during pregnancy on the preterm birth rate. A small effect on reducing preterm births has been found from the use of multiple micro-nutrient supplementation, and evidence suggests that calcium supplementation during pregnancy can reduce the incidence of preterm births in populations at risk of low calcium uptake [11]. New findings also suggest a link between supplementation of docosahexaenoic acid (DHA) and overall greater gestation duration and infant size [29]. Further research is needed to determine the optimal timing during a woman's life course of introducing nutritional interventions for reducing the risk of preterm birth and how best to implement these interventions within the broader context of efforts to improve the overall nutritional status of pregnant women and women of reproductive age. Pregnant women should be encouraged to take multi-vitamin supplements and to gain an adequate amount of weight based on their nutritional status at the beginning of their pregnancy, and for other health-promoting reasons such as reducing the risk of small for gestational age babies and neural tube defects.

Antenatal care services for prevention of preterm births, women at higher risk

Women at increased risk of preterm delivery can be identified during antenatal care based on obstetric history (e.g., known uterine or cervical anomaly or previous preterm birth, pre-existing conditions such as chronic diseases) or presenting pregnancy characteristics (e.g., hypertensive disorder of pregnancy, diabetes, multiple gestation, bleeding). Young adolescents also are at greater risk [30, 31]. Although prospective studies that evaluate the use of risk-screening tools based on epidemiologic, demographic biomarkers and clinical indicators in routine antenatal care are still needed, there are several approaches for providing preventive care for these women. One such approach includes specialized antenatal clinics for women with evident risk of preterm birth that provide enhanced health education, and more rigorous monitoring and treatment of risk factors and pregnancy complications. The evidence is scanty on such approaches in reducing the risk of preterm birth, but trials were conducted prior to the introduction of new screening tests. Another approach involves adopting the principles of personalized medicine that includes tailoring interventions to match each individual woman's risk profile.

Administration of progesterone to prolong pregnancy in high-risk women with a history of previous preterm birth has been shown effective in preventing a recurrence of preterm birth in these women and in decreasing the prevalence of low birthweight [2]. A recent clinical trial, however, found no advantage to vaginal progesterone therapy at 200 mg or 400 mg doses in the prevention of preterm birth in twin pregnancies [32]. Recent guidelines and professional opinion recommend administering vaginal progesterone to women with singleton pregnancies and short cervical length to reduce preterm birth and perinatal morbidity and mortality [33]. Most studies to date on the use of progesterone have been conducted in high-income countries. There is a need for evidence generation on progesterone use in resource-constrained settings including how this intervention can be scaled up at national level and the feasibility of introducing universal cervical length measurement screening.

Cochrane reviews have shown small reductions in preterm birth rates with treatment interventions for pre-eclampsia such as calcium supplementation. A recent randomized controlled trial has shown promising results for the use of a cervical pessary to lower rates of spontaneous preterm birth among women with a short cervix [34]. Results from another randomized controlled trial did not find any reductions in poor perinatal outcomes from use of a cervical pessary for prevention of preterm birth in women with a multiple pregnancy [35]. Another promising intervention in reducing the risk of preterm birth that requires further investigation is the placement of circumferential stitches on a structurally weak cervix (cerclage) [2, 3].

These interventions are only applicable to a small number of high-risk women, however, and the overall effect on general population rates of preterm birth is likely to be limited.

Management of women in preterm labour to improve survival chances of the premature baby

Once preterm labour has commenced, there are interventions that can prolong pregnancy and improve health outcomes and survival for the premature baby. To date, these interventions have not been designed to address the underlying mechanisms that trigger preterm labour.

Interventions to prolong pregnancy include the provision of tocolytic agents that inhibit uterine contractions to suppress labour (e.g., oxytocin antagonists, betamimetics, calcium channel blockers, magnesium sulphate), and clinical practices to ensure the optimal timing of caesarean birth and labour induction for indicated preterm births [2, 9, 15]. The provision of tocolytics has been shown effective in slowing down labour, enabling the administration of antenatal corticosteroids and transfer of mother and baby to a higher-level facility where appropriate care may be available. Any use of strategies to prolong labour, including delaying caesarean birth, must be evaluated against the potential risk of continued exposure of mother and fetus to sub-optimal conditions that may result in harmful effects. Further research is needed on the short- and long-term health consequences for mother and baby from efforts to prevent preterm labour.

There are three key interventions that can be delivered during the pregnancy period with evidence of effectiveness in improving health outcomes in babies born prematurely, although none of these are effective in reducing the incidence of preterm births: antenatal corticosteroids, antibiotics for pPROM, and magnesium sulphate.

The administration of antenatal corticosteroids to pregnant women at high risk of preterm birth possibly as early as 23 weeks can significantly reduce the premature baby's risk of death, respiratory distress and developmental problems (Figure 1) [8].

Preterm premature rupture of the membranes (pPROM) is strongly associated with infection of the amniotic membranes contributing to preterm birth and other poor fetal outcomes such as cerebral palsy and chronic lung disease. It is unclear if infection is a cause or consequence of pPROM. The incidence of pPROM has not measurably changed in the past 40 years, and there are currently no screening or diagnostic markers because the mechanisms responsible for a large proportion of pPROM cases are still poorly understood. Antibiotic treatment for pPROM has been shown to delay onset of labour for up to 48 hours and to reduce neonatal infections and abnormal cerebral ultrasound scans prior to hospital discharge [10]. Clinical management of pPROM including duration of administration of antibiotic prophylaxis depends upon the maternal-fetal condition, and other factors need to be considered such as timing of administration of antenatal corticosteroids and delivery.

The administration of magnesium sulphate to women at risk of preterm birth helps to protect the baby's brain, reduce rates of cerebral palsy and improve long-term neonatal health outcomes. Further studies are needed, however, to investigate side effects of the treatment for the mother (e.g., flushing, sweating, nausea, vomiting, headaches and a rapid heartbeat) and how these can be reduced [20].

Behaviour and community interventions for the prevention of preterm birth

Lifestyle factors including depression, intimate partner violence, smoking, substance abuse and stress are risk factors for preterm birth. Antenatal care models, including group models, that address these issues and provide social and financial support for pregnant women and particularly disadvantaged/at-risk population groups have been associated with reduced rates of preterm birth [36, 37]. There are numerous efforts underway to determine how best to integrate psychological and behavioural interventions, including programmes to prevent violence, into antenatal care to improve preterm birth rates and other maternal and neonatal health outcomes. Controlled trials need to be designed to further test the efficacy of antenatal care approaches that incorporate social and financial support measures so that such approaches can be introduced at scale in settings where they are most needed. A recent systematic review and meta-analysis on the effects of women's groups practicing participatory learning and action showed that these strategies are a cost-effective approach to improving maternal and neonatal health outcomes [38]. More research is needed on how women's empowerment approaches can translate into reduced preterm birth rates.

Smoking during pregnancy is a well-known cause of preterm birth, especially preterm birth complicated by pPROM. Smoking cessation interventions in high-income countries that combine counselling with additional social support services have been found to significantly reduce preterm birth and should be adapted for application in low- and middle-income countries where the large majority of smokers live [39]. These approaches could prove to be more successful than large scale campaigns in changing women's smoking habits during pregnancy. Greater understanding of the biomolecular pathways through which the chemicals in cigarette smoke trigger deleterious events during pregnancy could potentially lead to new interventions targeted at smokers unable to quit when pregnant.

Other programmes such as the Healthy Babies are Worth the Wait™ campaign of the March of Dimes and the "humanization of childbirth" social movement in Brazil and other Latin American countries that educate women with healthy pregnancies about the advantages of vaginal delivery and waiting until 39 weeks to deliver should be promoted, particularly in contexts characterized by high and rising elective caesarean birth rates [40, 41]. Health care provider education on the adverse health outcomes of late preterm birth and of inducing birth for non-medical reasons prior to 39 weeks has been shown to be effective in reducing preterm birth rates in some countries such as Brazil [40, 42, 43].

Policy interventions to promote healthy pregnancies

Pregnant women can experience a reduced risk of preterm birth and other health benefits from professional and public policies based on sound scientific evidence. Blencowe and colleagues show that the risk of preterm birth increases in women with twins and higher-order births [12]. Policies on infertility treatments and use of assisted reproductive technologies directed to limiting the number of embryos that can be transferred have shown success in reducing the number of higher-order births and the associated high risk of preterm birth in Europe, Australia and the United States [15, 44, 45].

Hospital policies aimed at lowering the primary caesarean birth rate and early induction rates, particularly for non-medically indicated reasons, are part of a growing effort to prolong pregnancy, promote healthy newborn outcomes and reverse the increasing trend of preterm birth. Such policies are especially needed in regions where caesarean birth rates, and particularly elective caesarean birth rates, are high or rising like in Latin America and many high-income countries. Legislation mandating universal access to maternal health care services and eliminating user fees in low- and middle-income countries also have been shown to be an important prerequisite to ensuring all women receive antenatal care.

Workplace policies designed to promote healthy pregnancies and protect pregnant women from occupational hazards can potentially reduce the risk of preterm birth. Examples include, but are not limited to, time off for antenatal care visits, paid pregnancy leave for a set number of weeks and exemption from night shifts and tasks requiring heavy lifting or standing for long periods of time [46]. Studies have shown that carrying heavy workloads and working more than 5 days a week are associated with preterm birth [47]. Measures that can improve general working conditions are especially important for pregnant women in low- and middle-income countries where they are more likely to be engaged in agricultural labour and other physically demanding tasks.

Pregnant women can benefit from legislation reducing their exposure to potentially harmful environmental risk factors such as second-hand smoke and air pollution (combustion and household sources) [48]. There is growing interest in understanding and developing policy and programmatic solutions to the association between air pollution and adverse pregnancy outcomes including preterm birth [49–54]. For example, the UN Foundation houses the Global Alliance for Clean Cookstoves, a multi-partner effort launched in 2010 to promote clean and efficient cookstoves. Traditional cookstoves and open fires, the primary means of cooking and heating for nearly three billion people in the developing world, place pregnant women at increased risk of preterm birth and other poor obstetrical outcomes.

Program opportunities to scale up

Coverage of antenatal care (at least one visit) is approximately 80% worldwide, with coverage levels dropping to about 50% for four or more visits. Inequities in coverage are pervasive, with coverage levels of four or more antenatal care visits hovering around 40% for the least developed countries [18]. These figures indicate that efforts aimed at improving availability of antenatal care, demand for care and women's ability to reach these services throughout the pregnancy period are needed, particularly in low-resource settings and amongst the most disadvantaged population groups. Adolescents are another group at high risk of preterm birth due to their young age and typically limited access to preconception and prenatal care [57].

Figure 2 shows median coverage of antenatal care services to pregnant women living in the Countdown to 2015 priority countries where more than 95% of all maternal and child deaths occur [58]. Consistent with the global data, the figure shows high levels of at least one visit of antenatal care across the Countdown countries, but considerably lower levels of the recommended four or more antenatal care visits. This indicates that the majority of women in these countries are not benefiting from the recommended basic package of antenatal care services. The figure also highlights substantial gaps in the quality of care pregnant women are receiving during antenatal care visits, with coverage levels of specific evidence-based interventions considerably lower than the ideal of universal coverage. A similar review of gaps in the provision of key components of antenatal care in sub-Saharan Africa, where the rates and absolute numbers of preterm birth are among the highest in the world, similarly showed low levels of coverage of several recommended components [59, 60]. These missed opportunities are a call to action for strengthening health systems in the Countdown priority and other low- and middle-income countries including ensuring practitioners are equipped with the skills and necessary drugs and equipment to deliver effective antenatal care that can potentially reduce the risk of preterm birth and improve health outcomes of the premature baby.

Priority research themes for the pregnancy period and childbirth

There is an imperative need for research on preterm birth that can yield quality data on the efficacy of existing and promising interventions delivered individually or as a package during the pregnancy period. There is an equally critical need for implementation research to improve the scale up of proven policy and health care interventions in low- and middle-income countries. There has been increasing interest in preterm birth in recent years and in developing a comprehensive research paradigm to address this growing cause of neonatal mortality. A major emphasis of the paradigm has been on discovery science to shed light on the basic biology of normal and abnormal pregnancies so that the pathological process of preterm birth can be understood and effective interventions developed. This research will also potentially result in the development of better screening tools for the prediction and prevention of preterm labour. The link between genetics, gene-environment interactions and preterm birth is being investigated with the hope of gaining an understanding of differences in preterm birth rates across racial and ethnic groups that can be translated into more effective and equitable clinical care guidelines including counselling and screening services [26, 62]. Research is underway to explore the connections between maternal infections, nutritional status and preterm birth within a broader framework of research on prematurity, low birthweight and intrauterine growth restriction (Figure 3). In addition, research on the social determinants of preterm birth is being conducted to explore the pathways between social disadvantage, behavioural and lifestyle factors and preterm birth [63–65]. A major goal of this research is to help develop strategies for addressing social and economic disparities in preterm birth rates, inequities in access to needed care between and within countries as well as how to best integrate social and behavioural interventions into antenatal care.

Prescription for action during the pregnancy period and childbirth

As a first step, national policies and guidelines for comprehensive antenatal, labour and delivery, emergency obstetric and postnatal care should be established in all countries to promote universal access to quality maternal and perinatal services. Pro-poor legislation (e.g., to abolish user fees, introduce conditional cash transfer programmes, etc.) for maternal and perinatal services should be considered in low- and middle-income countries where out-of-pocket expenses are high and/or coverage levels of antenatal and delivery care interventions are low. Protective legislation is needed to improve general working conditions for pregnant women, and to reduce pregnant women's exposure to potentially harmful environmental, behavioural and lifestyle risk factors such as second-hand smoke and violence against women.

The implementation of national and professional policies and guidelines that are in-line with science-based recommendations, such as those made by WHO, needs to be prioritized. All countries and their partners should allocate sufficient resources to strengthening health care systems to facilitate the implementation process and enable the equitable and early delivery of quality antenatal care. Resources also are needed to develop clearly defined care and referral pathways. Prevention needs to be prioritized through improving access to screening and diagnostic tests and appropriate treatment during antenatal care with adequate follow-up and referral of women identified at high risk of preterm birth.

Efforts to strengthen health systems must include increased and regular training opportunities for health care providers on the use of effective interventions, and on tailoring clinical care to the individual woman based on her risk profile throughout the duration of her pregnancy. The delivery of all recommended components of antenatal care should be regularly instituted and monitored through supportive supervision.

These health care system readiness efforts need to be complemented by communication and education campaigns to increase demand for maternal and perinatal care services and to ensure prospective parents and community members are fully informed about a healthy pregnancy and potential complications.

In settings with greater capacity, professional policies regulating assisted reproductive technologies and infertility treatments should be put into place to reduce the number of multiple gestations at higher risk of preterm birth. Genetic counselling and adequate counselling for women over the age of 35 on pregnancy risks also should be included as components of antenatal care.

All women should be provided with access to quality antenatal care services and a functional referral system throughout pregnancy. Women should be encouraged to give birth in healthcare facilities and have access to health care facilities where quality maternal services are guaranteed. Community members need to be informed about the importance of all women receiving antenatal care and delivering in functioning health care facilities as well as warning signs in pregnancy including preterm labour. In low- and middle-income countries, communities need to be supported in developing appropriate mechanisms that enable women to seek care, particularly the most disadvantaged women who face multiple barriers to accessing timely care.

The integration of effective services should be promoted to best use antenatal care visits as a platform for the delivery of a package of interventions and to leverage scarce resources for women's and children's health. The integration of HIV, malaria, and social and financial support programmes into routine antenatal care, for example, represents an efficient use of resources with potential to reach a large majority of pregnant women.

Health care facilities need to be equipped with trained staff and ample and consistent supplies of drugs and equipment so that women can be guaranteed provision of antibiotics for pPROM, antenatal corticosteroids, progesterone, magnesium sulphate and tocolytics as needed.

Countries need to engage in collaborative and multi-center research for the development of high-quality evidence on available and promising interventions delivered singly and as a package during antenatal care or labour and delivery. Adequate funding is needed for basic science research on the etiology of preterm birth, the physiological processes of healthy and abnormal pregnancies and the linkages between preterm birth and genetics, environment, stress and depression, infection and nutrition. Findings from such research will guide the development of preventive interventions, diagnostic markers and related screening tools and better clinical management guidelines for all women and for women at high risk of preterm birth. These cross-country, multi-disciplinary research efforts will ultimately facilitate the discovery and development of interventions with universal application.

Implementation research is essential for determining how research findings can be best translated into practical application in low- and middle-income countries where resource constraints and inequities in intervention coverage are more pronounced and where innovations in service delivery strategies are most needed. Efforts are needed, for example, on how to most effectively integrate evidence-based interventions into antenatal care in specific contexts so that pregnant women are reached with comprehensive and culturally appropriate packages of care.

National audit and other monitoring and evaluation systems at facility level need to be put into place as a quality control measure to track preterm birth rates and the use of effective services during antenatal care and labour and delivery.

In all settings, ongoing monitoring and evaluation of the implementation of guidelines and policies are essential for ensuring that pregnant women receive high-quality care based on the best evidence.