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1.  Global report on preterm birth and stillbirth (2 of 7): discovery science 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S2.
Normal and abnormal processes of pregnancy and childbirth are poorly understood. This second article in a global report explains what is known about the etiologies of preterm births and stillbirths and identifies critical gaps in knowledge. Two important concepts emerge: the continuum of pregnancy, beginning at implantation and ending with uterine involution following birth; and the multifactorial etiologies of preterm birth and stillbirth. Improved tools and data will enable discovery scientists to identify causal pathways and cost-effective interventions.
Pregnancy and parturition continuum
The biological process of pregnancy and childbirth begins with implantation and, after birth, ends with the return of the uterus to its previous state. The majority of pregnancy is characterized by rapid uterine and fetal growth without contractions. Yet most research has addressed only uterine stimulation (labor) that accounts for <0.5% of pregnancy.
The etiologies of preterm birth and stillbirth differ by gestational age, genetics, and environmental factors. Approximately 30% of all preterm births are indicated for either maternal or fetal complications, such as maternal illness or fetal growth restriction. Commonly recognized pathways leading to preterm birth occur most often during the gestational ages indicated: (1) inflammation caused by infection (22-32 weeks); (2) decidual hemorrhage caused by uteroplacental thrombosis (early or late preterm birth); (3) stress (32-36 weeks); and (4) uterine overdistention, often caused by multiple fetuses (32-36 weeks). Other contributors include cervical insufficiency, smoking, and systemic infections. Many stillbirths have similar causes and mechanisms. About two-thirds of late fetal deaths occur during the antepartum period; the other third occur during childbirth. Intrapartum asphyxia is a leading cause of stillbirths in low- and middle-income countries.
Utilizing new systems biology tools, opportunities now exist for researchers to investigate various pathways important to normal and abnormal pregnancies. Improved access to quality data and biological specimens are critical to advancing discovery science. Phenotypes, standardized definitions, and uniform criteria for assessing preterm birth and stillbirth outcomes are other immediate research needs.
Preterm birth and stillbirth have multifactorial etiologies. More resources must be directed toward accelerating our understanding of these complex processes, and identifying upstream and cost-effective solutions that will improve these pregnancy outcomes.
PMCID: PMC2841774  PMID: 20233383
2.  Global report on preterm birth and stillbirth (3 of 7): evidence for effectiveness of interventions 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S3.
Interventions directed toward mothers before and during pregnancy and childbirth may help reduce preterm births and stillbirths. Survival of preterm newborns may also be improved with interventions given during these times or soon after birth. This comprehensive review assesses existing interventions for low- and middle-income countries (LMICs).
Approximately 2,000 intervention studies were systematically evaluated through December 31, 2008. They addressed preterm birth or low birth weight; stillbirth or perinatal mortality; and management of preterm newborns. Out of 82 identified interventions, 49 were relevant to LMICs and had reasonable amounts of evidence, and therefore selected for in-depth reviews. Each was classified and assessed by the quality of available evidence and its potential to treat or prevent preterm birth and stillbirth. Impacts on other maternal, fetal, newborn or child health outcomes were also considered. Assessments were based on an adaptation of the Grades of Recommendation Assessment, Development and Evaluation criteria.
Most interventions require additional research to improve the quality of evidence. Others had little evidence of benefit and should be discontinued. The following are supported by moderate- to high-quality evidence and strongly recommended for LMICs:
• Two interventions prevent preterm births—smoking cessation and progesterone
• Eight interventions prevent stillbirths—balanced protein energy supplementation, screening and treatment of syphilis, intermittant presumptive treatment for malaria during pregnancy, insecticide-treated mosquito nets, birth preparedness, emergency obstetric care, cesarean section for breech presentation, and elective induction for post-term delivery
• Eleven interventions improve survival of preterm newborns—prophylactic steroids in preterm labor, antibiotics for PROM, vitamin K supplementation at delivery, case management of neonatal sepsis and pneumonia, delayed cord clamping, room air (vs. 100% oxygen) for resuscitation, hospital-based kangaroo mother care, early breastfeeding, thermal care, and surfactant therapy and application of continued distending pressure to the lungs for respiratory distress syndrome
The research paradigm for discovery science and intervention development must be balanced to address prevention as well as improve morbidity and mortality in all settings. This review also reveals significant gaps in current knowledge of interventions spanning the continuum of maternal and fetal outcomes, and the critical need to generate further high-quality evidence for promising interventions.
PMCID: PMC2841444  PMID: 20233384
3.  Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy 
While the use of creatine in human pregnancy is yet to be fully evaluated, its long-term use in healthy adults appears to be safe, and its well documented neuroprotective properties have recently been extended by demonstrations that creatine improves cognitive function in normal and elderly people, and motor skills in sleep-deprived subjects. Creatine has many actions likely to benefit the fetus and newborn, because pregnancy is a state of heightened metabolic activity, and the placenta is a key source of free radicals of oxygen and nitrogen. The multiple benefits of supplementary creatine arise from the fact that the creatine-phosphocreatine [PCr] system has physiologically important roles that include maintenance of intracellular ATP and acid–base balance, post-ischaemic recovery of protein synthesis, cerebral vasodilation, antioxidant actions, and stabilisation of lipid membranes. In the brain, creatine not only reduces lipid peroxidation and improves cerebral perfusion, its interaction with the benzodiazepine site of the GABAA receptor is likely to counteract the effects of glutamate excitotoxicity – actions that may protect the preterm and term fetal brain from the effects of birth hypoxia. In this review we discuss the development of creatine synthesis during fetal life, the transfer of creatine from mother to fetus, and propose that creatine supplementation during pregnancy may have benefits for the fetus and neonate whenever oxidative stress or feto-placental hypoxia arise, as in cases of fetal growth restriction, premature birth, or when parturition is delayed or complicated by oxygen deprivation of the newborn.
PMCID: PMC4007139  PMID: 24766646
4.  Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S1.
This is the first of seven articles from a preterm birth and stillbirth report. Presented here is an overview of the burden, an assessment of the quality of current estimates, review of trends, and recommendations to improve data.
Preterm birth
Few countries have reliable national preterm birth prevalence data. Globally, an estimated 13 million babies are born before 37 completed weeks of gestation annually. Rates are generally highest in low- and middle-income countries, and increasing in some middle- and high-income countries, particularly the Americas. Preterm birth is the leading direct cause of neonatal death (27%); more than one million preterm newborns die annually. Preterm birth is also the dominant risk factor for neonatal mortality, particularly for deaths due to infections. Long-term impairment is an increasing issue.
Stillbirths are currently not included in Millennium Development Goal tracking and remain invisible in global policies. For international comparisons, stillbirths include late fetal deaths weighing more than 1000g or occurring after 28 weeks gestation. Only about 2% of all stillbirths are counted through vital registration and global estimates are based on household surveys or modelling. Two global estimation exercises reached a similar estimate of around three million annually; 99% occur in low- and middle-income countries. One million stillbirths occur during birth. Global stillbirth cause-of-death estimates are impeded by multiple, complex classification systems.
Recommendations to improve data
(1) increase the capture and quality of pregnancy outcome data through household surveys, the main data source for countries with 75% of the global burden; (2) increase compliance with standard definitions of gestational age and stillbirth in routine data collection systems; (3) strengthen existing data collection mechanisms—especially vital registration and facility data—by instituting a standard death certificate for stillbirth and neonatal death linked to revised International Classification of Diseases coding; (4) validate a simple, standardized classification system for stillbirth cause-of-death; and (5) improve systems and tools to capture acute morbidity and long-term impairment outcomes following preterm birth.
Lack of adequate data hampers visibility, effective policies, and research. Immediate opportunities exist to improve data tracking and reduce the burden of preterm birth and stillbirth.
PMCID: PMC2841772  PMID: 20233382
5.  A thematic analysis of factors influencing recruitment to maternal and perinatal trials 
Recruitment of eligible participants remains one of the biggest challenges to successful completion of randomised controlled trials (RCTs). Only one third of trials recruit on time, often requiring a lengthy extension to the recruitment period. We identified factors influencing recruitment success and potentially effective recruitment strategies.
We searched MEDLINE and EMBASE from 1966 to December Week 2, 2006, the Cochrane Library Methodology Register in December 2006, and hand searched reference lists for studies of any design which focused on recruitment to maternal/perinatal trials, or if no studies of maternal or perinatal research could be identified, other areas of healthcare. Studies of nurses' and midwives' attitudes to research were included as none specifically about trials were located. We synthesised the data narratively, using a basic thematic analysis, with themes derived from the literature and after discussion between the authors.
Around half of the included papers (29/53) were specific to maternal and perinatal healthcare. Only one study was identified which focused on factors for maternal and perinatal clinicians and only seven studies considered recruitment strategies specific to perinatal research. Themes included: participant assessment of risk; recruitment process; participant understanding of research; patient characteristics; clinician attitudes to research and trials; protocol issues; and institutional or organisational issues. While no reliable evidence base for strategies to enhance recruitment was identified in any of the review studies, four maternal/perinatal primary studies suggest that specialised recruitment staff, mass mailings, physician referrals and strategies targeting minority women may increase recruitment. However these findings may only be applicable to the particular trials and settings studied.
Although factors reported by both participants and clinicians which influence recruitment were quite consistent across the included studies, studies comparing different recruitment strategies were largely missing. Trials of different recruitment strategies could be embedded in large multicentre RCTs, with strategies tailored to the factors specific to the trial and institution.
PMCID: PMC2532678  PMID: 18687110
6.  Global report on preterm birth and stillbirth (4 of 7): delivery of interventions 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S4.
The efficacious interventions identified in the previous article of this report will fail unless they are delivered at high and equitable coverage. This article discusses critical delivery constraints and strategies.
Barriers to scaling up interventions
Achieving universal coverage entails addressing major barriers at many levels. An overarching constraint is the lack of political will, resulting from the dearth of preterm birth and stillbirth data and the lack of visibility. Other barriers exist at the household and community levels, such as insufficient demand for interventions or sociocultural barriers; at the health services level, such as a lack of resources and trained healthcare providers; and at the health sector policy and management level, such as poorly functioning, centralized systems. Additional constraints involve weak governance and accountability, political instability, and challenges in the physical environment.
Strategies and examples
Scaling up maternal, newborn and child health interventions requires strengthening health systems, but there is also a role for focused, targeted interventions. Choosing a strategy involves identifying appropriate channels for reaching high coverage, which depends on many factors such as access to and attendance at healthcare facilities. Delivery channels vary, and may include facility- and community-based healthcare providers, mass media campaigns, and community-based approaches and marketing strategies. Issues related to scaling up are discussed in the context of four interventions that may be given to mothers at different stages throughout pregnancy or to newborns: (1) detection and treatment of syphilis; (2) emergency Cesarean section; (3) newborn resuscitation; and (4) kangaroo mother care. Systematic reviews of the literature and large-scale implementation studies are analyzed for each intervention.
Equitable and successful scale-up of preterm birth and stillbirth interventions will require addressing multiple barriers, and utilizing multiple delivery approaches and channels. Another important need is developing strategies to discontinue ineffective or harmful interventions. Preterm birth and stillbirth interventions must also be placed in the broader maternal, newborn and child health context to identify and prioritize those that will help improve several outcomes at the same time. The next article discusses advocacy challenges and opportunities.
PMCID: PMC2841777  PMID: 20233385
7.  Global report on preterm birth and stillbirth (6 of 7): ethical considerations 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S6.
Despite the substantial global burden of preterm and stillbirth, little attention has been given to the ethical considerations related to research and interventions in the global context. Ethical dilemmas surrounding reproductive decisions and the care of preterm newborns impact the delivery of interventions, and are not well understood in low-resource settings. Issues such as how to address the moral and cultural attitudes surrounding stillbirths, have cross-cutting implications for global visibility of the disease burden. This analysis identifies ethical issues impacting definitions, discovery, development, and delivery of effective interventions to decrease the global burden of preterm birth and stillbirth.
This review is based on a comprehensive literature review; an ethical analysis of other articles within this global report; and discussions with GAPPS's Scientific Advisory Council, team of international investigators, and a community of international experts on maternal, newborn, and child health and bioethics from the 2009 International Conference on Prematurity and Stillbirth. The literature review includes articles in PubMed, Academic Search Complete (EBSCO), and Philosopher's Index with a range of 1995-2008.
Advancements in discovery science relating to preterm birth and stillbirth require careful consideration in the design and use of repositories containing maternal specimens and data. Equally important is the need to improve clinical translation from basic science research to delivery of interventions, and to ensure global needs inform discovery science agenda-setting. Ethical issues in the development of interventions include a need to balance immediate versus long-term impacts—such as caring for preterm newborns rather than preventing preterm births. The delivery of interventions must address: women's health disparities as determinants of preterm birth and stillbirth; improving measurements of impact on equity in coverage; balancing maternal and newborn outcomes in choosing interventions; and understanding the personal and cross-cultural experiences of preterm birth and stillbirth among women, families and communities.
Efforts to improve visibility, funding, research and the successful delivery of interventions for preterm birth and stillbirth face a number of ethical concerns. Thoughtful input from those in health policy, bioethics and international research ethics helped shape an interdisciplinary global action agenda to prevent preterm birth and stillbirth.
PMCID: PMC2841776  PMID: 20233387
8.  Global report on preterm birth and stillbirth (7 of 7): mobilizing resources to accelerate innovative solutions (Global Action Agenda) 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S7.
Preterm birth and stillbirth are complex local and global health problems requiring an interdisciplinary approach and an international commitment. Stakeholders developed recommendations for a Global Action Agenda (GAA) at the 2009 International Conference on Prematurity and Stillbirth. The primary goal of this GAA is to forge a collaborative effort toward achieving common goals to prevent preterm birth and stillbirth, and to improve related maternal, newborn, and child health outcomes.
Conference participants
GAPPS co-convened this four-day conference with the Bill & Melinda Gates Foundation, March of Dimes, PATH, Save the Children, UNICEF and the World Health Organization. Participants included about 200 leading international researchers, policymakers, health care practitioners and philanthropists. A near-final draft of this report was sent three weeks in advance to help co-chairs and participants prepare for workgroup discussions.
Global Action Agenda
Twelve thematic workgroups, composed of interdisciplinary experts, made recommendations on short-, intermediate-, and long-term milestones, and success metrics. Recommendations are based on the following themes: (1) advance discovery of the magnitude, causes and innovative solutions; (2) promote development and delivery of low-cost, proven interventions; (3) improve advocacy efforts to increase awareness that preterm birth and stillbirth are leading contributors to the global health burden; (4) increase resources for research and implementation; and (5) consider ethical and social justice implications throughout all efforts.
The conference provided an unprecedented opportunity for maternal, newborn and child health stakeholders to create a collaborative strategy for addressing preterm birth and stillbirth globally. Participants and others have already completed or launched work on key milestones identified in the GAA. Updates will be provided at
PMCID: PMC2841775  PMID: 20233388
9.  Global report on preterm birth and stillbirth (5 of 7): advocacy barriers and opportunities 
BMC Pregnancy and Childbirth  2010;10(Suppl 1):S5.
Efforts to achieve the Millennium Development Goals (MDGs) to improve maternal and child health can be accelerated by addressing preterm birth and stillbirth. However, most global health stakeholders are unaware of the inextricable connections of these adverse pregnancy outcomes to maternal, newborn and child health (MNCH). Improved visibility of preterm births and stillbirths will help fuel investments and strengthen commitments in the discovery, development and delivery of low-cost solutions globally. This article addresses potential barriers and opportunities to increasing global awareness and understanding.
Qualitative research was conducted to analyze current knowledge, attitudes and commitments toward preterm birth and stillbirth; identify advocacy challenges; and learn more about examples of programs that successfully advocate for research and appropriate interventions. Forty-one individuals from 14 countries on six continents were interviewed. They included maternal, newborn, and child health advocates and implementers, United Nations agency representatives, policymakers, researchers, and private and government donors.
A common recognition of three advocacy challenges with regard to preterm birth and stillbirth emerged from these interviews: (1) lack of data about the magnitude and impact; (2) lack of awareness and understanding; and (3) lack of low-cost, effective and scalable interventions. Participants also identified advocacy opportunities. The first of these opportunities involves linking preterm birth and stillbirth to the MDGs, adding these outcomes to broader global health discussions and advocacy efforts, and presenting a united voice among advocates in the context of broader MNCH issues when addressing preterm birth and stillbirth. Another key opportunity is putting a human face to these tragedies—such as a parent who can speak to the personal impact on the family. Lastly, several interviewees suggested identifying and engaging champions to garner additional visibility and strengthen efforts. Ideal champions will work collaboratively with these and other maternal, newborn and child health issues. Conclusion: Advocacy efforts to add preterm births and stillbirths to broader MNCH goals, such as the MDGs, and to identify champions for these issues, will accelerate interdisciplinary efforts to reduce these adverse outcomes. The next article in this report presents an overview of related ethical considerations.
PMCID: PMC2841773  PMID: 20233386
10.  The HELLP syndrome: Clinical issues and management. A Review 
The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10–20% of cases with severe preeclampsia. The present review highlights occurrence, diagnosis, complications, surveillance, corticosteroid treatment, mode of delivery and risk of recurrence.
Clinical reports and reviews published between 2000 and 2008 were screened using Pub Med and Cochrane databases.
Results and conclusion
About 70% of the cases develop before delivery, the majority between the 27th and 37th gestational weeks; the remainder within 48 hours after delivery. The HELLP syndrome may be complete or incomplete. In the Tennessee Classification System diagnostic criteria for HELLP are haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets < 100·109/L. The Mississippi Triple-class HELLP System further classifies the disorder by the nadir platelet counts. The syndrome is a progressive condition and serious complications are frequent. Conservative treatment (≥ 48 hours) is controversial but may be considered in selected cases < 34 weeks' gestation. Delivery is indicated if the HELLP syndrome occurs after the 34th gestational week or the foetal and/or maternal conditions deteriorate. Vaginal delivery is preferable. If the cervix is unfavourable, it is reasonable to induce cervical ripening and then labour. In gestational ages between 24 and 34 weeks most authors prefer a single course of corticosteroid therapy for foetal lung maturation, either 2 doses of 12 mg betamethasone 24 hours apart or 6 mg or dexamethasone 12 hours apart before delivery. Standard corticosteroid treatment is, however, of uncertain clinical value in the maternal HELLP syndrome. High-dose treatment and repeated doses should be avoided for fear of long-term adverse effects on the foetal brain. Before 34 weeks' gestation, delivery should be performed if the maternal condition worsens or signs of intrauterine foetal distress occur. Blood pressure should be kept below 155/105 mmHg. Close surveillance of the mother should be continued for at least 48 hours after delivery.
PMCID: PMC2654858  PMID: 19245695

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