Given the myriad steps involved in fetal growth, each presenting the opportunity for developmental mischief, it is not surprising that more than 7,000 kinds of birth defects are known to occur. The causes of birth defects remain largely a mystery, however, although a few culprits have been identified as important contributors, including some environmental agents.Reducing Birth Defects: Meeting the Challenge in the Developing World. Experts in the developed world often have similar concerns, because in many regions birth defects are the largest single cause of infant deaths.In the developing world, where malnutrition, poverty, disease, and lack of access to health care elevate prenatal risk, birth defects impose “enormous personal and societal consequences,” according to the 2003 Institute of Medicine report But reliable numbers for both defects and cases remain unclear, due in large part to a lack of funding, coordinated monitoring efforts, and adequate data. The causes of only about 30% of birth defects are somewhat well understood, and knowledge even of those is sometimes spotty. The 70% still unknown leaves open the possibility that environmental factors could play a significant role. “There are all kinds of classification and data challenges that are tough to overcome,” says Ted Schettler, science director of the nonprofit Science and Environmental Health Network. “It almost makes cancer tracking look easy—[those researchers are] getting pretty standardized data that’s completely not available in the world of birth defects.”There is no universally accepted definition of what constitutes a birth defect. The term is sometimes limited to apparent structural problems, but often is expanded to include defects in function, metabolism, or body chemistry that lead to physical or mental problems or to death. Premature birth and low birth weight, which are linked with numerous health problems later in life, also can be influenced by birth defects, although factors such as young maternal age and poor access to medical care contribute as well. Birth defects also can be a contributing factor to some miscarriages and stillbirths.Global Report on Birth Defects: The Hidden Toll of Dying and Disabled Children, a 2006 report by the March of Dimes Foundation, a birth defects research and advocacy group. The authors say their report is the first to provide global, country-by-country data on birth defects, with information from more than 190 nations. The report is especially helpful as a springboard for further investigation because 85% of the world’s birth defects occur in developing countries, but only four such countries have birth defect programs that can track occurrences, says Li Zhu, director of China’s National Reference Laboratory on Reproductive and Child Health.Worldwide, at least 7.9 million people are born each year with a birth defect, according to Global Report. Of those that survive, about 3.2 million will be mentally or physically disabled for life, although some of these effects may be mitigated with appropriate care. Actual numbers may be much higher, according to some experts, because they don’t account for certain functional and developmental birth defects, and because surveillance data on birth defects remain relatively primitive. Moreover, elective abortion after defects are detected via screening can mask the true incidence.Of the children affected by birth defects, at least 3.3 million worldwide die each year before age 5, according to the Based on the report’s estimates, birth defects affect about 4% of live births in high-income countries and about 8% in low-income countries, with a global average of about 6%. In the United States, the Centers for Disease Control and Prevention (CDC) estimates 3% of children born each year have a major structural birth defect that appears by the sixth birthday. That translates to about 130,000 U.S. children per year, although other estimates put the number as high as 325,000. These and other estimates often don’t include stillborn deaths, of which about 16% are caused by birth defects, according to the California Birth Defects Monitoring Program.Figures from the National Center for Health Statistics indicate that birth defects cause about 20% of infant deaths in the United States. There are large geographical differences in the United States for infant death rates overall and for deaths attributed to birth defects. For deaths associated with birth defects, which averaged 0.43% of all infant deaths from 1999 to 2005, the South and Midwest are both about 40% higher than the Northeast. These large geographic variations readily allow for the possibility that variations in environmental exposures may be playing a role. They also reflect differences in local culture, socioeconomics, health care, and genes (some of these factors can in turn influence the rate of elective abortion). But they likely also reflect reporting and data quality variations, says Craig Mason, president of the National Birth Defects Prevention Network—hence the need for improved surveillance systems at a time when such programs are being cut or risk being eliminated altogether.Lorenzo Botto, an associate professor in the University of Utah Division of Medical Genetics, agrees, saying, “A real problem is lack of funding. Birth defect programs are being cut, even in terms of basic surveillance infrastructure, or funded just to maintain basic monitoring capacity. This is true in the United States [but] even more so in developing countries, where there is not much spare capacity to look at environmental studies.”When it comes to fetal exposures, any exposure that occurs by way of the mother typically is considered “environmental.” A relatively small proportion of birth defects can be attributed, at least in part, to specific environmental causes such as maternal disease  or use of pharmaceuticals . However, the majority of birth defects are considered the result of multiple environmental and/or genetic causes acting together. Lack of sufficient folic acid in the diet, for example, is one environmental factor now being remedied with supplements and food fortification. Among other environmental exposures with some incriminating evidence are other nutrient imbalances, maternal smoking and alcohol use, pesticides, tap water disinfection by-products, plastics and plastics components, solvents, metals, and numerous air pollutants .Pinning down the role of environ mental agents remains a daunting challenge, however. “Of all the antecedents of birth defects, environmental factors are least well understood,” says Michael Katz, March of Dimes senior vice president for research and global programs. “This is inevitable inasmuch as there are few isolated influences. In most situations the environment imposes an avalanche of possible stimuli, some beneficial, many neutral, and others possibly harmful. Add to this the possibility that interactions between two such factors—or more likely among many—may result in different effects, and you have an inkling of the complexity of the problem.” Officials from the California Birth Defects Monitoring Program also point to the difficulty of extrapolating from animal data to human health effects, our lack of knowledge about the role of genetic factors in birth defects, and the lack of data on both exposures during pregnancy and the effects of specific exposures on the fetus.Many experts are concluding that genetic factors are always implicated in birth defects. “We don’t know of any environmental exposures where a hundred percent of kids are affected,” says Tina Chambers, a perinatal epidemiologist in the Division of Dysmorphology and Teratology at the University of California, San Diego. “We think there are gene–environment interactions with all these [cases].” However, even with the many environmental red flags that have been raised so far, the field of investigation remains vast. “We really don’t know the right questions to ask,” Chambers says.There’s no shortage of ideas on ways to improve our understanding of birth defects and the role of the environment. Stuart Newman, a professor of cell biology and anatomy at New York Medical College, is in the camp of those recommending major shifts in thinking. He would like to see birth defects as a whole addressed at multiple levels from the micro to the macro. “It will take a more integrated and holistic approach,” he says. His preference is to meld the fields of genetics, developmental biology, evolutionary developmental biology, environmental science, and sociology—fields that often have a near or total disconnect among them—although he acknowledges there aren’t yet good models for how to do this.Betty Mekdeci, executive director of the advocacy group Birth Defect Research for Children, says there are many problems with the basics of how birth defects are tracked and evaluated. Her experience of more than 30 years—prompted by her efforts, and those of her husband, to figure out why their son was born with multiple birth defects—led her to conclude that some of the most important limitations include inadequate medical diagnostic codes for classifying many birth defects, inaccurate use of codes by health care practitioners to meet insurance billing requirements, and the inability of many health care practitioners to diagnose a birth defect at birth or in follow-up visits, and skepticism toward the input of parents, who usually know better than any one doctor about the full range of health problems their child is having.To overcome some of these problems, Mekdeci and her colleagues have developed an alternative method of tracking birth defect incidence based on parent responses to a lengthy questionnaire. About 6,000 completed questionnaires have been collected since 1990. Mekdeci and her staff analyze the questionnaire responses for patterns, and she reports they have identified about half a dozen clusters so far. Although the group readily acknowledges these are self-reports from a self-selected population, some of the clusters have later been confirmed by various government agencies. For instance, in Dickson, Tennessee, they detected a cleft palate cluster that was confirmed by the CDC. The group sees its role as identifying birth defect cases and then encouraging health agencies to investigate.Journal of Trace Elements in Medicine and Biology, this interaction may be very important to public health, he says. However, it has rarely been studied in humans.Assuming the current modes of thinking and operating continue for a while, Schettler says better use of existing information and resources can still be very beneficial. “We should be doing some cross-agency work to better simulate [exposures in] the world we live in,” he says. “It’s sort of a failure of our [research] system to not think out of our silos.” As one example of such failures, he cites evidence based on animal studies that the teratogenic action of valproic acid is exacerbated with concurrent zinc deficiency and reduced with zinc supplementation. Because zinc deficiency affects an estimated 25–40% of the general population worldwide, according to a report by Wolfgang Maret and Harold H. Sandstead in the 10 May 2006 Put another way, says Helen Dolk, project leader for EUROCAT , “On the one hand we act too little on the environmental causes we know about, and on the other hand we do too little research to find out more about the environmental causes.”However, Dolk points out, “There is surveillance, and there is research, and there is a spectrum between the two. We need specifically designed research—this does not need to be nationwide, but components of it will need very big population numbers, as birth defects are relatively rare. Research will be largely hypothesis-testing. . . . We also need surveillance, or tracking, which will throw up areas of concern and is more frequently hypothesis-generating. Putting all our resources in one of these areas without the other will not achieve the results we need.”Moreover, she adds, “Funding often follows ‘fashions’ and dogma, and we need a balanced approach, judging case–control, cohort, and other studies on their own merits, rather than completely turning from one type to another.”Even if none of the recommended shifts in overall approach occur, other major adjustments are needed before much more progress can occur, says Christopher Howson, vice president for global programs at the March of Dimes. Paramount among these is more leadership and guidance from the World Health Organization (WHO). “The WHO is a very important player in international health,” Howson says. “To get the imprimatur of the WHO gives health ministers the authority they need to address [specific health] issues.”The WHO has addressed birth defects to some extent, but the issue “has not been on the priority list of the WHO agenda yet,” Zhu says. Dolk adds, “The WHO needs to incorporate prevention of birth defects into programs to tackle major health determinants and improve maternal and reproductive health, recognizing the importance of environmental causes of birth defects.”Howson says it’s critical to have individual countries establish a consistent national policy and approach for certain key elements, including the birth defects covered and the identification and tracking methods used. Within such a framework, he recommends designating a point person in one federal agency in each country as having central responsibility. That official would coordinate with representatives from other agencies to orchestrate consistency of identification, tracking, and reporting methods; agreement on what birth defects to track; and even basic logistical elements such as ensuring that software packages used are compatible with various computer systems. With that kind of structure in place, he would like to see all health-related programs in a country incorporate relevant birth defect information into their work, whether it’s related to nutrition, disease, pollutants, genetics, or other fields. He also would like to see the WHO and individual countries develop extensive education programs to inform both citizens and health professionals about birth defects, known causes and remedies, and other basic information.Dolk raises another issue—that of data confidentiality and parental consent for babies with birth defects to be included in surveillance systems. “Experience shows that most parents do not refuse [to participate] and even expect this for the good of future babies,” she says. “However, requirements to obtain consent can be logistically very difficult and costly to implement—in a number of European countries this problem has not been solved adequately to allow data to be fully used.”In still another arena, experts are split to some degree on whether a centralized national health system, in which everyone’s comprehensive health records are accessible from one source, is necessary for robust surveillance. Dolk says, “Experience has generally been that centralized national systems result in poor data compared to decentralized systems closer to those producing and using the data.” However, she adds, this depends on the size of the country and on the types of information systems available for use and linkage. “Thus,” she says, “national Scandinavian systems work well.”Norway and Denmark have extensive data for just about everyone in the country, including health records, socioeconomic and occupational information, and other demographics. “These countries have been able to do some very cool linkage studies,” says Andrew Olshan, chairman of the Department of Epidemiology at the University of North Carolina at Chapel Hill. Some of those studies have been conducted through the Norwegian Mother and Child Cohort Study and the Danish National Birth Cohort Study. Each study is evaluating about 100,000 women and their children over the course of at least 15–20 years for a wide range of factors, including selected birth defects. However, evaluation of any links between birth defects and environmental exposures is likely to be limited due to constraints on the quality and availability of data for specific toxic exposures.Birth Defects Research: Part A: Clinical and Molecular Teratology.Margaret Honein, Birth Defects Branch chief in the CDC’s National Center on Birth Defects and Developmental Disabilities, believes a decentralized approach also can work. “I think what’s needed is to make sure it’s possible to do good surveillance, with nothing obstructing [state programs],” she says. “What’s most important is to get high-quality data from all the programs.” However, in the United States, about 10% of states don’t even have a birth defects registry, about 20% have very limited data, and the remaining 70% have data that often can’t be compared state-to-state, according to “Population-Based Birth Defects Surveillance Data from Selected States, 2001–2005,” a CDC report that constitutes the December 2008 issue of Birth Defects and Developmental Disabilities: The Search for Causes and Cures. The number of states that track such links in at least some way may be slightly higher now, says Mason, although he reiterates that recent economic problems are causing some states to cut back on their birth defect programs.Even more limiting, from an environmental perspective, is that two-thirds of U.S. states don’t explore any links between birth defects and environmental exposures, according to a 2005 report from the health advocacy group Trust for America’s Health titled The National Children’s Study (NCS), just getting under way in the United States, is expected to include extensive data on the effect of environmental exposures on fetal and child health. The NCS offers the best chance in the near term of improving our knowledge of links between environmental factors and birth defects, according to Chambers.Most birth defects research to date has been conducted retrospectively, relying on recall of study participants of events often occurring many years earlier, and lacking data on actual specific exposures of participants. In contrast, the NCS aims to enroll 100,000 women from representative populations and follow their children from conception through age 21. The NCS will collect biological samples from parents and children as well as samples of air, drinking water, interior dust, and soils from participants’ homes. These will be stored along with all medical records, giving future researchers the ability to evaluate a wide range of structural, functional, and developmental birth defects, says NCS acting director Steven Hirschfeld—even though we may not have the insights or tools to know what to look for or how to look for it today.Chambers, who is a principal investigator in the study, says early results should begin to trickle out in about five years; data on birth defects that show up soon after birth will be among the first available for each participant.The Oncologist, Karen R. Rabin and James A. Whitlock note that children with Down syndrome have a 10- to 20-fold higher risk of some form of childhood leukemia, although studies of potential environmental factors connecting the two conditions have been inconclusive. However, recent research is showing that the relationship between childhood leukemia and genetic abnormalities present at birth may extend further, says Carol Kasten, a geneticist at the U.S. National Cancer Institute—and I4C is expected to provide more insights.Even more statistical power could someday be available by combining study resources. A prototype for such research is the International Childhood Cancer Cohort Consortium (I4C), which is just beginning to analyze its first batches of data. The I4C project is an ambitious effort to facilitate apples-to-apples comparisons among multiple studies for specific end points. The initial focus is on childhood leukemia, which has been linked for many years with Down syndrome. In a review published in the February 2009 issue of The initial I4C group, whose first workshop was held in 2005, included 11 cohorts from 9 countries. Some of these studies were already well under way, others only just starting. Among those with higher numbers of participants are the NCS in the United States, the Danish and Norwegian studies, and studies in China and Israel. Others have far fewer participants, sometimes just a few thousand. But all combined, I4C includes about 700,000 mothers, and at least some of the cohorts will be able to provide data on environmental factors such as pesticides, tobacco smoke, and electromagnetic fields.Research projects from other countries that have been invited to attend a November 2009 I4C conference in Lyon, France, may also join the group. These include projects in Brazil, Canada, Japan, the European Union, South Korea, and South Africa. A second Chinese program  currently in its pilot phase could add hundreds of thousands more mothers.If the I4C program works as expected, it could bode well for birth defects research. “I’m sure we’ll get to birth defects at some point with I4C,” Kasten says. A similar program focusing specifically on birth defects of all types doesn’t exist yet, Kasten says, “but certainly people are wondering, ‘Why don’t we do that?’”In addition to these efforts, a few studies of links between certain birth defects and environmental agents have been conducted using data from some of the 43 registries in 20 countries that participate in EURO-CAT. This network of European population-based registries began in 1979 and today includes about 30% of the European birth population. A parallel compilation of continent-wide data has occurred since 1974 through the Latin American Collaborative Study of Congenital Malformations. This study focuses on genetics, pharmaceuticals, alcohol, smoking, nutrition, and maternal disease, but links to pollutants are studied extremely rarely. The International Clearinghouse for Birth Defects Surveillance and Research, also operating since 1974, provides a forum for collaboration among countries from around the world. It does not itself offer a specific mechanism for tracking impacts of specific environmental agents, but some of its members do conduct such research.Still more information on environmental links to birth defects may come from the Metropolitan Atlanta Congenital Defects Program, one of the oldest such programs in the world, operating since 1967. It is limited in geographic coverage, including residents of just five central-Atlanta counties, but it conducts active surveillance of major structural birth defects through doctors’ offices, clinics, and genetic laboratories rather than relying on hospital birth records, which is a limitation of some registries. Whereas many registries stop at birth or after the first year of life, the Atlanta program follows children up to their sixth birthday, which is important because some defects are not associated with any symptoms until the child is older. Honein says a few projects involving environmental substances (which she declined to name) are in the early stages, and results from initial studies may be available within a year or so.In addition to the Atlanta program, four of the nine CDC-supported Centers for Birth Defects Research and Prevention may soon begin to publish a few insights related to various environmental exposures, Honein says. These centers are participating in the National Birth Defects Prevention Study, the largest etiologic study of its type ever conducted. Each year, each center identifies approximately 300 new mothers of children with common birth defects as well as 100 control mothers. Doctors and researchers review each case in detail, looking for known or suspected factors. Various centers are studying agricultural pesticides, disinfection by-products, and hazardous waste emissions, among other exposures. The study began in 1997, and the database now includes about 25,000 births. In addition, CDC officials are in the early stages of considering studies of additional air, water, and soil pollutants and utilizing other environmental data, Honein says.Other efforts that may generate information related to environmental exposures are expected to trickle out via other independent and government agency research around the world. But although these efforts to improve information about environmental and other causes of birth defects offer some potential for expanded knowledge, the broader-scale limitations of making significant advances, including a perennial lack of funding, leave some critics skeptical.Others are more optimistic, however. Howson sees the progress made so far, and the groundwork that has been laid for future progress, as something akin to a favorite children’s activity: “It’s like a kid going out into the street to bang his drum. Another kid joins him, then another and another. By the end of the street, you have a parade.”


The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV was not available during several periods. We took advantage of this “natural experiment” to test the effect on mortality of receiving OPV at birth.Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR) of children who had received or not received OPV at birth.A total of 962 (22.1%) of the 4345 enrolled children did not receive OPV at birth; 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI = 0.46–1.03)), the effect being similar among recipients of VAS and placebo. There was a highly significant interaction between OPV at birth and sex (p = 0.006). Not receiving OPV at birth was associated with a weak tendency for increased mortality in girls (1.14 (0.70–1.89)) but significantly decreased mortality in boys (0.35 (0.18–0.71)).In our study OPV at birth had a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted. In low-income countries, the World Health Organization (WHO) recommends oral polio vaccine (OPV) at birth and in 3 doses together with diphtheria-tetanus-pertussis (DTP) vaccines at 6, 10, and 14 weeks of age Routine vaccinations in childhood may have non-specific and sex-differential effects on overall mortality a priori hypothesis was that not receiving OPV at birth would increase mortality, particularly for girls.We recently conducted a large vitamin A supplementation trial in Guinea-Bissau. Children were randomised to 50,000 IU vitamin A or placebo when they received BCG after delivery The Bandim Health Project (BHP) has a demographic surveillance system (DSS) which covers approximately 90,000 inhabitants in six suburban districts of the capital of Guinea-Bissau. All houses are visited monthly to register new pregnancies and births. Children are followed with home visits every third month to register vaccinations, infections, hospitalisations, feeding patterns and survival. The study area is economically poor. Most people live in multi-family mud-brick houses with zinc or straw roofs. More than 60% have no electric installations in the house. Around 30% of the mothers in the present trial had no education. During the trial, the prevalence of HIV-1 was around 5% in the study area among women of fertile age As described in detail elsewhere Details regarding the trial were explained to the mother by a trained assistant, who also asked the mother if she had any questions about the study. Oral consent was obtained. Written consent was obtained if the mother knew how to write her own name. If not, a statement that she had understood the information given and agreed to participate was signed by the assistant. The mother drew a lot from an envelope prepared by the study supervisor. Each envelope contained 100 lots, 50 marked “1”, and 50 marked “2”, indicating from which of two numbered bottles, “1” or “2”, the child should receive its supplement. Hence, half of the children received 50,000 IU vitamin A as retinyl palmitate and 20 IU vitamin E in ½ ml vegetable oil, the other half received only 20 IU vitamin E in ½ ml vegetable oil. The code was only opened when all children had reached 12 months of age.All children were followed through the DSS every third month and were visited by a special team at 12 months of age. Deaths were registered at each visit and followed by a verbal autopsy conducted by a trained local physician. The physician used a questionnaire designed by the INDEPTH network All trial infants were vaccinated intradermally in the upper left deltoid region with 0.05 ml BCG vaccine . The BHP provided BCG vaccine for the trial participants. According to recommendations all infants should also receive OPV at birth. OPV is administered orally. During the study three types of OPV were used in Guinea-Bissau, produced by Novartis, Sanofi Pasteur, and GlaxoSmithKline. All vaccines were supplied through the national immunization programme. However, OPV was missing during periods of the trial. Hence, the children who were BCG vaccinated during these periods would only receive BCG and not OPV. As part of our trial routines, we noted at the inclusion form whether the children received OPV or not. Based on the distribution of children who had not received OPV, OPV was missing at one or more inclusion sites 1) from the beginning of February 2004 to the beginning of June 2004, 2) briefly in late June 2004, and 3) from mid-October 2004 to the trial enrolment ended in November 2004 . Hence, We compared baseline characteristics of children who had or who had not received OPV at birth in a logistic regression analysis including all variables in order to identify important potential confounders, which could be adjusted for in subsequent analyses.not receiving OPV at birth on the following three outcomes: mortality, hospitalisation and risk of dying when hospitalised . All analyses were conducted including all children as well as stratified by sex, and without and with adjustment for potential confounders.In the main analyses we studied the effect of We compared mortality rates of children who had or who had not received OPV at birth in Cox proportional hazards models Incidence rates of hospitalisation were also compared in Cox models with age as the underlying time providing incidence rate ratios (IRR) with 95% CI. Multiple events were allowed, accounting for dependence within individuals using robust variance estimates. Infants provided follow-up time from enrolment until they reached 12 months of age, moved, or died.Hospital case-fatality was compared using a Poisson regression model with robust variance estimates providing relative risks with 95% CI We aimed to study potential effect modification. Effect modification was analysed by investigating the homogeneity of the effect of OPV in the different categories of the suspected modifier using Wald test statistics. Hence, we obtained p-values for equal effect of receiving or not receiving OPV in different strata of a covariable. When addressing the effect of OPV according to birth weight and arm circumference, we restricted the analysis to children enrolled on day 0 and 1 (N = 2572) for whom information on birth characteristics was available and dichotomised the anthropometric measurements into the lowest quartile and the three highest quartiles.Test for proportionality of hazard rates were computed using Schoenfeldt residuals and by visual inspection of the Nelson-Aalens estimator.not receive OPV at birth  of the 4345 enrolled children did at birth . There wat birth . Not havy season . Missingnot having received OPV had essentially no impact on the overall and sex-specific estimates or the interaction term ) but 20% lower mortality among children who had received OPV at birth (0.80 (0.58–1.11)).A total of 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality from enrolment to age 12 months . There wion term . In otheThere were two major periods without OPV. Among children enrolled from January 2004–June 2004, the overall adjusted estimate was 0.72 (0.38–1.38); 0.52 (0.18–1.49) in boys and 0.87 (0.38–2.00) in girls. Among children enrolled from July 2004 and until the end of the trial in November 2004 it was 0.62 (0.22–1.80); 0.24 (0.03–1.86) in boys and 1.22 (0.34–4.44) in girls.The cumulative mortality curves for all children and for boys and girls separately, are illustrated in The effect of missing OPV at birth was the same in the vitamin A and placebo groups (data not shown). The effect did not vary with age at inclusion (data not shown). Furthermore, the effect did not vary with place of enrolment , or by season (data not shown). The negative effect of missing OPV was seen in boys of educated as well as mothers without any schooling (data not shown), and in children with lower birth weight and arm circumference as well as those without (data not shown).We studied the effect of missing OPV at birth on the major causes of death: malaria, diarrhoea, respiratory diseases and septicaemia; 58 deaths had other less common causes of death or had no verbal autopsy conducted because the family had moved. Though none of the differences reached statistical significance, the sex-differential effect of OPV at birth was seen for all four major causes of death .Among study children, a total of 366 hospitalisations took place from enrolment to 12 months of age. We found no effect of missing OPV at birth on the risk of hospitalisations within the first year in either sex; the adjusted IRR among boys being 0.84 (0.59–1.20) and 1.05 (0.68–1.63) among girls. The effect of missing OPV at birth on hospital case-fatality also did not differ between boys and girls, the adjusted relative risks being 1.04 (0.45–2.40) and 1.30 (0.55–3.07), respectively.The WHO recommends OPV at birth. The effect of OPV on mortality has never been investigated. In our study, missing OPV at birth was associated with significantly reduced mortality among boys but a weak tendency for increased mortality among girls, indicating that OPV at birth may have a sex-differential effect on mortality.not receive OPV. These children may have had a higher risk of dying during the first year of life a priori. However, control for maternal education and arm circumference did not change the estimates much. Also, if it was the less well-off children who did not receive OPV, it would not explain the significantly lower mortality among boys who did not receive OPV. In conclusion, we do not think that there is any plausible uncontrolled background factor, which may explain our observation.The study was observational. Though it was a “natural experiment” in the sense that it was logistic that determined the availability of OPV there was nonetheless more children of uneducated mothers and with low arm circumference who did not receiving OPV was comparable during the two major independent periods without OPV. Though no significant associations were observed between not receiving OPV at birth and major causes of death, hospitalization or hospital case-fatality, the pattern was the same. For all major causes of death there was lower mortality for boys and higher for girls if they had not received OPV; for both hospitalization and case-fatality there was a 20–25% difference between boys and girls which went in the same direction as the overall result. Hence, the results are compatible with the hypothesis that OPV at birth increases mortality of infant boys. Many factors influence a mother's choice to bring the child to the hospital, and hospitalizations may not be the best proxy for severe disease. The vast majority of children died outside the hospital.It strengthens the observation that the effect of We have found sex-differential effects for almost all routine vaccinations. Our previous studies of OPV did not show any strong sex-differential effects OPV given with BCG at birth became policy for logistic reasons. Subsequently a single study showed that it may increase antibody titres. The effect of providing OPV at birth on overall mortality was never tested. Many routine vaccines have non-specific effects on mortality that affects boys and girls differently. This “natural experiment” suggests that the same may apply to OPV administered with BCG at birth. Not receiving OPV at birth was associated with a tendency for increased mortality in girls, but significantly decreased mortality in boys. There is political interest in substituting OPV with IPV The protocol was presented to the Ministry of Health in Guinea-Bissau and the Danish Central Ethical Committee for approval (624-02-0010). The study was registered under clinicaltrials.gov, number NCT00168597.Appendix S1Trial profile.(0.03 MB DOC)Click here for additional data file.


However, we found no evidence of associations between birth characteristics and risk of colorectal cancer ( Colorectal cancer is associated with type-2 diabetes  .2). Alcohol consumption  was classified according to the recommendations by World Health Organisation as low, medium or high  and uncertain correct identification of each twin within a twin pair at birth (n=2381), resulting in a final study population of 23 337 twins .For this study, all like-sexed male and female twins with known zygosity born in 1926–1958 were considered. For the 32 011 twins who were alive and without earlier diagnosis of colorectal cancer at start of follow-up in 1973, the birth record coverage was 73%. Restrictions were because of missing birth weight data in birth records  was accrued from the time of entry  until a first diagnosis of colorectal cancer or censored at the date of first emigration from Sweden, death or end of follow-up (31 December 2006). Cox proportional hazard models were used to estimate hazard ratios (HRs) for colorectal cancer with age (measured in months) as the underlying time scale, and robust standard error estimates to account for the dependence within twin pairs.We estimated the independent risk of colorectal cancer for all exposure variables . DiffereIn our cohort of 23 337 twins, 248 developed colorectal cancer during the follow-up period. n=8757) in the model and only adjusted for birth characteristics . There were no significant interactions between sex and birth weight or birth length with respect to risk, in neither the crude  nor the fully adjusted models .n=144), the mean birth weight (s.d.) was 2761 g (507) and 2756 g (487) among cases and co-twin controls, respectively (P=0.94). In monozygotic disease-discordant twin pairs (n=86), the corresponding mean birth weights (s.d.) were 2610 g (495) and 2642 g (550), respectively (P=0.69). Similarly, there were no differences in mean birth length within dizygotic or monozygotic disease-discordant twin pairs (data not shown).To account for familial  factors, we also carried out analyses within disease-discordant twin pairs. In dizygotic disease-discordant twin pairs  factors and perfectly match for gestational age, these negative findings further strengthen the hypothesis that foetal growth is not related to offspring risk of colorectal cancer.A J-shaped relation between self-reported birth weight and colorectal cancer was initially reported by a British study, including 96 cases (The generalisability of results from twin studies may be questionable as twins are in general more growth restricted than singletons, have shorter gestational age, and because they may differ in prenatal environment and upbringing. However, the incidence of colorectal cancer does not appear to be different in twins compared with singletons (This study lends no support for an association between birth characteristics and risk of colorectal cancer. The conflicting results from the few earlier studies may be because of limited statistical power, but it is relevant that the underlying biological reasons for an association with birth characteristics remain speculative.


Many phthalates and phenols are hormonally active and are suspected to alter the course of development.We investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth.We measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth.Median urinary concentrations were > 10 μg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age  and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol  predicted lower birth weight in boys . Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys.We observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors. Phthalates and phenols include a number of chemicals that are hormonally active and therefore might be expected to alter the course of fetal development. Fetal exposure is indicated by their detection in amniotic fluid . PhthalaLess is known about phenols and their precursors. Bisphenol A (BPA) has elicited great interest because of its hormonal activity; it is found in resins and polymers used for dental sealants and container linings. BPA is hormonally active in rodents exposed in early life . PrenataAmong U.S. residents, urinary concentrations of biomarkers derived from phthalates and phenols have been relatively high compared with pesticides . The hign = 3), infant or fetal demise (n = 2), very premature births  (n = 5), miscarriage (n = 1), delivery of an infant with genetic abnormalities or malformations (n = 5), inability to collect biologic specimens before birth (n = 12), change of hospital or residence outside New York City (n = 28), or loss to follow-up or refusal to continue to participate (n = 19). The study was approved by the Institutional Review Board of Mount Sinai School of Medicine; participants provided written informed consent before the study. Maternal urine samples were obtained, mostly during the third trimester: 25% of samples were collected between 25 and 30 gestational weeks, 45% between 31 and 35 weeks, and the remainder between 36 and 40 weeks. Questionnaire information regarding maternal characteristics was collected by interview, and birth outcomes  were obtained from a computerized perinatal database within the Department of Obstetrics, Gynecology, and Reproductive Science at Mount Sinai Hospital. Gestational age was assigned using reported date of last menstrual period.The Children’s Environmental Health Study is a prospective ethnically diverse birth cohort of 404 mother–infant pairs; the study design and protocols have been described previously in more detail . In brieWe analyzed maternal urine samples for 5 phenol and 10 phthalate metabolites using laboratory and quality control methods that have been reported previously . From thp < 0.10 by the Spearman correlation (rS), the Kruskal–Wallis rank-sum statistic, or the chi-square test. These included race/ethnicity (white vs. nonwhite), infant sex, gestational age at delivery , ln-creatinine, prenatal smoking (ever vs. never), maternal prepregnancy body mass index , education (high school or greater), and marital status . Associations that were significant at the p < 0.05 level in models with exposure represented as a continuous (log-transformed) variable we further examined by substituting tertiles of the biomarkers (micrograms per gram creatinine) to assess the linearity of the effects. We included ln-biomarker as micromoles per liter or micrograms per liter in these models; models that used biomarkers as the ln-μg/gC concentrations produced almost identical β-values. Timing of urine collection may reflect differences in use of products that cause exposure to these metabolites, such as sunscreen, or differences in water retention by mothers. Therefore, in sensitivity analyses, we entered the variables for year, season, and gestational age at urine collection individually into the multivariate-adjusted models; none altered the coefficients, so we did not include them in the final models. Weight gain during pregnancy was also available in a subset of the population; when included in the multivariate-adjusted models, it did not alter the coefficients of the exposure variables, and therefore we did not include it in the final models.Statistical analyses were performed using SAS-PC, version 9.1 . Continuous biomarker values and creatinine were natural log transformed (ln) to produce more normal distributions. Tertiles of biomarkers were created using the creatinine-corrected values. Predictors of birth weight, length, head circumference, and gestational age at delivery were analyzed using generalized linear models. Covariates were included in multivariate analyses if they were related to the birth outcomes or to biomarkers at n = 28) we excluded because they altered the β-values for almost all analytes by more than 10%. We also used this restriction in our earlier study of pesticides for the same reason . In addition, to further elucidate relationships between the phthalate metabolites and body size, we ran logistic regression models predicting small- or large-for-gestational age  . We also present deviations from additivity  .2, average birth weight was 3,266 ± 465 g, and average gestational age was 39 ± 1.6 weeks, reflecting in part the exclusion of very preterm births. There were more boys than girls in the cohort, and the proportion was similar for all ethnicities (not shown).The women in this population were young  and largely nonwhite, and most had at least a high school education . AveragerS = 0.91, Pearson’s r = 0.93).As expected, exposures were prevalent. The median urinary concentration of monoethyl phthalate (MEP) was > 100 μg/L; median levels were > 20 μg/L for 2,5-DCP, monobenzyl phthalate (MBzP), monobutyl phthalate (MBP), and mono-2-ethyl-5-carboxypentyl phthalate (MECPP) . In addiIn bivariate analyses, we examined the relationship between phthalate and phenol biomarkers and maternal characteristics. Several biomarkers were significantly inversely correlated with marital status, BMI, education, and smoking history (data not shown). Inverse relationships of biomarkers with maternal age were not statistically significant. Most of the phthalate biomarkers and three phenols were higher among nonwhites, but TCS and benzophenone-3 (BP3) were higher among whites. BPA, 2,5-DCP, and 2,4-DCP were positively correlated with maternal prepregnancy BMI if the biomarker was expressed as micrograms per liter, but not if expressed as micrograms per gram creatinine. BP3 was inversely correlated with BMI, regardless of creatinine correction. When expressed as micrograms per liter or micromoles per liter all phthalate metabolites except monomethyl phthalate (MMP) had significant positive correlations with BMI. With creatinine-corrected concentrations (micrograms per gram creatinine or μmol/gC), the only significant correlations with BMI among phthalate biomarkers were MBzP (positive) and MMP (negative).n = 269) and for Hispanics (n = 168); in both groups, the trends were similar to those among all women, with the third tertile of maternal BP3 associated with heavier boys and lighter girls. The number of white mothers (n = 66) was too small to examine separately. Effects of both 2,5-DCP and TCS on birth length were similar to findings on birth weight, such that boys were approximately 0.3 cm shorter  per ln-2,5-DCP  and gestational age  and in other studies  and strongly associated with urinary creatinine levels . And finally, low-MWP metabolites were also strongly correlated with creatinine . Therefore, it appears that, in our data, maternal anthropometric features may affect the measurement of the exposure level (low-MWP), the measurement of the metabolite-level correction factor (creatinine), and the measurement of the outcome . Because our estimates of anthropometry in this study population were relatively crude , residual confounding of the low-MWP–gestational age/birth length relationship by maternal anthropometry is possible.The positive association we report between low-MWP metabolites and gestational age at delivery and birth length, although biologically plausible based on the animal literature, may also reflect unresolved confounding by the following mechanism. The correlation between low-MWP metabolites and BMI in our data  phenol, and thus it is structurally similar to 2,5-DCP. Our finding of increased male birth weight with higher maternal BP3 concentrations is unexpected and has no clear biologic basis. Although BP3 levels were higher in whites, consistent with putative use of sunscreen, the associations of BP3 with birth weight did not differ by race/ethnicity in this study. We saw no effects with BPA in our study, but BPA urinary concentrations were much lower than those of 2,5-DCP, TCS, and BP3 and may not have reached a level of biologic significance.Pregnant ewes treated with BPA had offspring with reduced birth weights, and their blood levels were greater than 35 μg/L on average, with adipose concentrations of 200 mg/kg . Experimin vitro, where bioassays have shown weak to modest estrogenicity . An additional limitation is that we had biomarkers measured once in the third trimester for exposures that ordinarily have relatively short half-lives (days). Consistency in levels during pregnancy has been observed for some environmental exposure biomarkers (Overall, for both phenols and phthalates, we found few significant associations in this study; for example, the findings in omarkers , whereasomarkers . Howeveromarkers ; less isomarkers . It is rCreatinine correction is commonly used for urinary biomarkers of phthalates, pesticides, phenols, and phytoestrogens. There are limitations to the use of creatinine to normalize for urine dilution; other investigators have used specific gravity instead of creatinine to adjust phthalate urinary biomarkers for urine dilution, but we did not have specific gravity measurements. However, specific gravity is highly correlated with creatinine , and theThe exposures we studied are relatively prevalent, and some biomarker levels approach those with significant effects in experimental models. In a healthy cohort such as ours, effects of hormonally active environmental exposures on birth size may be small, yet more sensitive end points such as infant neurologic development may be affected. A further dimension to consider in future research is multiple exposures of hormonally active agents such as these. In terms of prevention, exposure to these chemicals can be avoided if the product contents are known; unfortunately, they often are not listed on the label because they are not “active” ingredients.


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. As discussed in article 1 on data . AdditioPreterm birth and stillbirth are nearly invisible to the majority of health decision makers globally. Yet, both issues are of growing concern among health experts, scientists, and advocates in low- and middle-income countries (LMICs) and in high-income countries (HICs). Deaths due to preterm birth are on the rise in many HICs—despite having health systems with more resources to devote to improving maternal, newborn and child health outcomes .Despite the magnitude of these public health burdens, many causes of both preterm birth and stillbirth remain largely unknown. While research has been undertaken in HICs, no effective interventions have been identified to prevent preterm birth. Additionally, there is a lack of systematic evaluations of solutions to reduce the burdens of both outcomes, particularly in LMICs. Few believe enough resources have been allocated to thoroughly research these issues.Raising awareness and advocating for these issues has been difficult because of the lack of knowledge about the magnitude of the health, economic, and social impacts of preterm birth and stillbirth. The lack of low-cost, scalable interventions with proven impact for low-resource settings remains a barrier to advocating for more resources and funding.The interviews conducted for this article provide insight into current attitudes and commitments of global health leaders and organizations, financial partners, researchers, healthcare practitioners and other key stakeholders. This will enable advocates to examine the best strategies to implement successful, sustained advocacy efforts to prevent preterm birth and stillbirth.This article summarizes qualitative research on advocacy issues relating to global preterm birth and stillbirth. The research sought to answer the following questions:• What is the extent of knowledge on preterm birth and stillbirth?• Who has made these issues priorities, and why?• What has prevented governments and organizations from making them a priority?• What would drive future commitment and focus?• What are the advocacy elements of successful programs working on these issues?• What are the main challenges to conducting preterm birth and stillbirth advocacy?Information on attitudes, behaviors, value systems, concerns, motivations, aspirations, cultures and lifestyles was gathered through phone and e-mail interviews. This article is not intended to be used as a comprehensive scientific accounting of all relevant advocacy issues, and should not serve as an advocacy plan for organizations focusing on preterm birth or stillbirth. Rather, this article highlights issues and raises questions to inform the work of global stakeholders. The analysis and article do not reflect the opinions or recommendations of the interviewers.To conduct a balanced and comprehensive landscape review, interviews were conducted with a multidisciplinary sampling of representatives from a diverse number of organizations around the globe. Forty-one individuals working on issues related to preterm birth and stillbirth participated in the research interviews, including maternal, newborn and child health (MNCH) advocates and implementers; representatives from United Nations (UN) agencies; Non-Governmental Organizations (NGOs); policymakers; academics; researchers; and private and government donors.Together, the interviewees, located in 14 countries across six continents, offered a global perspective to the advocacy landscape of preterm birth and stillbirth  about the magnitude and impact of preterm birth and stillbirth• The lack of awareness and understanding of preterm birth and stillbirth• The lack of low-cost, effective prevention methods and interventions for preterm birth and stillbirth "I think the biggest thing that's going to drive commitment and focus is to have…solid data on the magnitude of the problem. supported by doable interventions that are currently available…and showing the potential impact [of] those simple interventions"Mark Young, M.D., MHScUnited Nations Children's Fund (UNICEF)Country-level data on the prevalence and causes of preterm birth and stillbirth are largely unavailable and inadequate. Interviewees agree the lack of data greatly impedes efforts to get preterm birth and stillbirth on the global health agenda:"…if this information was consistently there every time you talk about maternal or infant mortality then the issue would get the visibility and the attention that it needs"						Nils Daulaire, M.D., M.P.H.Global Health Council					"…a lack of awareness and education about these deaths has hampered prevention efforts. In addition, there is a need for better data collection to help identify ways to prevent these deaths"Senator Frank R. Lautenberg, D-NJUnited States SenateInterview participants reported the following problems with data collection:• Preterm births and stillbirths are largely under-reported—whether in HICs or LMICs.• In most LMICs, health systems do not have the infrastructure and capacity to support the reporting of health data, especially on preterm birth and stillbirth.• Many women in rural settings do not deliver in facilities or with skilled attendants—if a baby is pre-term or stillborn, no formal record is kept.• There is often stigma associated with stillbirths, so women and families may keep them secret. As such:"…many stillbirths [and preterm births] go undetected and don't even become part of the statistics'.'Scott Jackson, M.B.A., C.F.R.E.PATHInterviewees also identified important challenges in collecting reliable data in HICs.• Because there are no national or international standards for reporting preterm births or stillbirths or for registries themselves, different information—and different levels of information—is recorded in different places, creating an inadequate and inconsistent database of information.• In order to create an international standard for reporting preterm births and stillbirths, international global health and government leaders must come to a consensus on some of the questions posed by some of our interviewees:- What are the rights of a stillborn?- Should stillbirths receive a birth certificate, a death certificate, or neither?- When a preterm baby or stillbirth is delivered, what is the standard set of data about the mother's background and health that should be recorded?- Are there any environmental factors that should be recorded?Interviewees broadly agreed that the lack of data—such as statistics, causes, and benchmark reports—is the main reason that countries, regardless of geographic location and GDP, have not made preterm birth and stillbirth priorities. The lack of data leaves important questions unanswered for policymakers and funders:• What is the magnitude of these issues?• What are the causes of these issues?• What can we do about these issues?• What are the costs and cost savings associated with addressing these issues?One interviewee reflected on her government: "I think that principally our government hasn't done much because they don't know the magnitude of the problems, and if they know the magnitude, they don't know what to do"Bertha Pooley, M.P.H.Save the Children, BoliviaAnother interview participant noted that advocates in this area can learn from similar efforts, particularly around neonatal deaths, where there have been similar challenges in lack of routine data collection and social taboos in mourning. The issue of newborn health is rising in importance on the global health agenda—not necessarily because of more data, but because of convincing systematic global estimates of numbers and causes of death, clearly framed links to the MDGs and a strong consensus on doable interventions:"[The issues of stillbirth and preterm birth] do not have to wait decades for perfect data—improved estimates and clear communication of the relevance of these for existing national goals and program investment is possible and crucial"Joy Lawn, BMedSci, M.B. B.S., M.R.C.P. (Paeds), M.P.H.Save the Children, Saving Newborn LivesWhile estimates of the magnitude of preterm birth and stillbirth do exist, these estimates are not the reliable numbers that advocates need in order to obtain funding for programmatic change. However, there are other ways to measure the impact, especially the economic and social impacts, of preterm birth and stillbirth. The results of which could be effectively used to raise awareness of the issues and advocate for resources or funding.Interview participants noted that the lack of information on the economic burden of preterm birth and stillbirth—a burden shared by governments, businesses and families—is debilitating, and that costing studies would be a very useful tool for advocates approaching policymakers and funders. Interviewees referenced the economic burden associated with the following list:• Preterm birth- Delivering and keeping preterm babies alive- The potential long-term health consequences of preterm babies - Women opting out of the workforce to take care of babies with health problems as a result of preterm birth- Additional cost of closer scrutiny to future pregnancies after a preterm birth• Stillbirth- Lost work days of mothers and fathers grieving for their stillbirths- Mental health and grief counseling- Women no longer participating in the workforce due to complications with pregnancy that can be avoided with prenatal care- Additional cost of closer scrutiny to future pregnancies after the delivery of a stillbirthMultiple experts indicated that because the majority of policymakers are men, hard numbers resonate more with topics like maternal health, where it might be harder to relate to personal stories about the plight and emotional burden of preterm birth and stillbirth for women and families. As Jill Sheffield stated about advocating to the G8 for maternal health funding:"The people who make decisions about the [allocation] of resources need [to know about] the economic impact [those resources and funds will have on the problem]."Jill SheffieldFamily Care InternationalInterviewees also reported the social and emotional impact that preterm birth and stillbirth have on families and communities:• Preterm birth- The emotional and financial strain that can be put on a family by the birth and the subsequent health conditions of a preterm baby- The integration issues a preterm child, enduring physical or learning disabilities, may face later in life• Stillbirth- The psychological and emotional burden on families having experienced stillbirth- The repercussions that having grief-stricken, anxious parents can have on siblings of a stillbirth.Because a stillbirth does not result in a baby needing care, multiple interviewees suggested that the public health burden of stillbirth is difficult for some policymakers and funders to understand—and therefore to allocate resources. As such, it will be important to explore and cost out the social impact of stillbirth to illustrate the public health burden of this issue.The lack of knowledge about preterm birth and stillbirth—promulgated by absent data and assessments of their economic and societal impact—has meant few opportunities for advocates to raise awareness of these issues.There are varying opinions on the degree to which different audiences—the healthcare community, policymakers, donors, the general public, and others—are aware of preterm birth and stillbirth as major health issues. However, there is general consensus that awareness and knowledge are sparse and incomplete, suggesting a long and important road ahead for advocacy and awareness-raising efforts.United States-based physicians and researchers reported a significant amount of research being conducted on preterm birth and stillbirth, and that these issues are priorities for obstetrician-gynecologists, neonatologists and pediatricians in HICs. According to these interviewees:• In HICs preterm birth receives far more attention than stillbirth, even within the medical community, as it is increasingly viewed as a public health burden with economic repercussions.• While there are studies on the causes of preterm birth, none have yielded conclusive findings to advance the prevention of preterm birth. Preterm birth rates continue to rise in both HICs and LMICs .• Though researchers have studied several therapies that could be used to prevent preterm birth, progesterone remains the only promising intervention at this time. Others reported the following:• The general public typically becomes aware of preterm birth and stillbirth through personal stories: giving birth to—or having an acquaintance deliver—a preterm baby or a stillborn.• Few audiences, including the medical community in HICs and LMICs, fully understand the link between preterm birth and all of the associated long-term health consequences.- Though people acknowledge the frailty of a preterm baby and potential complications that may ensue, they do not always establish linkages between preterm birth and potential repercussions such as cerebral palsy, vision problems, learning disabilities and others.• There exists a discrepancy in levels of awareness between HICs and LMICs.- Preterm birth and stillbirth are better known and recognized in countries like the United States, for example, where the medical community receives continuous training and organizations like the March of Dimes and First Candle conduct public education campaigns and political advocacy.- Preterm birth and stillbirth are relatively unknown in LMICs where preterm births and stillbirths are unreported, and few countries have stillbirth reporting systems.In LMICs, long-standing cultural misconceptions concerning preterm birth and stillbirth have perpetuated false information and beliefs, especially at the community level. Based on the experience of health campaigns and other similar advocacy efforts, these cultural beliefs, varying from country to country, will have to be factored into any successful advocacy plan .Interviewees identified numerous cultural nuances and perceptions about preterm birth and stillbirth. Below are some that could present challenges to advocacy efforts:• Misconceptions about the prevention of preterm birth and stillbirth- Preterm birth and stillbirth are inevitable— experts referred specifically to the deep sense of fatalism, hopelessness and defeat felt in many LMIC societies. In fact, in certain countries, babies are not named until they have survived their first year, given the high rates of neonatal mortality. In one interviewee's words, there is often a sense that:"… this is the way it's always been and it's the way it always will be"Nils Daulaire, M.D., M.P.H.Global Health Council- Stillbirth is sometimes seen as nature's way of intervening—when a baby is stillborn, some believe this means it was not meant to be born at that time, or had a physical or mental malformation. .• Societal treatment of preterm birth and stillbirth- Stillbirths are kept secret and are not to be discussed or mourned publically—families in LMICs (and in many HICs as well) view stillbirth as a taboo subject."Stillbirths are hidden. We know very little. It's kept quiet"Vinod Paul, M.D., Ph.D., F.A.M.S., F.I.A.P., F.N.N.F.All India Institute of Medical Sciences"…in many cultural situations there is a general mindset not to discuss stillbirth in an open fashion."George Little, M.D.Dartmouth Medical School- Preterm birth or stillbirth is perceived as the mother's fault, which leads to feelings of shame and remorse for women.•  Misconceptions related to science, medicine, and development- Stillbirths are like miscarriages—some believe that stillbirths do not have the same standing as babies who are born alive.- Some health officials in LMICs believe that preterm babies and low birth weight babies are the same. While most HICs differentiate gestational age from birth weight, this is not the case yet for many in international health circles, pointing to a need for knowledge and education so that preterm birth rates can be reported accurately, and the right interventions can be sought for both preterm birth and stillbirth.- In certain countries preterm babies are abandoned—especially girls—when the costs to treat medical problems that result from a preterm birth are worth more than the baby's life itself to the family. Also, families in some countries assume preterm babies will always be weak and do not know that with proper care, preterm babies can thrive.- When preterm babies survive a number of days or reach certain milestones, they are perceived to be "in the clear" without future medical needs. This notion is often perpetuated by news stories of miracle babies and by physicians failing to mention the long-term consequences a preterm baby may endure . Stillbirth is too unbearable for some organizations  to associate with, and preterm birth is an easier cause to advocate for because it still results in a baby that needs ongoing treatment and assistance, and not in a death.There is also a perception that there are little or no consequences on a baby's health and development if the delivery is scheduled several weeks early via C-section for the mother's convenience—a trend that is growing rapidly in HICs.As the examples illustrate, interview participants firmly believe that no country is the same when it comes to cultural nuances and perceptions surrounding maternal health, childbearing, newborn health, and other related issues. For successful advocacy, cultural nuances and perceptions must be closely examined and efforts must be tailored and adapted for each country and implemented by actors who will be cognizant of the cultural sensitivities at play . As one participant stated, this will be a matter of examining:"…the major issues for each country.rather than [taking] a global perspective."Marian Sokol, Ph.D., M.P.H.First CandleTo dispel some of the false cultural notions that are associated with preterm birth and stillbirth, interviewees suggest that advocates will need to build strategies based on reliable global, regional, and local data that are not available at this time.The lack of knowledge about the magnitude and impact of preterm birth and stillbirth, and the ensuing lack of awareness and understanding globally, remain some of the largest obstacles to conducting successful advocacy efforts. The advocacy challenge that must be resolved is not only quantifying the magnitude and the impact of preterm birth and stillbirth, but also presenting low-cost, effective interventions:"…showing what potential impact those simple interventions could have on the problem [. ] that's the most powerful thing that's needed."Brian HansfordUnited Nations Children's Fund (UNICEF)"If they can't propose coherent solutions, then policymakers are going to move on to the next issue. They'd rather put their resources into something they know they can do something about."Jeremy Schiffman, Ph.D.Syracuse UniversityAssessing the impact and magnitude of preterm birth and stillbirth is an important piece of the puzzle in creating a successful advocacy roadmap, though as many pointed out, it cannot be the whole puzzle:"…For governments and organizations to make this a priority, […] providing them with some examples of what can actually be done is going to make a huge difference"O. Massee Bateman, M.D., D.T.M&H.Save the ChildrenIn order to achieve this, one of the most important goals for preterm birth and stillbirth advocates will be to research and identify interventions that meet four key criteria:• Low-cost• Effective• Scalable• High impactInterviewees agreed that as of yet, there is no single and straightforward intervention or package of interventions for preterm birth and stillbirth that meet all of these criteria. As one interviewee acknowledged, policymakers and funders may recognize that preterm birth and stillbirth are important issues, but they do not have a clear, low-cost and scalable solution comparable to those of diarrheal disease, pneumonia and diseases requiring antibiotics or vaccines . While the effectiveness of Kangaroo Mother Care was referenced by multiple interview participants, several also noted that it is not an intervention that can be used in isolation.Multiple interviewees reported that preterm birth and stillbirth are indicators for maternal health, and that maternal health, in turn, can be considered an indicator for the strength, effectiveness and capacity of a country's health system. A high number of preterm births and stillbirths in LMICs—many of the latter happening at birth—could be prevented if women had better access to regular care and quality prenatal care, and had skilled attendants or access to a health facility at delivery in the event of a labor complication. There is a growing consensus that a high number of preterm births resulting in newborn deaths could be prevented by home and community-based newborn care that includes preventing or treating neonatal infections .These interventions, while taken for granted in the Western world, are not simple and low-cost in LMICs, where they have major infrastructure implications: education, training, technology, and transportation, among others .Several interviewees indicated that an increased emphasis on preventive interventions for preterm birth and stillbirth may resonate with policymakers and funders . A change in focus is needed to shift from saving preterm newborns to preventing preterm births and reduce the strain on countries' health systems:"If you increase the number of [preterm newborns] and reduce mortality, you still have not guaranteed good health to mothers and children, because once a child is preterm there is no guarantee that they will be able to actually catch up and grow up to be as robust as a child that was carried full-term"Joy PhumaphiWorld BankAccording to many interviewees, successful advocacy outreach efforts to policymakers, thought leaders, and funders will need to provide a defined roadmap for action, or clear steps to creating that roadmap . Steps may include demonstrating the magnitude of these issues, the impact they have on societies and country budgets, and how allocating funds to developing and scaling low-cost, scalable interventions can provide an important return on investment. Advocacy should include efforts to encourage donors, the United Nations, and other organizations to incorporate the scale-up of priority interventions in their funding strategies. In other words, as one participant succinctly explained:"…showing them it can be done. It can be done, and it doesn't [have to] cost much"Monir Islam, M.D., M.P.H.Making Pregnancy Safer, WHOThe following section presents the advocacy opportunities identified by interview participants, including:• Linking preterm birth and stillbirth to the United Nations Millennium Development Goals (MDGs)• Adding preterm birth and stillbirth to broader global health discussions• Presenting a united voice• Putting a human face on the issues• Identifying and engaging champions"I think when you can put a face [and] a name [to] a real story and present that to public policy makers, suddenly they get it and that's one of the huge […] opportunities that we have now'.'Marian Sokol, Ph.D., M.P.H.First CandleInterview participants across sectors identified several advocacy opportunities for advocates, including GAPPS, its partners, and like-minded organizations working to place preterm birth and stillbirth on the global health agenda. In addition, participants from Save the Children, UNICEF, March of Dimes and White Ribbon Alliance shared best practices from their experience conducting successful, high-visibility MNCH advocacy campaigns.Without addressing preterm birth and stillbirth, MDG 4 will not be achieved, as preterm birth is a primary cause of neonatal death. In addition, investing in interventions to prevent stillbirth would align with and support the reduction of maternal mortality and neonatal death, thereby addressing both MDGs 4 and 5. As one participant expressed, the prevention of preterm birth and stillbirth has not yet been recognized as crucial to achieving the MDGs . This said, the halfway point to 2015 has passed, and policymakers, funders, and thought leaders across the globe are focused on crossing the finish line while assessing what is achievable, and what is not. As one participant said:"…governments, at this point in time, are focused on Millennium Development Goal 4 and 5"Zulfiqar Bhutta, M.B.B.S., F.R.C.P., F.R.C.P.C.H., F.C.P.S., Ph.D.Aga Khan University, PakistanAnother participant explained that donors who fund MNCH programs tend to focus either more on child health  or maternal health , leaving room for advocates to link preterm birth and stillbirth to MDGs 4 and 5 and promote a continuum of care .						With regard to stillbirth in particular, a participant noted that there is enormous ground to be gained by linking stillbirth to maternal health outcomes:"…advocates might consider linking preterm birth advocacy to infant and child health, and linking stillbirth explicitly to maternal health, as stillbirth is often assumed to be an indicator of poor maternal health"Ann Starrs, M.P.A.Family Care International						A question for preterm birth and stillbirth advocates is:"How do you create a framework that links […] preterm birth and stillbirth to overall child survival goals, so that by having a campaign dedicated to preterm birth and stillbirth, you are adding to the conversation about the funding, the public awareness of the broader maternal and child health MDGs and goals that people have had some focus on."Scott Jackson, M.B.A., C.F.R.E.PATHThis framework presents advocates with a unique opportunity to advocate for resources and funding, within the context of achieving MDGs 4 and 5, aimed at preventing preterm birth and stillbirth.The majority of interview participants for this research do not view preterm birth and stillbirth as "stand-alone" issues. Rather, each is intimately nestled into a larger MNCH framework (though neither receives enough visibility). Several interviewees offered that, in order to conduct the most successful advocacy effort, the existing MNCH community should be mobilized:"I would recommend that this group gets seen as an additive…to be able to create a whole set of new materials that can help other people who are already advocating for the bigger piece of the pie. To have additional stories, additional messages, additional champions to add into the pot as opposed to carving out their own part that might take away from others…"Rachel Wilson, M.P.H.PATHOne participant suggested that, in order to be successful, advocates would need to develop a phased approach to advocacy, one that focuses first on raising awareness of the scale and impact of preterm birth and stillbirth. With more awareness, advocacy efforts could shift to winning political support and funding to continue to identify interventions and solutions. Along these same lines, interview participants identified the need to bring together different sectors working across the many aspects of MNCH to have a unified voice on preterm birth and stillbirth. For example, Occupational Safety and Hazard offices—which exist in many countries and are perhaps not obvious partners at first glance—can play an important role in LMICs by regulating work conditions to limit adverse outcomes for mothers .Or, in many countries, funds for MNCH programming are held by multiple entities: both Ministries of Health and Ministries of Finance, but also ministries dealing with women and family, nutrition, or infrastructure. There is an opportunity to convene these allies from across many different sectors and advocate in a united voice.There is also an opportunity for organizations working on different aspects of preterm birth and stillbirth— research, advocacy and implementation, for example—to convene and learn about efforts and initiatives being carried out and commit to working as a more cohesive, multi-disciplinary entity. When asked who they believed are the leaders on preterm birth and stillbirth, interviewees most frequently identified organizations in their own fields or within their own countries and regions. This said, some marked trends appeared, including:• WHO and UNICEF were frequently recognized as leading authorities for global data and statistics• The International Stillbirth Alliance was often referred to by interviewees as the first body to have started an global conversation about stillbirth• First Candle, March of Dimes, Save the Children, and White Ribbon Alliance were the most frequently named organizations for advocacy activitiesThere is a visible opportunity for organizations across spanning sectors and disciplines to convene and synchronize efforts to and elevate the issues of preterm birth and stillbirth in a united voice.While illustrations of the global economic and social impact of preterm birth and stillbirth have the potential to resonate loudly with funders and policymakers, the sharing of personal stories can also be a powerful and effective approach to raising awareness on these issues, especially stillbirth. The best advocates for resources to prevent stillbirth can be the parents who have experienced this tragedy and can speak to its impact on their lives. U.S. Representative Peter King, J.D. (R-NY) was so moved when a constituent shared her story with him that he introduced the Stillbirth Awareness and Research Act of 2008."Her story and the story of so many other women and their families are by far the most effective way to show legislators that more action is necessary, especially at the federal level"Peter King, J.D., R-NYUnited States House of RepresentativesAdvocates like Marian Sokol of First Candle, Vicki Flenady of the International Stillbirth Alliance, and others confirm that parent advocates all over the world have been on the front lines of stillbirth advocacy efforts, and have achieved successes thanks to their efforts."Parent groups like SIDS and Kids were drivers with the SIDS agenda; […] the wonderful work they've done in this country in reducing SIDS has laid a very strong foundation for the stillbirth initiative"Vicki Flenady, M.Med.Sc.Centre for Clinical Studies, the Mater Mother's Hospital, AustraliaSeveral interview participants commented on the important role that champions can play in garnering visibility for an issue. One interviewee specifically referenced political leaders, first ladies, queens, actors, and women who have had a personal experience as potentially powerful ambassadors for the issues of preterm birth and stillbirth .Multiple participants referenced Sarah Brown's work as a Global Patron of the White Ribbon Alliance as a model case study. Cultivating a relationship with a champion for preterm birth and stillbirth and building a successful campaign around their stories may provide an excellent opportunity for advocates to effectively reach media, policymakers, funders, the medical community and the general public to elevate these issues.With an eye on 2015, there is a lot of activity and momentum in the global health and the MNCH community and advocates have an unprecedented opportunity to complement and strengthen existing efforts.While there is a range of opinion among the interview participants about the knowledge and awareness of the impact of preterm birth and stillbirth, there is general consensus that raising awareness and advocating for these issues has been difficult and has been an obstacle to the development of scalable, cost-effective interventions. To that end, several key questions were raised throughout the interviews, and several are flagged here for consideration:The challenge of creating an advocacy and messaging framework for preterm birth and stillbirth within the existing MNCH and MDG frameworks: messaging for MNCH and the MDGs are already established. A smart strategy is needed to create a framework for preterm birth and stillbirth within these two existing frameworks so as not to compete, but rather, add to the conversation.• Consistency of messaging around preterm birth: Because of the complexity of the issue and potential interventions, existing preterm birth advocacy messages can be at cross purposes: currently, one set of messages focuses on provision of proper care to preterm newborns so that they can thrive after birth; another highlights prevention in order to avoid a lifetime of health and societal challenges that are costly and consume vast resources to address.• The importance of prioritizing interventions: Interview participants agreed that there is no consensus on which interventions should be used, especially in LICs. Furthermore, most agree that there needs to be a shift toward more preventive interventions but that this has not yet been addressed by the global health community in a constructive way.• The need to come to consensus on numbers: The research, medical, global health and NGO communities must come to agreement on the preterm birth and stillbirth estimates to use in messaging and advocacy materials. Without consistent numbers, it will be extremely difficult to convey a clear and powerful message to policymakers and funders.• According to interview participants across sectors and in different areas of the world, there is broad acknowledgement of significant scientific, policy and advocacy knowledge gaps on the issues of preterm birth and stillbirth. Interviews with a diverse sampling of representatives from the nonprofit sector, non-governmental organizations, UN agencies, global health organizations and others revealed three major challenges to successful advocacy efforts on the issues of preterm birth and stillbirth:• A lack of knowledge of the magnitude and impact of preterm birth and stillbirth• A lack of understanding and awareness of the issues• A lack of effective, low-cost, scalable and highly impactful interventions that take into consideration the existing cultural beliefs within each settingThere are, however, opportunities that exist in advocating to prevent preterm birth and stillbirth—notably an opportune timeframe with the MDGs as governments focus on achievable results; a mobilized maternal, newborn and child health community; and parent advocates who are succeeding in putting a face on the public health tragedies. Interview participants broadly acknowledge that the global stage is set for advocacy on preterm birth and stillbirth, though many questions—some difficult— remain to be addressed.Ethical and social justice considerations relating to preterm birth and stillbirth are discussed in the next article of this report . PrecediThe article was written and reviewed by MS, AF and RZ. CR helped conceive of this article as part of a global report on preterm birth and stillbirth, and participated in its design and coordination.The authors declare that they have no competing interests.