Michael G. Gravett

Global report on preterm birth and stillbirth (1 of 7): definitions, description of the burden and opportunities to improve data

IntroductionThis 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 birthFew 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.StillbirthStillbirths 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.ConclusionLack 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.

Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis

Maternal genital infection, particularly subclinical amniotic fluid infection, may cause preterm labor and a premature delivery. The prevalence of subclinical amniotic fluid infection was studied in 54 consecutive afebrile women in preterm labor with singleton gestations and intact fetal membranes. Microorganisms were recovered from the amniotic fluid by transabdominal amniocentesis in 13 (24%) of 54 patients. Bacteria or Candida albicans were recovered from six (11%), and genital mycoplasmas from seven (13%). Compared with women with sterile amniotic fluid, patients whose amniotic fluid contained bacteria or Candida organisms had a shorter interval from onset of preterm labor until delivery (0.6 versus 34.3 days, P less than .01), were less responsive to tocolytic therapy (0 versus 81% success rate, P less than .005), and more frequently developed subsequent intrapartum fever (83 versus 2.4%, P less than .005). In contrast, women whose amniotic fluid contained genital mycoplasmas did not differ in these parameters from those with sterile fluid. Also compared was cervical-vaginal infection among these patients in preterm labor with matched control subjects without preterm labor. In this analysis, bacterial vaginosis was identified in 43% of patients with and 14% of women without preterm labor (P = .02), yielding a relative risk of preterm labor for patients with bacterial vaginosis of 3.8. These data underscore the importance of amniotic fluid bacterial infections in preterm labor and premature delivery, and suggest that bacterial vaginosis is associated with prematurity.

International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project

BACKGROUND In 2006, WHO published international growth standards for children younger than 5 years, which are now accepted worldwide. In the INTERGROWTH-21(st) Project, our aim was to complement them by developing international standards for fetuses, newborn infants, and the postnatal growth period of preterm infants. METHODS INTERGROWTH-21(st) is a population-based project that assessed fetal growth and newborn size in eight geographically defined urban populations. These groups were selected because most of the health and nutrition needs of mothers were met, adequate antenatal care was provided, and there were no major environmental constraints on growth. As part of the Newborn Cross-Sectional Study (NCSS), a component of INTERGROWTH-21(st) Project, we measured weight, length, and head circumference in all newborn infants, in addition to collecting data prospectively for pregnancy and the perinatal period. To construct the newborn standards, we selected all pregnancies in women meeting (in addition to the underlying population characteristics) strict individual eligibility criteria for a population at low risk of impaired fetal growth (labelled the NCSS prescriptive subpopulation). Women had a reliable ultrasound estimate of gestational age using crown-rump length before 14 weeks of gestation or biparietal diameter if antenatal care started between 14 weeks and 24 weeks or less of gestation. Newborn anthropometric measures were obtained within 12 h of birth by identically trained anthropometric teams using the same equipment at all sites. Fractional polynomials assuming a skewed t distribution were used to estimate the fitted centiles. FINDINGS We identified 20,486 (35%) eligible women from the 59,137 pregnant women enrolled in NCSS between May 14, 2009, and Aug 2, 2013. We calculated sex-specific observed and smoothed centiles for weight, length, and head circumference for gestational age at birth. The observed and smoothed centiles were almost identical. We present the 3rd, 10th, 50th, 90th, and 97th centile curves according to gestational age and sex. INTERPRETATION We have developed, for routine clinical practice, international anthropometric standards to assess newborn size that are intended to complement the WHO Child Growth Standards and allow comparisons across multiethnic populations. FUNDING Bill & Melinda Gates Foundation.

An experimental model for intraamniotic infection and preterm labor in rhesus monkeys

OBJECTIVE Our purpose was to describe the temporal and quantitative relationship between intraamniotic infection and preterm labor in a nonhuman primate model. STUDY DESIGN On day 130 of gestation (term 167 days) four chronically instrumented rhesus monkeys (Macaca mulatta) were infected with an intraamniotic inoculation of 10(6) colony-forming units of group B streptococci. Four additional noninfected monkeys were followed up to spontaneous parturition as controls. Amniotic fluid was serially sampled in all monkeys both before and after inoculation for bacterial growth, tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, prostaglandin E2, and prostaglandin F2 alpha, and uterine activity was continuously recorded. RESULTS Increases in uterine contractility occurred 28 hours (range 14 to 40 hours) after inoculation and were preceded by increases in amniotic fluid cytokines and prostaglandins. Intraamniotic concentrations of tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta all rose dramatically 9, 15, and 18 hours after infection and 10 to 20 hours before increases in uterine contractility. In spontaneous parturition only interleukin-6 concentrations rose moderately (from 0.1 to 1.2 ng/ml). Increases in prostaglandin E2 and prostaglandin F2 alpha paralleled those of the cytokines. Peak prostaglandin concentrations in intraamniotic infection exceeded by severalfold concentrations seen in spontaneous parturition (16,046 pg/ml vs 2765 pg/ml for prostaglandin E2, p < 0.05; and 5547 pg/ml vs 708 pg/ml for prostaglandin F2 alpha, p < 0.05). In spite of intraamniotic none of the monkeys were febrile or had peripheral leukocytosis at the onset of labor. CONCLUSION In the rhesus monkey, after intraamniotic infection, there is a predictable and sequential increase in amniotic fluid tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, followed by increases in prostaglandin E2 and prostaglandin F2 alpha. These increases all occur before an increase in uterine contractility and before clinical signs of infection. Our data provide evidence for a cause-and-effect relationship between intraamniotic infection and preterm labor and support the utility of measuring interleukin-6 or other cytokines in the diagnosis of intraamniotic infection.

International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project

BACKGROUND In 2006, WHO produced international growth standards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee. Using the same methods and conceptual approach, the Fetal Growth Longitudinal Study (FGLS), part of the INTERGROWTH-21(st) Project, aimed to develop international growth and size standards for fetuses. METHODS The multicentre, population-based FGLS assessed fetal growth in geographically defined urban populations in eight countries, in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided. We used ultrasound to take fetal anthropometric measurements prospectively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction. All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown-rump length in the first trimester. The five primary ultrasound measures of fetal growth--head circumference, biparietal diameter, occipitofrontal diameter, abdominal circumference, and femur length--were obtained every 5 weeks (within 1 week either side) from 14 weeks to 42 weeks of gestation. The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study. FINDINGS We screened 13,108 women commencing antenatal care at less than 14 weeks and 0 days of gestation, of whom 4607 (35%) were eligible. 4321 (94%) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations (the analysis population). We documented very low maternal and perinatal mortality and morbidity, confirming that the participants were at low risk of adverse outcomes. For each of the five fetal growth measures, the mean differences between the observed and smoothed centiles for the 3rd, 50th, and 97th centiles, respectively, were small: 2·25 mm (SD 3·0), 0·02 mm (3·0), and -2·69 mm (3·2) for head circumference; 0·83 mm (0·9), -0·05 mm (0·8), and -0·84 mm (1·0) for biparietal diameter; 0·63 mm (1·2), 0·04 mm (1·1), and -1·05 mm (1·3) for occipitofrontal diameter; 2·99 mm (3·1), 0·25 mm (3·2), and -4·22 mm (3·7) for abdominal circumference; and 0·62 mm (0·8), 0·03 mm (0·8), and -0·65 mm (0·8) for femur length. We calculated the 3rd, 5th 10th, 50th, 90th, 95th and 97th centile curves according to gestational age for these ultrasound measures, representing the international standards for fetal growth. INTERPRETATION We recommend these international fetal growth standards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across populations. FUNDING Bill & Melinda Gates Foundation.

Preventing Preterm Birth and Neonatal Mortality: Exploring the Epidemiology, Causes, and Interventions

Globally, each year, an estimated 13 million infants are born before 37 completed weeks of gestation. Complications from these preterm births are the leading cause of neonatal mortality. Preterm birth is directly responsible for an estimated one million neonatal deaths annually and is also an important contributor to child and adult morbidities. Low- and middle-income countries are disproportionately affected by preterm birth and carry a greater burden of disease attributed to preterm birth. Causes of preterm birth are multifactorial, vary by gestational age, and likely vary by geographic and ethnic contexts. Although many interventions have been evaluated, few have moderate-to high-quality evidence for decreasing preterm birth: smoking cessation and progesterone treatment in women with a high risk of preterm birth in low- and middle-income countries and cervical cerclage for those in high-income countries. Antepartum and postnatal interventions (eg, antepartum maternal steroid administration, or kangaroo mother care) to improve preterm neonatal survival after birth have been demonstrated to be effective but have not been widely implemented. Further research efforts are urgently needed to better understand context-specific pathways leading to preterm birth; to develop appropriate, efficacious prevention strategies and interventions to improve survival of neonates born prematurely; and to scale-up known efficacious interventions to improve the health of the preterm neonate.

Interleukin-Iβ Intra-Amniotic Infusion Induces TUmor Necrosis Factor-α, Prostaglandin Production, and Preterm COntractions in Pregnant Rhesus Monkeys

Objective: To describe the temporal and quantitative consequences of intra-amniotic interleukin-1β infusion in a nonhuman primate model. Methods: On days 128-138 of gestation (term 167 days), four chronically instrumented rhesus monkeys (Macaca mulatta) underwent serial intra-amniotic infusions of 2, 5, and 10-20 μg recombinant human interleukin-1β. Each infusion was for 2 hours, and subsequent infusions were at least 48 hours later. Amniotic fluid was sampled serially both before and after infusion for interleukin-1β, tumor necrosis factor-α (TFN-α), and prostaglandin (PG) E2 and F2α by specific assays, and uterine activity in each monkey was recorded continuously. Results: Intra-amniotic concentrations of interleukin-1β rose dramatically after infusion. This rise was rapidly followed by the appearance of TNF-α in the amniotic cavities of all animals, with maximal levels reached 5 hours after the initiation of the infusion. Both interleukin-1β and TNF-α were rapidly cleared from the amniotic fluid and returned to baseline levels by 24-48 hours. Increases in PGE2 and F2α paralleled those of the two cytokines but remained elevated for the duration of the experiments. The stimulation of uterine contractility from a pre-infusion level of 200 mmHg · seconds/hour to 6000 mmHg · seconds/hour occurred an average of 6-10 hours after interleukin-1β infusion. These stimulations were transient, usually abating by 22 hours after infusion, and did not result in frank labor. Conclusion: In the rhesus monkey, intra-amniotic infusion of interleukin-1β rapidly induces production of intra-amniotic TNF-α as well as PGE2 and F2α, followed by uterine contractility. Uterine activity diminishes as cytokine levels return to pre-infusion levels, even in the presence of elevated intra-amniotic PG levels. Tumor necrosis factor-α may act synergistically with interleukin-1β in the pathophysiology of cytokine-related preterm labor.

Global report on preterm birth and stillbirth (2 of 7): discovery science

BackgroundNormal 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 continuumThe 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.EtiologiesThe 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.RecommendationsUtilizing 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.ConclusionPreterm 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.

Ureaplasma parvum or Mycoplasma hominis as Sole Pathogens Cause Chorioamnionitis, Preterm Delivery, and Fetal Pneumonia in Rhesus Macaques

The authors assess causal, cellular and inflammatory links between intraamniotic infection with Ureaplasma parvum or Mycoplasma hominis and preterm labor in a nonhuman primate model. Long-term catheterized rhesus monkeys received intraamniotic inoculations of clinical isolates of Ureaplasma parvum serovar 1, M hominis, media control or physiological saline. Genital mycoplasmas were quantified in amniotic fluid (AF) and documented in fetal tissues by culture and PCR. In association with elevated AF colony counts for U parvum or M hominis, there was a sequential upregulation of AF leukocytes, proinflammatory cytokines, prostaglandin E2 and F2a, metalloproteinase-9 and uterine activity ( P< .05). Fetal membranes and lung were uniformly positive for both microorganisms; fetal blood and cerebrospinal fluid cultures and PCR were more often positive for M hominis than U parvum. Histopathologic findings of chorioamnionitis, a systemic fetal inflammatory response and pneumonitis worsen with duration of in utero infection. U parvum or M hominis, as sole pathogens, elicit a robust proinflammatory response which contributes to preterm labor and fetal lung injury.

The objectives, design and implementation of the INTERGROWTH‐21st Project

Please cite this paper as: Villar J, Altman D, Purwar M, Noble J, Knight H, Ruyan P, Cheikh Ismail L, Barros F, Lambert A, Papageorghiou A, Carvalho M, Jaffer Y, Bertino E, Gravett M, Bhutta Z, Kennedy S, for the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH‐21st). The objectives, design and implementation of the INTERGROWTH‐21st Project. BJOG 2013; 120 (Suppl. 2): 9–26.