Michael S. Kramer

The Epidemiology of Adverse Pregnancy Outcomes: An Overview

This paper provides an overview of the occurrence, etiology and temporal trends of adverse pregnancy outcomes. Disparities between developed and developing countries are highlighted for maternal mortality, infant mortality, stillbirth and low birth weight. The higher rate of low birth weight in developing countries is primarily due to intrauterine growth restriction rather than preterm birth. Much of the excess intrauterine growth restriction is caused by short maternal stature, low prepregnancy body mass index and low gestational weight gain (due to low energy intake). No important contribution has been established for micronutrient intake, nor have different fetal growth trajectories been demonstrated to reflect the timing of exposure to nutritional or other etiologic factors. Infant mortality has declined substantially over time both in developed and developing countries despite no decline (and even an increase) in low birth weight. Several developed countries have reported a temporal increase in fetal growth in infants born at term, a reduction in stillbirth rates and prevention of neural tube defects. More progress is required, however, in understanding the etiology and prevention of preterm birth.

Determinants of Preterm Birth Rates in Canada from 1981 through 1983 and from 1992 through 1994

BACKGROUND The rates of preterm birth have increased in many countries, including Canada, over the past 20 years. However, the factors underlying the increase are poorly understood. METHODS We used data from the Statistics Canada live-birth and stillbirth data bases to determine the effects of changes in the frequency of multiple births, registration of births occurring very early in gestation, patterns of obstetrical intervention, and use of ultrasonographic dating of gestational age on the rates of preterm birth in Canada from 1981 through 1983 and from 1992 through 1994. All births in 9 of the 12 provinces and territories of Canada were included. Logistic-regression analysis and Poisson regression analysis were used to estimate changes between the two three-year periods, after adjustment for the above-mentioned determinants of the likelihood of preterm births. RESULTS Preterm births increased from 6.3 percent of live births in 1981 through 1983 to 6.8 percent in 1992 through 1994, a relative increase of 9 percent (95 percent confidence interval, 7 to 10 percent). Among singleton births, preterm births increased by 5 percent (95 percent confidence interval, 3 to 6 percent). Multiple births increased from 1.9 percent to 2.1 percent of all live births; the rates of preterm birth among live births resulting from multiple gestations increased by 25 percent (95 percent confidence interval, 21 to 28 percent). Adjustment for the determinants of the likelihood of preterm birth reduced the increase in the rate of preterm birth to 3 percent among all live births and 1 percent among singleton births. CONCLUSIONS The recent increase in preterm births in Canada is largely attributable to changes in the frequency of multiple births, obstetrical intervention, and the use of ultrasound-based estimates of gestational age.

Effect of neighbourhood income and maternal education on birth outcomes: a population-based study

Background: Maternal socioeconomic status (SES) is an important determinant of inequity in maternal and fetal health. We sought to determine the extent to which associations between adverse birth outcomes and SES can be identified using individual-level measures (maternal level of education) and community-level measures (neighbourhood income). Methods: In Quebec, the birth registration form includes a field for the mothers years of education. Using data from birth registration certificates, we identified all births from 1991 to 2000. Using maternal postal codes that can be linked to census enumeration areas, we determined neighbourhood income levels that reflect SES. Results: Lower levels of both maternal education and neighbourhood income were associated with elevated crude risks of preterm birth, small-for-gestational-age (SGA) birth, stillbirth and neonatal and postneonatal death. The effects of maternal education were stronger than, and independent of, those of neighbourhood income. Compared with women in the highest neighbourhood income quintile, women in the lowest quintile were significantly more likely to have a preterm birth (adjusted odds ratio [OR] 1.14, 95% confidence interval [CI] 1.10–1.17), SGA birth (OR 1.18, 95% CI 1.15–1.21) or stillbirth (OR 1.30, 95% CI 1.13–1.48); compared with mothers who had completed community college or at least some university, mothers who had not completed high school were significantly more likely to have a preterm birth (adjusted OR 1.48, 95% CI 1.44–1.52), SGA birth (OR 1.86, 95% CI 1.82–1.91) or stillbirth (OR 1.54, 95% CI 1.36–1.74). Interpretation: Individual and, to a lesser extent, neighbourhood-level SES measures are independent indicators for subpopulations at risk of adverse birth outcomes. Women with lower education levels and those living in poorer neighbourhoods are more vulnerable to adverse birth outcomes and may benefit from heightened clinical vigilance and counselling.

Stress Pathways to Spontaneous Preterm Birth: The Role of Stressors, Psychological Distress, and Stress Hormones

The authors investigated a large number of stressors and measures of psychological distress in a multicenter, prospective cohort study of spontaneous preterm birth among 5,337 Montreal (Canada)-area women who delivered from October 1999 to April 2004. In addition, a nested case-control analysis (207 cases, 444 controls) was used to explore potential biologic pathways by analyzing maternal plasma corticotrophin-releasing hormone (CRH), placental histopathology, and (in a subset) maternal hair cortisol. Among the large number of stress and distress measures studied, only pregnancy-related anxiety was consistently and independently associated with spontaneous preterm birth (for values above the median, adjusted odds ratio = 1.8 (95% confidence interval: 1.3, 2.4)), with a dose-response relation across quartiles. The maternal plasma CRH concentration was significantly higher in cases than in controls in crude analyses but not after adjustment (for concentrations above the median, adjusted odds ratio = 1.1 (95% confidence interval: 0.8, 1.6)). In the subgroup (n = 117) of participants with a sufficient maternal hair sample, hair cortisol was positively associated with gestational age. Neither maternal plasma CRH, hair cortisol, nor placental histopathologic features of infection/inflammation, infarction, or maternal vasculopathy were significantly associated with pregnancy-related anxiety or any other stress or distress measure. The biologic pathways underlying stress-induced preterm birth remain poorly understood.

Effect of prolonged and exclusive breast feeding on risk of allergy and asthma: cluster randomised trial

Objective To assess whether exclusive and prolonged breast feeding reduces the risk of childhood asthma and allergy by age 6.5 years. Design Cluster randomised trial. Setting 31 Belarussian maternity hospitals and their affiliated polyclinics. Participants A total of 17 046 mother-infant pairs were enrolled, of whom 13 889 (81.5%) were followed up at age 6.5 years. Intervention Breastfeeding promotion intervention modelled on the WHO/UNICEF baby friendly hospital initiative. Main outcome measures International study of asthma and allergies in childhood (ISAAC) questionnaire and skin prick tests of five inhalant antigens. Results The experimental intervention led to a large increase in exclusive breast feeding at 3 months (44.3% v 6.4%; P<0.001) and a significantly higher prevalence of any breast feeding at all ages up to and including 12 months. The experimental group had no reduction in risks of allergic symptoms and diagnoses or positive skin prick tests. In fact, after exclusion of six sites (three experimental and three control) with suspiciously high rates of positive skin prick tests, risks were significantly increased in the experimental group for four of the five antigens. Conclusions These results do not support a protective effect of prolonged and exclusive breast feeding on asthma or allergy. Trial registration Current Controlled Trials ISRCTN37687716.

The Impact of the Increasing Number of Multiple Births on the Rates of Preterm Birth and Low Birthweight: An International Study

OBJECTIVES We studied the effects of twins and triplets on perinatal health indicators in the overall population in the 1980s and 1990s in Canada, England and Wales, France, and the United States. METHODS Data were derived mostly from live birth registration. We used rates, relative risks, and population attributable risks for twins and triplets separately. RESULTS In each country, the increase in multiple births, and the increase in preterm delivery among multiple births, contributed almost equally to the rise in or stabilization of the overall rates of preterm delivery. Twins contributed a much larger proportion of the preterm deliveries and low-birthweight newborns than did triplets. CONCLUSIONS Twins have a major population-based impact on the trends of perinatal health indicators.

Very Low Birth Weight: A Problematic Cohort for Epidemiologic Studies of Very Small or Immature Neonates

Despite widespread acceptance of the concept of very low birth weight (VLBW), i.e., birth weight of less than or equal to 1,500 g, VLBW infants represent an extremely heterogeneous group of newborns, including those with very immature gestational age and those who are more mature but extremely growth retarded. To demonstrate how use of the VLBW rubric can lead to confounding bias that is not only large in magnitude but impossible to control satisfactorily, the authors divided 640 consecutive live neonates born in the Royal Victoria Hospital, Montreal, Canada, from 1978 to 1987 into two overlapping groups: a VLBW cohort (birth weight, 500-1500 g; n = 573) and a gestational age cohort (gestational age, 23-30 completed weeks; n = 466). Variation in growth status by gestational age was much more uniform in the 23- to 30-week cohort. Thus, although mean birth weight was similar in the 500- to 1,500-g and 23- to 30-week cohorts (1,055 vs. 1,064 g), the 500- to 1,500-g cohort was more mature (mean gestational age, 28.8 vs. 27.8 weeks; upper range, 39.7 vs. 30.9 weeks) and had twice the rate of intrauterine growth retardation (25.7 vs. 11.5%). These differences in maturity and growth resulted in a misleading protective effect of intrauterine growth retardation against in-hospital death in the 500- to 1,500-g cohort (crude odds ratio = 0.55 (95% confidence interval 0.36-0.83] and a greater discrepancy in maturity between cesarean- and vaginally delivered infants (3.1 vs. 1.5 weeks) in the 500- to 1,500-g vs. 23- to 30-week cohorts. These differences arise from inextricable confounding of growth status and maturity in the 500- to 1,500-g cohort, the most mature infants also being the most growth retarded. The removal of well-grown infants with birth weights of greater than 1,500 g from the VLBW cohort leads to a progressively distorted spectrum of growth with advancing gestational age and an artifactual blunting of the beneficial effects of increasing maturity. The authors suggest that whenever fetal growth is an important exposure, outcome, or confounding variable, epidemiologic studies of extremely small or immature newborns should be based on gestational age rather than the VLBW criterion.

TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P.

The pleiotropic growth factor TGFβ(1) promotes many of the pathogenic mechanisms observed in lung fibrosis and airway remodeling, such as aberrant extracellular matrix deposition due to both fibroblast activation and fibroblast to myofibroblast differentiation. Serum amyloid P (SAP), a member of the pentraxin family of proteins inhibits bleomycin-induced lung fibrosis through an inhibition of pulmonary fibrocyte and pro-fibrotic alternative (M2) macrophage accumulation. It is unknown if SAP has effects downstream of TGFβ(1), a major mediator of pulmonary fibrosis. Using the lung specific TGFβ(1) transgenic mouse model, we determined that SAP inhibits all of the pathologies driven by TGFβ(1) including apoptosis, airway inflammation, pulmonary fibrocyte accumulation and collagen deposition, without affecting levels of TGFβ(1). To explore the role of monocyte derived cells in this model we used liposomal clodronate to deplete pulmonary macrophages. This led to pronounced anti-fibrotic effects that were independent of fibrocyte accumulation. Administration of SAP mirrored these effects and reduced both pulmonary M2 macrophages and increased chemokine IP10/CXCL10 expression in a SMAD 3-independent manner. Interestingly, SAP concentrations were reduced in the circulation of IPF patients and correlated with disease severity. Last, SAP directly inhibited M2 macrophage differentiation of monocytes obtained from these patients. These data suggest that the beneficial anti-fibrotic effects of SAP in TGFβ(1)-induced lung disease are via modulating monocyte responses.

How big is too big? The perinatal consequences of fetal macrosomia.

OBJECTIVE The objective of the study was to examine the birthweight at which risks of perinatal death, neonatal morbidity, and cesarean delivery begin to rise and the causes and timing (antenatal, early or late neonatal, or postneonatal) of these risks. STUDY DESIGN This was a cohort study based on 1999-2001 US-linked stillbirth, live birth, and infant death records. Singletons weighing 2500 g or larger born to white non-Hispanic mothers at 37-44 weeks of gestation were selected (n = 5,983,409). RESULTS Infants with birthweights from 4000 to 4499 g were not at increased risk of mortality or morbidity vs those at 3500-3999 g, whereas those 4500-4999 g had significantly increased risks of stillbirth, neonatal mortality (especially because of birth asphyxia), birth injury, neonatal asphyxia, meconium aspiration, and cesarean delivery. Births at 5000 g or larger had even higher risks, including risk of sudden infant death syndrome. CONCLUSION Birthweight greater than 4500 g, and especially greater than 5000 g, is associated with increased risks of perinatal and infant mortality and morbidity.

Differences in late fetal death rates in association with determinants of small for gestational age fetuses: population based cohort study

Abstract Objective: To examine differences in late fetal death rates in association with determinants of small for gestational age fetuses. Design: Population based cohort study. Subjects: 1 026 249 pregnancies without congenital malformations. Setting: Sweden 1983-92. Main outcome measure: Late fetal death rate. Results: Depending on underlying determinants late fetal death rates were greatly increased in extremely small for gestational age fetuses (range 16 to 45 per 1000) compared with non-small for gestational age fetuses (1.4 to 4.6). In extremely small for gestational age fetuses late fetal death rates were increased from 31 per 1000 in mothers aged less than 35 years to 45 per 1000 in older mothers, and from 22 per 1000 in women <155 cm in height to 33 per 1000 in women ≥175 cm tall. Late fetal death rates were also higher in extremely small for gestational age fetuses in singleton compared with twin pregnancies and in non-hypertensive pregnancies compared with pregnancies complicated by severe pre-eclampsia or other hypertensive disorders. Slightly higher late fetal death rates were observed in nulliparous compared with parous women and in non-smokers compared with smokers. Conclusions: Although the risk of late fetal death is greatly increased in fetuses that are extremely small for gestational age the risk is strongly modified by underlying determinants—for example, there is a lower risk of late fetal death in a small for gestational age fetus if the mother is of short stature, has a twin pregnancy, or has hypertension. Key messages Small for gestational age fetuses are at increased risk of late fetal death regardless of the underlying determinants The effect of birthweight ratio on risk of late fetal death is modified by underlying determinants, except maternal age Regardless of birthweight ratio the rates of late fetal death are higher among women aged 35 years or older compared with younger women In pregnancies of extremely small for gestational age fetuses lower rates of late fetal death are associated with a maternal age of less than 35 years, short maternal stature, multiple births, and hypertensive disorders In pregnancies with non-malformed fetuses late fetal death rates are increased in smokers, in multiple births, and in women with severe pre-eclampsia.