Effects of interpregnancy intervals on preterm birth,intrauterine growth retardation,and fetal loss

Abstract

This study examines the magnitude and shape of the interpregnancy interval (IPI) effect on three pregnancy outcomes: preterm low birthweight (PRETERM‐LBW), intrauterine growth‐retardation low birthweight (IUGR‐LBW), and fetal loss (LOSS). A multinomial logistic regression model is estimated, based on data from the 1988 National Survey of Family Growth which contains pregnancy histories. The results indicate that both short and long intervals raise the risk of IUGR‐LBW and LOSS, net of sociodemographic and behavioral variables, but IPI effects on PRETERM‐LBW are not clear.     

Effects of interpregnancy intervals on preterm birth, intrauterine growth retardation, and fetal loss.

This study examines the magnitude and shape of the interpregnancy interval (IPI) effect on three pregnancy outcomes: preterm low birthweight (PRETERM-LBW), intrauterine growth-retardation low birthweight (IUGR-LBW), and fetal loss (LOSS). A multinomial logistic regression model is estimated, based on data from the 1988 National Survey of Family Growth which contains pregnancy histories. The results indicate that both short and long intervals raise the risk of IUGR-LBW and LOSS, net of sociodemographic and behavioral variables, but IPI effects on PRETERM-LBW are not clear.     

Genetic studies in rat models: insights into cardiovascular disease

PURPOSE OF REVIEW: Limited to 2003-2004 publications, this review focuses on 'big picture' concepts learned from rat genetic studies of cardiovascular disease. RECENT DEVELOPMENTS: Analysis reveals insights into pathogenic paradigms, as well as experimental perspectives into rat-based systems of analyses of complex cardiovascular disease. Key concepts are forwarded. Multiple susceptibility genes underlie several quantitative trait loci for blood pressure suggesting a 'quantitative trait loci cluster' concept; hypertension end-organ disease quantitative trait loci are distinct from blood pressure quantitative trait loci indicating differential susceptibility paradigms for hypertension and each complication (stroke, renal disease, cardiac hypertrophy); distinct blood pressure quantitative trait loci are found in males and females indicating gender-specific susceptibility; and genetic subtypes comprise polygenic hypertension in rat models suggesting a genetic basis for clinical heterogeneity of human essential hypertension. Gender specific genetic susceptibility plays a key role in coronary artery disease susceptibility; multiple distinct quantitative trait loci underlie hyperlipidemia and type-2 diabetes, indicating multiple susceptibilities in risk factors for cardiovascular disease. Studies in transgenic inbred rat-strain models demonstrate value for serial, complex, cardiovascular pathophysiological analyses within a genetic context. SUMMARY: Cognizant of the limitations of animal model studies, observations from rat genetic studies provide insight into respective modeled human cardiovascular diseases and risk factor susceptibility, as well as systematically dissect the multifaceted complexities apparent in human complex cardiovascular disease. Given the recapitulation of many features of human cardiovascular disease, the value of rat model-based genetic studies for complex cardiovascular disease is unequivocal, thus mandating the expansion of resources for maximization of rat-based genetic studies.     

Maternal malaria, birth size and blood pressure in Nigerian newborns: insights into the developmental origins of hypertension from the Ibadan growth cohort

Background

Hypertension is an increasing health issue in sub-Saharan Africa where malaria remains common in pregnancy. We established a birth cohort in Nigeria to evaluate the early impact of maternal malaria on newborn blood pressure (BP).

Methods

Anthropometric measurements, BP, blood films for malaria parasites and haematocrit were obtained in 436 mother-baby pairs. Women were grouped to distinguish between the timing of malaria parasitaemia as ‘No Malaria’, ‘Malaria during pregnancy only’ or ‘Malaria at delivery’, and parasite density as low (<1000 parasites/µl of blood) and high (≥1000/µl).

Results

Prevalence of maternal malaria parasitaemia was 48%, associated with younger maternal age (p<0.001), being primigravid (p = 0.022), lower haematocrit (p = 0.028). High parasite density through pregnancy had the largest effect on mean birth indices so that weight, length, head and mid-upper arm circumferences were smaller by 300 g, 1.1 cm, 0.7 cm and 0.4 cm respectively compared with ‘No malaria’ (all p≤0.005). In babies of mothers who had ‘malaria at delivery’, their SBPs adjusted for other confounders were lower respectively by 4.3 and 5.7 mmHg/kg compared with ‘malaria during pregnancy only’ or ‘none’. In contrast the mean newborn systolic (SBP) and diastolic BPs (DBP) adjusted for birth weight were higher by 1.7 and 1.4 mmHg/kg respectively in babies whose mothers had high compared with low parasitaemia.

Conclusions

As expected, prenatal malarial exposure had a significant impact on fetal growth rates. Malaria at delivery was associated with the lowest newborn BPs while malaria through pregnancy, which may attenuate growth of the vascular network, generated higher newborn BPs adjusted for size. These neonatal findings have potential implications for cardiovascular health in sub-Saharan Africa.     

IL-6 trans-signaling system in intra-amniotic inflammation, preterm birth, and preterm premature rupture of the membranes

Classic IL-6 signaling is conditioned by the transmembrane receptor (IL-6R) and homodimerization of gp130. During trans-signaling, IL-6 binds to soluble IL-6R (sIL-6R), enabling activation of cells expressing solely gp130. Soluble gp130 (sgp130) selectively inhibits IL-6 trans-signaling. To characterize amniotic fluid (AF) IL-6 trans-signaling molecules (IL-6, sIL-6R, sgp130) in normal gestations and pregnancies complicated by intra-amniotic inflammation (IAI), we studied 301 women during second trimester (n = 39), third trimester (n = 40), and preterm labor with intact (n = 131, 85 negative IAI and 46 positive IAI) or preterm premature rupture of membranes (PPROM; n = 91, 61 negative IAI and 30 positive IAI). ELISA, Western blotting, and real-time RT-PCR were used to investigate AF, placenta, and amniochorion for protein and mRNA expression of sIL-6R, sgp130, IL-6R, and gp130. Tissues were immunostained for IL-6R, gp130, CD15(+) (polymorphonuclear), and CD3(+) (T cell) inflammatory cells. The ability of sIL-6R and sgp130 to modulate basal and LPS-stimulated release of amniochorion matrix metalloprotease-9 was tested ex vivo. We showed that in physiologic gestations, AF sgp130 decreases toward term. AF IL-6 and sIL-6R were increased in IAI, whereas sgp130 was decreased in PPROM. Our results suggested that fetal membranes are the probable source of AF sIL-6R and sgp130. Immunohistochemistry and RT-PCR revealed increased IL-6R and decreased gp130 expression in amniochorion of women with IAI. Ex vivo, sIL-6R and LPS augmented amniochorion matrix metalloprotease-9 release, whereas sgp130 opposed this effect. We conclude that IL-6 trans-signaling molecules are physiologic constituents of the AF regulated by gestational age and inflammation. PPROM likely involves functional loss of sgp130.     

Maternal selenium status during early gestation and risk for preterm birth

Background

Preterm birth occurs in 5%–13% of pregnancies. It is a leading cause of perinatal mortality and morbidity and has adverse long-term consequences for the health of the child. Because of the role selenium plays in attenuating inflammation, and because low concentrations of selenium have been found in women with preeclampsia, we hypothesized that low maternal selenium status during early gestation would increase the risk of preterm birth.

Methods

White Dutch women with a singleton pregnancy (n = 1197) were followed prospectively from 12 weeks’ gestation. Women with thyroid disease or type 1 diabetes were excluded. At delivery, 1129 women had complete birth-outcome data. Serum concentrations of selenium were measured during the 12th week of pregnancy. Deliveries were classified as preterm or term, and preterm births were subcategorized as iatrogenic, spontaneous or the result of premature rupture of the membranes.

Results

Of the 60 women (5.3%) who had a preterm birth, 21 had premature rupture of the membranes and 13 had preeclampsia. The serum selenium concentration at 12 weeks’ gestation was significantly lower among women who had a preterm birth than among those who delivered at term (mean 0.96 [standard deviation (SD) 0.14] μmol/L v. 1.02 [SD 0.13] μmol/L; t = 2.9, p = 0.001). Women were grouped by quartile of serum selenium concentration at 12 weeks’ gestation. The number of women who had a preterm birth significantly differed by quartile (χ² = 8.01, 3 degrees of freedom], p < 0.05). Women in the lowest quartile of serum selenium had twice the risk of preterm birth as women in the upper three quartiles, even after adjustment for the occurrence of preeclampsia (adjusted odds ratio 2.18, 95% confidence interval 1.25–3.77).

Interpretation

Having low serum selenium at the end of the first trimester was related to preterm birth and was independent of the mother having preeclampsia. Low maternal selenium status during early gestation may increase the risk of preterm premature rupture of the membranes, which is a major cause of preterm birth.Preterm birth occurs in 5%–13% of pregnancies and is a major public health concern worldwide.¹ Preterm birth, defined as delivery before 37 weeks’ gestation, is the leading cause of perinatal mortality and morbidity.² Short- and long-term consequences to the health of the child include cerebral palsy, respiratory distress syndrome, neurodevelopmental impairment, learning difficulties and behavioural problems.² Despite substantial efforts to explain the mechanisms involved, the incidence of preterm birth is on the rise. For example, in the United States, the incidence increased from 9.5% in 1981 to 12.7% in 2005.¹ Consequently, it is important to identify factors that may contribute to preterm birth, particularly those factors that are preventable.Maternal risk factors for preterm birth include a previous preterm delivery, black race, low socioeconomic status, poor nutrition or becoming pregnant soon after a previous delivery.¹ Risk factors for preterm birth during gestation include multiple-gestation pregnancy and an intrauterine infection that triggers an inflammatory response.^1,3 Endocrine conditions such as diabetes and dysfunction of the thyroid have also been associated with preterm birth, sometimes linked to preterm premature rupture of the membranes.^4,5The trace mineral selenium, available from food (though to a greater or lesser extent according to region), can interact with a number of these risk factors.^6–9 It has been implicated in pregnancy outcome,^9–12 and it plays a role in the immune response and the body’s resistance to infection.⁶ Enzymes containing the mineral, selenoenzymes, can attenuate the excessive inflammatory response associated with adverse pregnancy outcomes, downregulating the expression of pro-inflammatory genes.^6–8 A polymorphism in the gene encoding the selenoprotein SEPS1 has been shown to affect the risk of preeclampsia, a condition that has a strong inflammatory component that is an important cause of preterm birth.⁸ In addition, low selenium status has been identified in women with preeclampsia.¹²We hypothesized that low maternal selenium status (as measured by low serum selenium concentration early in gestation would be associated with preterm birth. Previous small studies have compared plasma selenium and plasma/erythrocyte glutathione peroxidase in mothers and their babies during both term and preterm deliveries. Although lower values have often been found in mothers who had their babies preterm than in mothers who had their babies at term, the findings were inconsistent.^13–15 We did a prospective study to assess selenium status in a large cohort of pregnant women who were followed from early gestation to delivery.     

Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth

Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother–daughter pairs. We identified novel variants shared between the two mother–daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother–daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value = 6.91e?5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.     

Fibrocytes: Bringing new insights into mechanisms of inflammation and fibrosis

Regeneration and fibrosis are integral parts of the recovery process following tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. A population of bone marrow-derived mesenchymal progenitor cells known as fibrocytes, play an important role in tissue remodeling and fibrosis in both physiologic and pathologic settings. In this review we summarize the key concepts regarding the pathophysiology of wound healing and fibrosis, and present data to support the contention that circulating fibrocytes are important in both normal repair process and aberrant healing and fibrotic damage associated with a diverse set of disease states.     

Maternal smoking during pregnancy predicts adult offspring cardiovascular risk factors - evidence from a community-based large birth cohort study

Background

Maternal smoking during pregnancy is associated with offspring obesity. However, little is known about whether maternal smoking in pregnancy predicts other offspring cardiovascular risk factors including waist circumference (WC), waist-hip-ratio (WHR), pulse rate (PR), systolic (SBP), and diastolic blood pressure (DBP).

Methods

We studied a sub-sample of 2038 (50% males) young adults who were born in Brisbane, Australia to investigate the prospective association of maternal smoking during pregnancy with young adult cardiovascular risk factors. We compared offspring mean BMI, WC, WHR, SBP, DBP and PR and the risk of being overweight and obese at 21 years by three mutually exclusive categories of maternal smoking status defined as never smoked, smoked before and/or after pregnancy but not in pregnancy or smoked during pregnancy and other times.

Results

Offspring of mothers who smoked during pregnancy had greater mean BMI, WC, WHR and PR and they were at greater risk of being obese at 21 years compared to offspring of those mothers who never smoked. The mean of these risk factors among those adult offspring whose mothers stopped smoking during pregnancy, but who then smoked at other times in the child''s life, were similar to those mothers who never smoked. These results were independent of a range of potential confounding factors.

Conclusion

The findings of this study suggest a prospective association of maternal smoking during pregnancy and offspring obesity as well as PR in adulthood, and reinforce the need to persuade pregnant women not to smoke.     

Contribution of twin pregnancy to perinatal mortality and fetal growth retardation; reversal of growth retardation after birth.

A survey of factors associated with perinatal mortality in 511 twins and fetal growth retardation and its reversal in 262 twins is presented. The incidence of stillbirth was almost 50% higher in twins than in singletons and the neonatal mortality was six times as high. Eighty percent of the neonatal deaths occurred in infants born prior to or at 30 weeks of gestation; 93% of the deaths were in infants weighing less than 1500 g and 75% occurred within 48 hours of birth. Fetal malnutrition was the main cause of stillbirth, and respiratory distress syndrome and asphyxia neonatorum were the main causes of neonatal death. One quarter of the twins had fetal growth retardation, a prevalence 10 times that in singletons. In almost all, the growth retardation was reversed by high-energy feedings. Although twins represented only 1% of all pregnancies and 2% of live births, they composed 12% of infants with early neonatal death and 17% of growth-retarded infants. A program is suggested for reduction of twin mortality and morbidity.     

Neocentromeres: new insights into centromere structure, disease development, and karyotype evolution

Since the discovery of the first human neocentromere in 1993, these spontaneous, ectopic centromeres have been shown to be an astonishing example of epigenetic change within the genome. Recent research has focused on the role of neocentromeres in evolution and speciation, as well as in disease development and the understanding of the organization and epigenetic maintenance of the centromere. Here, we review recent progress in these areas of research and the significant insights gained.     

Babesiosis: recent insights into an ancient disease

Ever since the discovery of parasitic inclusions in erythrocytes of cattle in Romania by Victor Babes at the end of the 19th century, newly recognised babesial pathogens continue to emerge around the world and the substantial public health impact of babesiosis on livestock and man is ongoing. Babesia are transmitted by ixodid ticks and infection of the host causes a host-mediated pathology and erythrocyte lysis, resulting in anemia, hyperbilirubinuria, hemoglobinuria, and possibly organ failure. Recently obtained molecular data, particularly for the 18S rRNA gene, has contributed significantly to a better understanding of the sometimes puzzling phylogenetic situation of the genus Babesia and new information has been added to help determine the taxonomic position of many species. Moreover, it seems that owing to higher medical awareness the number of reported cases in humans is rising steadily. Hitherto unknown zoonotic babesias are now being reported from geographical areas where babesiosis was not known to occur and the growing numbers of immunocompromised individuals suggest that the frequency of cases will continue to rise. This review covers recent insights into human babesiosis with regard to phylogeny, diagnostics and treatment in order to provide new information on well known as well as recently discovered parasites with zoonotic potential.     

Anti-inflammatory lipid mediators and insights into the resolution of inflammation

The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.