A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia

Objective Severe pulmonary hypoplasia and pulmonary arterial hypertension are associated with reduced survival in congenital diaphragmatic hernia (CDH). We aimed to determine whether fetal endoscopic tracheal occlusion (FETO) improves survival in cases of severe isolated CDH. Methods Between May 2008 and July 2010, patients whose fetuses had severe isolated CDH (lung-to-head ratio < 1.0, liver herniation into the thoracic cavity and no other detectable anomalies) were assigned randomly to FETO or to no fetal intervention (controls). FETO was performed under maternal epidural anesthesia supplemented with fetal intramuscular anesthesia. Tracheal balloon placement was achieved with ultrasound guidance and fetoscopy between 26 and 30 weeks of gestation. All cases that underwent FETO were delivered by the EXIT procedure. Postnatal therapy was the same for both treated fetuses and controls. The primary outcome was survival to 6 months of age. Other maternal and neonatal outcomes were also evaluated. Results Twenty patients were enrolled randomly to FETO and 21 patients to standard postnatal management. The mean gestational age at randomization was similar in both groups (P = 0.83). Delivery occurred at 35.6 +/- 2.4 weeks in the FETO group and at 37.4 +/- 1.9 weeks in the controls (P < 0.01). In the intention-to-treat analysis, 10/20 (50.0%) infants in the FETO group survived, while 1/21 (4.8%) controls survived (relative risk (RR), 10.5 (95% CI, 1.5-74.7), P < 0.01). In the receivedtreatment analysis, 10/19 (52.6%) infants in the FETO group and 1/19 (5.3%) controls survived (RR, 10.0 (95% CI, 1.4-70.6) P < 0.01). Conclusion FETO improves neonatal survival in cases with isolated severe CDH. Copyright (C) 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Prediction and probability of neonatal outcome in isolated congenital diaphragmatic hernia using multiple ultrasound parameters

Objectives To evaluate the accuracy and probabilities of different fetal ultrasound parameters to predict neonatal outcome in isolated congenital diaphragmatic hernia (CDH). Methods Between January 2004 and December 2010, we evaluated prospectively 108 fetuses with isolated CDH (82 left-sided and 26 right-sided). The following parameters were evaluated: gestational age at diagnosis, side of the diaphragmatic defect, presence of polyhydramnios, presence of liver herniated into the fetal thorax (liver-up), lung-to-head ratio (LHR) and observed/expected LHR (o/e-LHR), observed/expected contralateral and total fetal lung volume (o/e-ContFLV and o/e-TotFLV) ratios, ultrasonographic fetal lung volume/fetal weight ratio (US-FLW), observed/expected contralateral and main pulmonary artery diameter (o/e-ContPA and o/eMPA) ratios and the contralateral vascularization index (Cont-VI). The outcomes were neonatal death and severe postnatal pulmonary arterial hypertension (PAH). Results Neonatal mortality was 64.8% (70/108). Severe PAH was diagnosed in 68 (63.0%) cases, of which 63 died neonatally (92.6%) (P < 0.001). Gestational age at diagnosis, side of the defect and polyhydramnios were not associated with poor outcome (P > 0.05). LHR, o/eLHR, liver-up, o/e-ContFLV, o/e-TotFLV, US-FLW, o/eContPA, o/e-MPA and Cont-VI were associated with both neonatal death and severe postnatal PAH (P < 0.001). Receiver-operating characteristics curves indicated that measuring total lung volumes (o/e-TotFLV and US-FLW) was more accurate than was considering only the contralateral lung sizes (LHR, o/e-LHR and o/e-ContFLV; P < 0.05), and Cont-VI was the most accurate ultrasound parameter to predict neonatal death and severe PAH (P < 0.001). Conclusions Evaluating total lung volumes is more accurate than is measuring only the contralateral lung size. Evaluating pulmonary vascularization (Cont-VI) is the most accurate predictor of neonatal outcome. Estimating the probability of survival and severe PAH allows classification of cases according to prognosis. Copyright (C) 2011 ISUOG. Published by John Wiley & Sons, Ltd.

Maternal iNOS genetic polymorphisms and hypertensive disorders of pregnancy

Increased expression and activity of inducible nitric oxide synthase (iNOS) may contribute to the pathogenesis of pre-eclampsia (PE) and gestational hypertension (GH). However, no previous study has examined whether genetic polymorphisms in the iNOS gene are associated with PE or GH. We examined whether two functional, clinically relevant iNOS genetic polymorphisms (the C(-1026)A polymorphism, rs2779249, in the promoter region, and the G2087A polymorphism, rs2297518, in exon 16) are associated with GH or with PE. We studied 565 pregnant women: 212 healthy pregnant (HP), 166 pregnant with GH and 187 pregnant with PE. Genotypes were determined by real-time PCR, using the Taqman allele discrimination assay. The PHASE 2.1 program was used to estimate haplotype distributions in the three study groups. We found no significant association between the C(-1026)A polymorphism and PE or GH (P>0.05). However, we found the GA genotype and the A allele for the G2087A polymorphism at higher frequency in PE, but not in GH, compared with HP (P<0.05). The haplotype analysis showed no significant intergroup differences (P>0.05). These findings suggest that iNOS genetic variants may affect the susceptibility to PE, but not to GH. Journal of Human Hypertension (2012) 26, 547-552; doi:10.1038/jhh.2011.65; published online 30 June 2011

Brazilian multicenter study on prevalence of preterm birth and associated factors

Abstract Background The occurrence of preterm birth remains a complex public health condition. It is considered the main cause of neonatal morbidity and mortality, resulting in a high likelihood of sequelae in surviving children. With variable incidence in several countries, it has grown markedly in the last decades. In Brazil, however, there are still difficulties to estimate its real occurrence. Therefore, it is essential to establish the prevalence and causes of this condition in order to propose prevention actions. This study intend to collect information from hospitals nationwide on the prevalence of preterm births, their associated socioeconomic and environmental factors, diagnostic and treatment methods resulting from causes such as spontaneous preterm labor, prelabor rupture of membranes, and therapeutic preterm birth, as well as neonatal results. Methods/Design This proposal is a multicenter cross-sectional study plus a nested case-control study, to be implemented in 27 reference obstetric centers in several regions of Brazil (North: 1; Northeast: 10; Central-west: 1; Southeast: 13; South: 2). For the cross sectional component, the participating centers should perform, during a period of six months, a prospective surveillance of all patients hospitalized to give birth, in order to identify preterm birth cases and their main causes. In the first three months of the study, an analysis of the factors associated with preterm birth will also be carried out, comparing women who have preterm birth with those who deliver at term. For the prevalence study, 37,000 births will be evaluated (at term and preterm), corresponding to approximately half the deliveries of all participating centers in 12 months. For the case-control study component, the estimated sample size is 1,055 women in each group (cases and controls). The total number of preterm births estimated to be followed in both components of the study is around 3,600. Data will be collected through a questionnaire all patients will answer after delivery. The data will then be encoded in an electronic form and sent online by internet to a central database. The data analysis will be carried out by subgroups according to gestational age at preterm birth, its probable causes, therapeutic management, and neonatal outcomes. Then, the respective rates, ratios and relative risks will be estimated for the possible predictors. Discussion These findings will provide information on preterm births in Brazil and their main social and biological risk factors, supporting health policies and the implementation of clinical trials on preterm birth prevention and treatment strategies, a condition with many physical and emotional consequences to children and their families.

Cesarean section and increased body mass index in school children: two cohort studies from distinct socioeconomic background areas in Brazil

Abstract Background Recent studies have raised controversy regarding the association between cesarean section and later obesity in the offspring. The purpose of this study was to assess the association of cesarean section with increased body mass index (BMI) and obesity in school children from two Brazilian cities with distinct socioeconomic backgrounds. Methods Two birth cohorts respectively born in 1994 in Ribeirao Preto, a wealthy city in Southeast, and in 1997/98 in Sao Luis, a less wealthy city in Northeast of Brasil, were evaluated. After birth, 2,846 pairs of mothers-newborns were evaluated in Ribeirao Preto and 2,542 in Sao Luis. In 2004/05, 790 children aged 10/11 years were randomly reassessed in Ribeirao Preto and 673 at 7/9 years in Sao Luis. Information on type of delivery, maternal and child characteristics, socioeconomic position and anthropometric measurements were collected after birth and at school age. Obesity was defined as BMI ≥ 95th percentile at school age. Results Obesity rate was 13.0% in Ribeirao Preto and 2.1% in Sao Luis. Cesarean section was associated with obesity and remained significant after adjustment only in Ribeirao Preto [OR = 1.74 (95% CI: 1.04; 2.92)]. The association between cesarean section and BMI remained significant after adjustment for maternal schooling, maternal smoking during pregnancy, duration of breastfeeding, gender, birth weight and gestational age, type of school and, only in Sao Luis, pre-pregnancy maternal weight. In Ribeirao Preto children born by cesarean section had BMI 0.31 kg/m2 (95%CI: 0.11; 0.51) higher than those born by vaginal delivery. In Sao Luis BMI of children born by cesarean section was 0.28 kg/m2 higher (95%CI: 0.08; 0.49) than those born by vaginal delivery. Conclusion A positive association between cesarean section and increased BMI z-score was demonstrated in areas with different socioeconomic status in a middle-income country.

Periodontal disease and diabetes mellitus

Periodontal disease (PD) is one of the most commonly known human chronic disorders. The relationship between PD and several systemic diseases such as diabetes mellitus (DM) has been increasingly recognized over the past decades. Objective The purpose of this review is to provide the reader with knowledge concerning the relationship between PD and DM. Many articles have been published in the English and Portuguese literature over the last 50 years examining the relationship between these two chronic diseases. Data interpretation is often confounded by varying definitions of DM, PD and different clinical criteria were applied to determine the prevalence, extent and severity of PD, levels of glycemic control and diabetes-related complications. Methods This paper provides a broad overview of the predominant findings from research conducted using the BBO (Bibliografia Brasileira de Odontologia), MEDLINE, LILACS and PubMed for Controlled Trials databases, in English and Portuguese languages published from 1960 to October 2012. Primary research reports on investigations of relationships between DM/DM control, PD/periodontal treatment and PD/DM/diabetes-related complications identified relevant papers and meta-analyses published in this period. Results 7This paper describes the relationship between PD and DM and answers the following questions: 1- The effect of DM on PD, 2- The effects of glycemic control on PD and 3- The effects of PD on glycemic control and on diabetes-related complications. Conclusions The scientific evidence reviewed supports diabetes having an adverse effect on periodontal health and PD having an adverse effect on glycemic control and on diabetes-related complications. Further research is needed to clarify these relationships and larger, prospective, controlled trials with ethnically diverse populations are warranted to establish that treating PD can positively influence glycemic control and possibly reduce the burden of diabetes-related complications.

Pathogenesis of reproductive failure induced by Trypanosoma vivax in experimentally infected pregnant ewes

The present study was aimed at investigating the effect of experimental infection by Trypanosoma vivax in different stages of pregnancy, determining the pathogenesis of reproductive failure, and confirming transplacental transmission. We used 12 pregnant ewes distributed into four experimental groups: G1, was formed by three ewes infected with T. vivax in the first third of pregnancy (30 days); G2 comprised three infected ewes in the final third of pregnancy (100 days); G3 and G4 were composed of three non-infected ewes with the same gestational period, respectively. Each ewe of G1 and G2 was inoculated with 1.25 × 105 tripomastigotes. Clinical examination, determination of parasitemia, serum biochemistry (albumin, total protein, glucose, cholesterol, and urea), packed cell volume (PCV), serum progesterone, and pathological examination were performed. Placenta, amniotic fluid, blood and tissues from the fetuses and stillbirths were submitted to PCR. Two ewes of G1 (Ewe 1 and 3) presented severe infection and died in the 34th and 35th days post-infection (dpi), respectively; but both fetuses were recovered during necropsy. In G2, Ewe 5 aborted two fetuses on the 130th day (30 dpi) of pregnancy; and Ewe 6 aborted one fetus in the 140th day (40 dpi) of gestation. Ewes 2 and 4 delivered two weak lambs that died five days after birth. Factors possibly involved with the reproductive failure included high parasitemia, fever, low PCV, body score, serum glucose, total protein, cholesterol, and progesterone. Hepatitis, pericarditis, and encephalitis were observed in the aborted fetuses. The presence of T. vivax DNA in the placenta, amniotic fluid, blood, and tissues from the fetuses confirms the transplacental transmission of the parasite. Histological lesion in the fetuses and placenta also suggest the involvement of the parasite in the etiopathogenesis of reproductive failure in ewes.

Morphometric analysis of the placenta in the New World mouse Necromys lasiurus (Rodentia, Cricetidae): a comparison of placental development in cricetids and murids

Background: Stereology is an established method to extrapolate three-dimensional quantities from two-dimensional images. It was applied to placentation in the mouse, but not yet for other rodents. Herein, we provide the first study on quantitative placental development in a sigmodontine rodent species with relatively similar gestational time. Placental structure was also compared to the mouse, in order to evaluate similarities and differences in developmental patterns at the end of gestation. Methods: Fetal and placental tissues of Necromys lasiurus were collected and weighed at 3 different stages of gestation (early, mid and late gestation) for placental stereology. The total and relative volumes of placenta and of its main layers were investigated. Volume fractions of labyrinth components were quantified by the One Stop method in 31 placentae collected from different individuals, using the Mercator® software. Data generated at the end of gestation from N. lasiurus placentae were compared to those of Mus musculus domesticus obtained at the same stage. Results: A significant increase in the total absolute volumes of the placenta and its main layers occurred from early to mid-gestation, followed by a reduction near term, with the labyrinth layer becoming the most prominent area. Moreover, at the end of gestation, the total volume of the mouse placenta was significantly increased compared to that of N. lasiurus although the proportions of the labyrinth layer and junctional zones were similar. Analysis of the volume fractions of the components in the labyrinth indicated a significant increase in fetal vessels and sinusoidal giant cells, a decrease in labyrinthine trophoblast whereas the proportion of maternal blood space remained stable in the course of gestation. On the other hand, in the mouse, volume fractions of fetal vessels and sinusoidal giant cells decreased whereas the volume fraction of labyrinthine trophoblast increased compared to N. lasiurus placenta. Conclusions: Placental development differed between N. lasiurus and M. musculus domesticus. In particular, the low placental efficiency in N. lasiurus seemed to induce morphological optimization of fetomaternal exchanges. In conclusion, despite similar structural aspects of placentation in these species, the quantitative dynamics showed important differences.

Birth defects in newborns and stillborns: an example of the Brazilian reality

Abstract Background This study constitutes a clinical and genetic study of all newborn and stillborn infants with birth defects seen in a period of one year in a medical school hospital located in Brazil. The aims of this study were to estimate the incidence, causes and consequences of the defects. Methods For all infants we carried out physical assessment, photographic records, analysis of medical records and collection of additional information with the family, besides the karyotypic analysis or molecular tests in indicated cases. Result The incidence of birth defects was 2.8%. Among them, the etiology was identified in 73.6% (ci95%: 64.4-81.6%). Etiology involving the participation of genetic factors single or associated with environmental factors) was more frequent 94.5%, ci95%: 88.5-98.0%) than those caused exclusively by environmental factors (alcohol in and gestational diabetes mellitus). The conclusive or presumed diagnosis was possible in 85% of the cases. Among them, the isolated congenital heart disease (9.5%) and Down syndrome (9.5%) were the most common, followed by gastroschisis (8.4%), neural tube defects (7.4%) and clubfoot (5.3%). Maternal age, parental consanguinity, exposure to teratogenic agents and family susceptibility were some of the identified risk factors. The most common observed consequences were prolonged hospital stays and death. Conclusions The current incidence of birth defects among newborns and stillbirths of in our population is similar to those obtained by other studies performed in Brazil and in other underdeveloped countries. Birth defects are one of the major causes leading to lost years of potential life. The study of birth defects in underdeveloped countries should continue. The identification of incidence, risk factors and consequences are essential for planning preventive measures and effective treatments.

Insulin analogues in the treatment of diabetes in pregnancy

Pregnancy affects both maternal and fetal metabolism, and even in non-diabetic women, it exerts a diabetogenic effect. Among pregnant women, 2% to 14% develop gestational diabetes. Pregnancy can also occur in women with preexisting diabetes, which may predispose the fetus to many alterations in organogenesis, restrict growth, and the mother, to some diabetes-related complications, such as retinopathy and nephropathy, or to acceleration of the course of these complications, if they are already present. Women with gestational diabetes generally start their treatment with diet and lifestyle changes; when these changes are not enough for optimal glycemic control, insulin therapy must then be considered. Women with type 2 diabetes using oral hypoglycemic agents are advised to change to insulin therapy. Those with preexisting type 1 diabetes should start intensive glycemic control. As basal insulin analogues have frequently been used off-label in pregnant women, there is a need to evaluate their safety and efficacy. The aim of this review is to report the use of both short- and long-acting insulin analogues during pregnancy and to enable clinicians, obstetricians, and endocrinologists to choose the best insulin treatment for their patients.

Fatores maternos e neonatais associados ao mecônio no líquido amniótico em um centro de parto normal

OBJETIVO: Analisar a frequência e os fatores maternos e neonatais associados ao mecônio no líquido amniótico no parto. MÉTODOS: Estudo transversal com 2.441 nascimentos em um centro de parto normal hospitalar em São Paulo, SP, em março e abril de 2005. A associação entre mecônio no líquido amniótico e as variáveis independentes (idade materna, paridade, ter ou não cesariana prévia, idade gestacional, antecedentes obstétricos, uso de ocitocina no trabalho de parto, dilatação cervical na admissão, tipo do parto atual, peso do RN, índice de Apgar de 1º e 5º minutos de vida) foi expressa como razão de prevalência. RESULTADOS: Verificou-se mecônio no líquido amniótico em 11,9% dos partos; 68,2% desses foram normais e 38,8%, cesarianas. O mecônio esteve associado a: primiparidade (RP = 1,49; IC95% 1,29;1,73), idade gestacional ≥ 41 semanas (RP = 5,05; IC95% 1,93;13,25), ocitocina no parto (RP = 1,83, IC95% 1,60;2,10), cesariana (RP = 2,65; IC95% 2,17;3,24) e índice de Apgar < 7 no 5º minuto (RP = 2,96, IC95% 2,94;2,99). A mortalidade neonatal foi 1,6/1.000 nascidos vivos; mecônio no líquido amniótico foi encontrado em 50% das mortes neonatais e associado a maiores taxas de partos cirúrgicos. CONCLUSÕES: Emprego de ocitocina, piores condições do recém-nascido logo após o parto e aumento de taxas de cesariana foram fatores associados ao mecônio. A utilização rotineira de ocitocina no intraparto poderia ser revista por sua associação com mecônio no líquido amniótico.

Post-partum testosterone administration partially reverses the effects of perinatal cadmium exposure on sexual behavior in rats

This study investigated the effects of perinatal cadmium exposure on sexual behavior, organ weight, and testosterone levels in adult rats. We examined whether immediate postpartum testosterone administration is able to reverse the toxic effects of the metal. Forty pregnant Wistar rats were divided into three groups: 1) control, 2) 10 mg kg-1 cadmium chloride per day, and 3) 20 mg kg-1 cadmium chloride per day. These dams were treated on gestational days 18 and 21 and from lactation 1 to 7. Immediately after birth, half of the offspring from the experimental and control groups received 50 μl (i.p.) of 0.2% testosterone. Male sexual behavior, histological analysis and weight of organs as well as serum testosterone levels were assessed. Results showed that both cadmium doses disrupted sexual behavior in male rats, and postnatal treatment with testosterone reversed the toxic effects of 10 mg kg-1 cadmium and attenuated the effects of 20 mg kg-1 cadmium. Body weight and absolute testis, epididymis, and seminal vesicle weight were decreased by the higher cadmium dose, and testosterone supplementation did not reverse these effects. Serum testosterone levels were unaffected by both cadmium doses. No histological changes were detected in all organs analyzed. Maternal cadmium exposure effects in sexual parameters of male rat offspring were explained by the altered masculinization of the hypothalamus. We suggest that cadmium damaged cerebral sexual differentiation by its actions as an endocrine disruptor and supported by the changes discretely observed from early life during sexual development to adult life, reflected by sexual behavior. Testosterone supplementation after birth reversed some crucial parameters directly related to sexual behavior.

Maternal immune activation increases the corticosterone response to acute stress without affecting the hypothalamic monoamine content and sleep patterns in male mice offspring

Background/Aims: Early life experiences are homeostatic determinants for adult organisms. We evaluated the impact of prenatal immune activation during late gestation on the neuroimmune-endocrine function of adult offspring and its interaction with acute stress. Methods: Pregnant Swiss mice received saline or lipopolysaccharide (LPS) on gestational day 17. Adult male offspring were assigned to the control or restraint stress condition. We analyzed plasmatic corticosterone and catecholamine levels, the monoamine content in the hypothalamus, striatum and frontal cortex, and the sleep-wake cycle before and after acute restraint stress. Results and Conclusion: Offspring from LPS-treated dams had increased baseline norepinephrine levels and potentiated corticosterone secretion after the acute stressor, and no effect was observed on hypothalamic monoamine content or sleep behavior. The offspring of immune-activated dams exhibited impairments in stress-induced serotonergic and dopaminergic alterations in the striatum and frontal cortex. The data demonstrate a distinction between the plasmatic levels of corticosterone in response to acute stress and the hypothalamic monoamine content and sleep patterns. We provide new evidence regarding the influence of immune activation during late gestation on the neuroendocrine homeostasis of offspring.

STAT3 and SOCS3 expression patterns during murine placenta development

Signal transducers and activators of transcription 3 (STAT3) has been identified as an important signal transducer in the invasive phenotype of the trophoblasts cells in in vitro studies. However, the in situ distribution and patterns of expression of this molecule in trophoblast cells during the development of the placenta are still under-elucidated. Mice uteri of gestational ages between 7 and 14 days of pregnancy (dop) were fixed in methacarn and processed with immunoperoxidase techniques for detection of STAT3 and its phosphorylation at serine (p-ser727) residues, as well as the suppressor of cytokine signaling 3 (SOCS3) expression. STAT3 was observed at 7 through 9 dop in both the antimesometrial and mesometrial deciduas, while continued immunoreactivity between 10 and 13 dop was seen only in the mesometrial decidua. In the placenta, STAT3 was detected in the cytotrophoblast cells of labyrinth and giant trophoblast cells between 10 and 14 dop. Immunoreactivity for STAT3 was also seen in trophoblast cells surrounding the maternal blood vessels. On days 10 and 11 of pregnancy, p-ser727 was detectable in the mesometrial decidua and in giant trophoblasts, while during 12-14 dop in the spongiotrophoblast region. In addition, SOCS3 was immunodetected in maternal and placental tissues, principally in the giant trophoblast cells during the whole period of the study. The present in situ study shows the distribution of STAT3, its serine activation and SOCS3 in different maternal and fetal compartments during murine placental development, thus further supporting the idea that they play a role during physiological placentation in mice.

Long-term type 1 diabetes impairs decidualization and extracellular matrix remodeling during early embryonic development in mice

Introduction: Endometrial decidualization and associated extracellular matrix (ECM) remodeling are critical events to the establishment of the maternal-fetal interface and successful pregnancy. Here, we investigated the impact of type 1 diabetes on these processes during early embryonic development, in order to contribute to the understanding of the maternal factors associated to diabetic embryopathies. Methods: Alloxan-induced diabetic Swiss female mice were bred after different periods of time to determine the effects of diabetes progression on the development of gestational complications. Furthermore, the analyses focused on decidual development as well as mRNA expression, protein deposition and ultrastructural organization of decidual ECM. Results: Decreased number of implantation sites and decidual dimensions were observed in the group mated 90-110 days after diabetes induction (D), but not in the 50-70D group. Picrosirius staining showed augmentation in the fibrillar collagen network in the 90e110D group and, following immunohistochemical examination, that this was associated with increase in types I and V collagens and decrease in type III collagen and collagen-associated proteoglycans biglycan and lumican. qPCR, however, demonstrated that only type I collagen mRNA levels were increased in the diabetic group. Alterations in the molecular ratio among distinct collagen types and proteoglycans were associated with abnormal collagen fibrillogenesis, analyzed by transmission electron microscopy. Conclusions: Our results support the concept that the development of pregnancy complications is directly related with duration of diabetes (progression of the disease), and that this is a consequence of both systemic factors (i.e. disturbed maternal endocrine-metabolic profile) and uterine factors, including impaired decidualization and ECM remodeling