Prenatal diagnostics ultrasound was established in Russia in 2000 as a routine method of screening for birth defects. The aims of the current study were twofold: to assess changes in birth defects prevalence at birth and perinatal mortality after ultrasound screening was implemented and to estimate prenatal detection rates for congenital malformations in the city of Monchegorsk .The Murmansk County Birth Registry and the Kola Birth Registry were the primary sources of information, and include 30 448 pregnancy outcomes in Monchegorsk for the period 1973–2011. Data from these registries were supplemented with information derived from hospital records about pregnancy terminations for 2000–2007.p < 0.05) in the birth prevalence of congenital malformations of the circulatory system, the musculoskeletal system (including deformations), and other (excluding multiple); those of the urinary system increased from 0.9/1000 to 17.1/1000 (p < 0.0001). The perinatal mortality among newborns with any kind of malformation decreased from 106.6 per 1000 newborns with birth defects (95 % CI = 84.3-129.1) to 21.2 (95 % CI = 4.3-38.1). Mothers who had undergone at least one ultrasound examination during pregnancy (n = 9883) had a decreased risk of having a newborn die during the perinatal period [adjusted OR = 0.49 (95 % CI = 0.27-0.89)]. The overall prenatal detection rate was 34.9 % with the highest for malformations of the nervous system.The total number of newborns with any kind of birth defects in Monchegorsk during 1973–2011 was 1099, of whom 816 were born in the 1973–2000 period. The prevalence of defects at birth increased from 34.2/1000 (95 % CI = 31.9-36.5) to 42.8/1000 newborns (95 % CI = 38.0-47.7) after prenatal ultrasound screening was formally implemented. We observed significant decreases (Improved detection of severe malformations with subsequent pregnancy termination was likely the main contributor to the observed decrease in perinatal mortality in Murmansk County, Russia. Prenatal diagnosis is the identification of birth defects prior to delivery and constitutes a routine practice in most of European countries . PrenataThe effectiveness of PS can be estimated by the prenatal detection rate, which represents the proportion of BD recognized before delivery. It depends on the type of defect, quality of equipment and experience of the operator. According to the European Surveillance of Congenital Anomalies (EUROCAT) data, 64 % of BD could be diagnosed before birth although it varies widely, from 94 % for anencephaly to 87 % for omphalocele, and as low as 27 % for the transposition of great vessels . For chrThe PS of malformations has an influence on the stillbirth rate, as they lead to terminations of pregnancies when severe defects are diagnosed. Surgical correction of defects during the first days of life can also reduce neonatal mortality .In Russia, prenatal ultrasound examination was established in the early 1990s, and became part of a screening program offered to all pregnant women in compliance with a national law promulgated in 2000. It is free of charge and is offered by obstetricians to every pregnant woman. Refusal must be put in writing. The Russian Ministry of Health stipulates a two-stage approach to PS , terminaTen years after the establishment of PS in Russia, it is pertinent to assess its efficiency in the detection of BD and impact on pregnancy continuations. However, the available information is limited. In 2001–2003, researchers from the Komi republic (Northwestern District) estimated a prenatal detection rate based on more than 29 thousands pregnancies, and reported that it was the highest (74.5 %) for neural tube defects and lowest (4.7 %) for cardiovascular malformations; for Down syndrome it was 33.3 % . AnotherA countywide population-based birth registry established in 2005 for Murmansk County provides a unique opportunity to study BD epidemiology at the population level . Since lOur study population includes all newborns delivered in Monchegorsk during the period 1973–2011 and registered either in the Kola Birth Registry (KBR) or in the Murmansk County Birth Registry (MCBR).The KBR was established in 1998 by a retrospective retrieval from hospital delivery department records of information about all births from week 28 of gestation on that occurred in Monchegorsk as of March 1973. Registration continued prospectively until the end of 2005. Details of its construction, description, suitability for epidemiological studies and selected applications are available , 15, 16.th week of pregnancy in cases with medical indications .The logistic regression analysis indicated that mothers who had undergone at least one ultrasound examination during pregnancy , the circulatory system , multiple malformations , congenital malformations of the kidney , diaphragm hernia , other malformations .Prenatal diagnoses of the BD pertaining to the 25 pregnancy terminations involved the nervous system . Consequently, the estimated reduction in the stillborn rate linked to the abortion of fetuses with severe BD was 38 %, and 30 % for perinatal mortality.After inclusion of TOPFA in the mortality analysis, the stillborn rate in 2000–2007 increased to 13.8/1000 (95 % CI = 10.9-13.6) from that based on the registry data [8.5/1000 (95 % CI 5.8-11.1)].The perinatal mortality was 17.7/1000 (95 % I = 14.7-22.0) Our study showed clearly that the implementation of PS had an impact on perinatal mortality and BD prevalence. The five-fold decrease observed in perinatal mortality among newborns after the implementation of PS exceeded that reported for the mentioned Helsinki trial . The latThe prevalence of TOPFA in 2000–2007 was 5.4 per 1000 births. In Europe, such indicator varies from zero in Ireland, Malta and Poland  to 10/1000 births in France . In RussAt first glance, one might suggest that the establishment of screening has not influenced pregnancy continuation. It could be argued that due to the multiplicity of medical reasons for termination the dynamics of abortion incidence could not truly represent the influence of PS. However, our results contradict this. Adjustment by year in the logistic regression analysis excluded a potential influence of medical progress over time, and this suggested that the effect of decreasing the number of perinatal deaths was related to the early detection of pathological conditions and medical intervention. More accurate determination of gestational age was likely an issue as well.The observed increase in the birth prevalence of BD during 2001–2011 .A decrease in musculoskeletal malformation’s prevalence , staffed with specialists in ultrasound diagnostics. The mean number of examinations per woman during pregnancy was high, although of rather poor quality, as half of the malformations were not diagnosed before birth . Some RuA primary feature of the PS program in Monchegorsk is the poor detection of chromosomal defects. For example, no diagnosis of Down syndrome was made before birth. The likely reason is that Monchegorsk is a relatively small city (about 45 000 inhabitants compared to around 300 000 in Murmansk), and such municipal hospitals have been recognized to have problems with both the quality of the medical equipment and of medical staff training, especially during the first years of PS. Chromosomal defects are difficult recognize and diagnose. They were more frequently addressed in regional clinics, which are staffed with genetic specialists and consultants for the second stage of PS, as described above.Our study is the first in Northern Russia to analyze the effectiveness of PS at the population level that is based on validated sources of information, including TOPFA data. Furthermore, the two birth registries used provided full coverage of all pregnancy’s outcomes, although our study was limited to information about BD diagnosed during the first week of life. The latter could have led to a possible underestimation of the prevalence of small birth defects, although it did not influence the prenatal mortality. We did not have data on TOPFA for the whole study period, and consequently could not include them in the prevalence analyses. Thus, we aimed to estimate prevalence at birth and, we suppose, that inclusion of TOPFA would have increased the estimated prevalence somewhat. In this instance, prevalence of severe BD would also have increased. Some pregnant women suspected to give birth to newborns with serious BD did so at major hospitals in Murmansk, Moscow or Saint Petersburg and their neonates were not included in our analysis. Inclusion of such newborns could increase the prenatal detection rates, but the proportion of such cases was not high. For example, according to the data provided by the Monchegorsk Hospital six newborns (6.8 %) with prenatally diagnosed BD  were born in Murmansk or Moscow. Due to differences in coding between registries and the large proportion (up to 5 %) of missing information, our regression model did not include all possible confounders such as comorbidities of mothers and complications of pregnancy, previous history of stillborn and maternal socio-economic status.The birth prevalence of BD doubled after the introduction of routine PS, but less than half of the defects were diagnosed before birth. Improved detection of severe malformations with subsequent termination is likely to have been the main contributor to the observed decrease in perinatal mortality during 2001–2011 in Murmansk County, Russia.


Structural birth defects together of are a prominent cause of mortality and morbidity and are gaining importance with improving obstetric care and reduction in infective causes. Advances in understanding genetic (G) and environmental (E) factors and their interaction have added newer dimensions to the etiology of birth defects. Epigenetic is one such interesting field expected to provide mechanistic links between whether and how the environment interacts with maternal and fetal genomes. Some classical examples of environmental insults such as teratogens, maternal medical disorders and nutritional deficiencies as well as G-E interactions leading to birth defects will be discussed. It is important that the relevant scientific information should reach professionals and public for better awareness, appropriate policy decisions to prevent birth defects.


Lynne Mofenson and Heather Watts discuss the context and implications of the study by J. Sibuide and colleagues, which provides a detailed analysis of birth defects in infants with in utero antiretroviral drug exposure in the French Perinatal Cohort.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001635Sibiude J, Mandelbrot L, Blanche S, Le Chenadec J, Boullag-Bonnet N, et al. (2014) Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11). PLoS Med 11(4): e1001635. Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.One of the greatest public health successes has been the development and implementation of antiretroviral interventions to prevent mother-to-child HIV transmission (MTCT). The landmark 1994 Pediatric AIDS Clinical Trials Group (PACTG) 076 results, demonstrating zidovudine given to HIV-infected pregnant women and their infants reduced MTCT by nearly 70%, led to rapid implementation in the Unites States, with subsequent decline in MTCT from 25% to 4%–5% within two years Additionally, there has been striking progress in reducing MTCT in resource-constrained countries, with 1 million children prevented from acquiring HIV between 2003 and 2013 because of maternal and infant antiretroviral prophylaxis PLOS Medicine provide a detailed analysis related to birth defects in infants with in utero antiretroviral drug exposure in the French Perinatal Cohort However, accompanying this success is a rapidly expanding population of HIV-exposed but uninfected children with substantial exposure to antiretroviral drugs, both in utero and, in resource-constrained countries, while breastfeeding. There is an urgent need to better understand the consequences of antiretroviral drug exposure on HIV-uninfected children and to improve monitoring and management of any potential adverse effects in this burgeoning population. Sibiude and colleagues in this week's issue of Given the emphasis on early treatment of HIV in adults and the move toward initiation of life-long therapy in all pregnant women in many resource-constrained countries, it can be anticipated that there will be a dramatic increase over time in women who conceive while receiving antiretroviral drugs, with fetal exposure from conception onward. Data from epidemiologic studies suggest MTCT may be lowest in infants born to mothers receiving cART prior to conception and continued during pregnancy A critical factor in the risk of drug-related birth defects is fetal developmental stage at the time of exposure. During the first two weeks after conception, exposures are unlikely to cause malformations, as immediately after conception the embryo has not yet formed, and after its formation, an additional period of time intervenes before its cells become committed to specific developmental paths Animal studies have been used to evaluate whether drug exposures may be associated with teratogenic potential prior to use in humans. However, it is difficult to extrapolate animal findings because of species differences in placentation, embryonic development, innate predisposition to fetal abnormalities, and drug pharmacokinetics/dynamics The French Perinatal Cohort study reports on birth defect surveillance in 13,124 live-births to HIV-infected pregnant women delivering in 90 clinical centers in France between 1994 and 2010; 5,388 (42%) of infants had first trimester exposure to one or more antiretroviral drugs The primary finding in the the French Perinatal Cohort study was a significant association of first-trimester zidovudine exposure with congenital heart defects, which persisted after adjustment for a number of potential confounders. Most were ventricular or atrial septal defects  and persistent ductus arteriosus, and were not associated with other malformations. The clinical significance of these defects or whether these were primarily detected through active fetal ultrasound surveillance was not described. Spontaneous closure of ventricular septal defects (VSDs) is frequent; in a study of 249 fetuses with VSDs detected by fetal ultrasound, spontaneous closure of the VSD occurred in 5% of fetuses prenatally and 76% postnatally by age one year The authors also report a significant association between first-trimester efavirenz exposure and neurologic defects in the MACDP classification system of birth defects, but not the EUROCAT classification, which excludes minor anomalies with no serious medical or functional consequences Reassuringly, no association with birth defects were observed for other WHO-recommended first or second-line drugs, including tenofovir, lamivudine, and lopinavir/ritonavir The use of antiretroviral drugs by HIV-infected pregnant women has resulted in a paradigm shift in the maternal and pediatric HIV epidemics, with markedly improved maternal survival and dramatic reductions in MTCT. However, despite the widespread use of antiretroviral drugs by pregnant women, systematic evaluation of birth defects has been limited. The Antiretroviral Pregnancy Registry only enrolls ∼15% of HIV-infected pregnant women giving birth annually in the United States and only about 200 pregnant women from other countries The largest amount of data on birth defects and antiretroviral drug exposure comes from high-resource countries. However, the largest population of HIV-infected women of childbearing age resides in resource-constrained countries, where women are exposed to multiple factors that could increase risk of birth defects, such as under-nutrition, micronutrient deficiency, anemia, and co-infections. Additionally, in many resource-constrained countries, data on the background risk of birth defects in the general population are lacking. Determining the potential risk of birth defects due to antiretroviral drug exposure requires knowledge of the underlying risk of birth defects in the population being studied.Given that the HIV burden in women is greatest in resource-constrained countries, where rapid expansion in antiretroviral drugs use in pregnancy (and increasingly at conception) is expected with implementation of WHO guidelines, there is an ethical imperative to systematically and critically evaluate the safety of these recommendations for the fetus/infant, both in terms of potential teratogenicity but also long-term outcomes. While the Sibiude study raises some important questions, given the enormous benefits of maternal antiretroviral drugs, the unclear clinical significance of the heart defects and the lack of a specific pattern of CNS defects with efavirenz, no change in prescribing practices is indicated, but continued surveillance is critical.WHO has established a Pregnancy Registry protocol that is beginning to be implemented in several resource-constrained countries


Fetal macrosomia is defined as birth weight ≥4000 g. Several risk factors have been shown to be associated with fetal macrosomia. There has been an increased incidence of macrosomic babies delivered and the antecedent complications.This study assessed the risk factors, maternal and neonatal complications of fetal macrosomia in comparison with normal birth weight neonates.A case-control study was conducted at the Muhimbili National Hospital (MNH) maternity and neonatal wards. Cases comprised of neonates with birth weight ≥4000 g; controls were matched for sex and included neonates weighing 2500–3999 g. Detailed clinical and demographic information and laboratory investigations which included blood glucose, hematocrit and plasma calcium were collected. The child was followed up to discharge/death.p-value <0.05), while shoulder dystocia, uterine rupture and maternal death were recorded only among the cases and none occurred in the controls.The prevalence of macrosomic babies was 2.3 % (103 out of 4528 deliveries). Mean birth weight of macrosomic babies was 4.2 ± 0.31 kg whereas in the controls it was 3.2 ± 0.35 kg. Maternal weight ≥80 kg, maternal age ranging between 30 and 39 years, multiparity, presence of diabetes mellitus, and gestational age ≥40 years, previous history of fetal macrosomia and delivery weight ≥80 kg were significantly associated with fetal macrosomia. Macrosomic infants were more likely to have birth asphyxia, shoulder dystocia, hypoglycemia, respiratory distress and perinatal trauma and increased risk of death compared to controls. Maternal complications such as postpartum hemorrhage, second degree perineal tears and prolonged labor occurred more frequently in the macrosomia group compared to controls (Fetal macrosomia was an important cause of maternal and neonatal morbidity at Muhimbili National Hospital. Presence of risk factors should alert the obstetrician to closely monitor these pregnancies and plan on appropriate mode of delivery. Macrosomic neonates should be routinely screened and appropriately managed for hypoglycemia. Fetal macrosomia is common in obstetrics with problems to both the mother and the newborn. It has been associated with significant risk of morbidity and mortality. Over the years, the trend in fetal macrosomia has been shown to be increasing worldwide –3.Several risk factors have been identified in the causation of macrosomia. These include maternal diabetes, high pre-pregnancy Body Mass Index (BMI), excessive weight gain during pregnancy, multiparity, male sex, parental height, and prolonged gestation –18.During labour, cephalo-pelvic disproportion can result in fetal distress and difficult deliveries are frequent in this group of infants. Maternal complications include increased risk of Caesarian section, postpartum hemorrhage and perineal lacerations , 8, 19. Neonatal complications include birth asphyxia, birth trauma, and hypoglycemia , 21–25. The few studies on macrosomia have mainly focused on the risk factors and maternal outcome. Little attention has been given to the macrosomic infant even though they have high perinatal mortality and morbidity rates, particularly in our setting. Hence a need was felt to conduct this study on fetal macrosomia so as to aid in future identification of these pregnancies, anticipate their complications and plan on appropriate mode of management.This was a prospective matched case-control study conducted at MNH maternity and neonatal wards in Dar es Salaam, Tanzania. All infants with birth weight of 4000 g or greater delivered at the labor ward during the study period were selected as cases. The next infant of the same sex delivered with birth weight ranging from 2500 to 3999 g was selected and served as control. Cases and controls were matched for sex.Three trained nurse midwives at the labor ward (one nurse per shift) were selected and assisted in recruitment of study participants. Babies were recruited within the first hour after delivery and after written informed consent. Recruitment of patients and sample collection was done at any time of the day. On average two to three cases and controls were enrolled daily.2) of 13.6 % in controls [Assuming the percentage of exposure BMI > 28 kg/m kg/m2 ofAt recruitment, a drop of capillary blood was obtained by heel prick of the baby for random blood sugar estimation. This screening was repeated during the second, fourth and sixth hour after delivery. Results were confirmed by checking plasma glucose levels. Blood was drawn for hematocrit, plasma calcium and glucose estimation. Infants suspected to have a fracture underwent X-ray examination for confirmation. They were reported by an experienced radiologist. Management was based on the standard treatment guidelines of the unit and all recruited babies were followed-up while in the ward until recovery and discharge or death. Discharge was sub-classified as discharge with/without disability.p-value of less than 0.05 was considered as statistically significant.Analysis was done using SPSS  software version 15. Means were compared by using Wilcoxon signed ranks test. Univariate analysis of risk factors was carried out using conditional logistic regression in order to determine strength of association with the outcome. Multivariate conditional logistic regression analysis was carried out on variables that were significant in the univariate analysis. Indications for caesarean section (C/S) and maternal and neonatal complications of fetal macrosomia were analyzed using binary logistic regression. Odds ratio with 95 % confidence intervals (CIs) were calculated for risk factors and complications. A During the study period October 2009 to March 2010, there were a total of 4528 deliveries of which 103 had a weight greater than or equal to 4000 g. The prevalence of fetal macrosomia was 2.3 %.p-value 0.05). Mean parity was significantly greater in the macrosomia group compared to the controls . Other parameters including weight at delivery, mean height and gestational age at delivery were also significantly higher among the cases compared to the controls. Mean birth weight in the macrosomia group was similar among male and female macrosomic neonates . Infants delivered by caesarean section had a greater mean birth weight compared to those delivered vaginally (4800 vs. 4200 kg). However this was not statistically significant . There were more males than females in the study population and the overall male to female ratio was 1.5:1 .Majority of mothers delivering macrosomic babies were in the age group from 30 to 39 years (55.3 %); age groups less than 30 years and greater than or equal to 40 years were not significantly associated with macrosomia. Multiparity was present in 89.3 % of mothers in the macrosomia group. A significantly greater percentage (46.7 %) of mothers in the macrosomia group had previous history of delivering macrosomic infants (compared with 12.6 % among controls). Mothers having diabetes mellitus were 10 times more likely to deliver a macrosomic baby compared to those without diabetes mellitus.Most of the deliveries in the cases and control groups occurred at gestational ages of 37–39 weeks (66.0 and 83.5 % respectively). However, macrosomic infants were four times more likely than controls to be delivered at gestational age greater than or equal to 40 weeks. None of the mothers in our study had pregnancy that lasted longer than 42 weeks.When variables significant on univariate analysis were included in the multivariate logistic regression model, history of previous macrosomia and weight greater than 80 kg at delivery were the only maternal characteristics that were significantly associated with increased odds for macrosomic births . A greater percentage of macrosomic infants were delivered by emergency C/S compared to controls, but the difference was not statistically significant , assisted breech delivery (ABD) and low cavity vacuum extraction (LCVE). There was no significant difference in these modes of deliveries between the two groups. Majority of the macrosomic infants were delivered by C/S was (61.1 %) followed by SVD (34.0 %). The rate of C/S was higher among cases compared to their controls (61.1 vs. 49.5 %) but the difference was not statistically significant . There was no significant difference in other indications for C/S between the two groups (Table The commonest causes for caesarean deliveries included previous C/S scar (35.9 %), obstructed labor (29.8 %) and fetal distress (19.3 %). Some patients had more than one indication for C/S. Fetal macrosomia was identified as an indication for C/S in 20.6 % of cases, and this was significantly greater compared to the controls . Commonest complications in mothers delivering macrosomic infants included prolonged labor (27.2 %), 2nd degree perineal tears (22.3 %) and post-partum hemorrhage (PPH) (17.5 %). Mothers delivering macrosomic infants were five times more likely than the controls to develop PPH. Uterine atony, perineal tears and uterine rupture were the main causes of PPH. There were 3 cases of shoulder dystocia in the macrosomia group and uterine rupture occurred in 2 mothers in the macrosomia group (1.9 %). There was one maternal death in the macrosomia group; the cause of death was uterine rupture and PPH. No death occurred in the control group (Table p < 0.05). The commonest neonatal complications among the macrosomic group were hypoglycemia (22.7 %), respiratory distress (16.5 %), birth asphyxia (14.4 %) and birth trauma (14.4 %). Mortality was significantly higher in the macrosomia group compared to controls (p <0.05). Main causes of death among the cases included stillbirth (6 cases and 1 control) and birth asphyxia. Out of the 12 macrosomic neonates who died, three were born to diabetic mothers. The commonest injuries were cephalhematoma and fractures (5.7 %) followed by nerve palsy (3.1 %). They were more likely to occur in infants delivered by SVD, ABD and LCVE. Hypoglycemia occurred more frequently in the macrosomic group compared to the controls (22.7 vs. 6.9 %). In 96 % of cases, hypoglycemia occurred within 6 h of delivery. Hypoglycemia was also more frequent in infants born to mothers without diabetes mellitus (23.5 %) compared to those born to diabetic mothers (16.6 %); however the difference was not significant   compared to the controls ; however this difference was not significant.p-value <0.001)  Table .Table 7NThe prevalence of fetal macrosomia in our study was 2.3 %. Other studies in Africa have reported prevalence of 3.4 % in South Africa  and 3.5 This low prevalence may be explained by the lower pre-pregnancy weight and low socio-economic status in our population.There was a strong association between fetal macrosomia and maternal age greater than 30 years. This finding was similar to that seen in South Africa by Essel et al. . This maA history of diabetes mellitus  occurred more frequently among the cases compared to the controls. The finding of 11.6 % was much higher compared to 7.1 % in seen in Ibadan, Nigeria . DiabeteMothers with a weight at delivery greater than or equal to 80 kg were more likely than their controls to deliver a macrosomic infant. Other authors have found that weight greater than or equal to 90 kg to be significantly associated with fetal macrosomia , 31. PreThe high male to female ratio in the macrosomic group has been reported by other studies , 8, 18. Postpartum hemorrhage, second degree perineal lacerations and prolonged labor were significant maternal complications in the macrosomia group. This was similar to findings noted by other authors , 8, 19. Sixty one percent of macrosomic babies were delivered by C/S in our study. This rate is four times higher compared to other studies , 19. AltShoulder dystocia occurred in 3 mothers delivering macrosomic infants and was associated with brachial plexus injuries. Similar to a study done by Iffy et al.  all the Similar to other studies, macrosomia was shown to be associated with adverse neonatal outcomes , 21, 35.Birth trauma was greater in the macrosomia group compared to controls. Similar to other studies , 28, 34,Hypoglycemia occurred in 22.7 % of macrosomic neonates. This was higher than that observed by Oral et al. . ContrarSimilar to a study by Oral et al., there was no significant association between macrosomia with polycythemia and hypocalcemia . All theDue to non-availability of results of oral glucose tolerance test results during pregnancy some mothers with impaired glucose tolerance during pregnancy may have been missed. Diagnostic bias was minimized by measuring random blood sugar levels of all mothers in the study population. Only those with a previously documented history of diabetes mellitus or with abnormal random blood glucose readings were classified as having diabetes mellitus.Majority of the mothers booked during the second or third trimester of pregnancy and it was not possible to measure the total weight gain during pregnancy. As a result, only weight measured at time of delivery was recorded.Sixty three percent of the total sample size was reached and as a result reduced the power of the study to 80 %. This power is within acceptable value given the time limitations. Increasing the number of controls per case could have been used to increase the study power.The prevalence of fetal macrosomia at MNH was 2.3 % and an important cause of maternal and neonatal morbidity. Maternal risk factors include multiparity, previous history of macrosomia, presence of diabetes mellitus, gestational age of 40 weeks and above, delivery weight greater than or equal to 80 kg and maternal age ranging between 30 and 39 years. Complications included PPH, 2nd degree perineal lacerations, uterine rupture, and prolonged labor and maternal death. The neonatal complications included birth asphyxia, respiratory distress, hypoglycemia and death. We suggest that mothers should be screened using risk factors identified and be treated as a high risk delivery, with planned delivery and after care.


Autism spectrum disorders (ASD) constitute a major public health problem affecting one in 68 children. There is little understanding of the causes of ASD despite its serious social impact. Air pollution contains many toxicants known to have adverse effects on the fetus. We conducted a population based case–control study in southwestern Pennsylvania to estimate the association between ASD and 2005 US EPA modeled NATA  levels for 30 neurotoxicants.N = 224) frequency matched by child’s year of birth, sex and race with complete residential histories from prior to pregnancy through the child’s second birthday, and 2) 5,007 controls generated from a random sample of birth certificates (BC controls) using residence at birth. We used logistic regression analysis comparing higher to first quartile of exposure to estimate odds ratios (ORs) and 95 % confidence intervals (CI), adjusting for mother’s age, education, race, smoking status, child’s year of birth and sex.A total of 217 ASD cases born between 2005 and 2009 were recruited from local ASD diagnostic and treatment centers. There were two different control groups: 1) interviewed controls (p = 0.013) for the interviewed case–control analysis and 1.61  for the BC analysis. In the BC comparison, chromium also exhibited an elevated OR of 1.60 , which was similarly elevated in the interviewed analysis . There were borderline significant ORs for the BC comparison for methylene chloride  and PAHs .Comparing fourth to first quartile exposures for all births, the adjusted OR for styrene was 2.04  contains supplementary material, which is available to authorized users. Autism spectrum disorders (ASD) constitute a major public health problem, affecting approximately one in every 68 children and their families . ASDs ar2.5, ozone, NO2, pesticides, heavy metals, solvents, and diesel exhaust [Despite its serious social impact , the cau exhaust –16.2, PM2.5, and PM10 [2.5, NO, and NO2 [Although there are differences in the time periods of the investigations, geographical regions under study and the exposure assessments, a growing number of studies suggest a potential role of ASD and air pollution. Recently, several investigations have focused on ASD risk and ambient criteria air pollutants (traffic related and/or from industry) –16. Volkand PM10 . Becerra and NO2 .To date, there have been three case–control studies of ASD risk that utilized data from the National Air Toxics Assessment (NATA) to examine exposure to specific neurological toxicants, developmental toxicants, or suspected endocrine disruptors during pregnancy –19. NATAN = 768). ASD risk was increased per interquartile range increase in average concentrations during pregnancy for several correlated toxics, including 1,3-butadiene, meta/para xylene, other aromatic solvents, PERC and formaldehyde, after adjustment for mother’s age, race/ethnicity, education, insurance type, parity, sex and birth year [Von Ehrenstein et al. (2014) considered the risk of autistic disorder related to ground level measured exposure to monitored ambient air toxics from urban emissions during the pregnancy period . Birth rrth year .a priori agents: arsenic, cadmium, chromium, lead, mercury, manganese, nickel, styrene, trichloroethylene, methylene chloride, vinyl chloride, and diesel particulate matter. Further, we examined additional compounds identified as neurotoxicants, endocrine disruptors, or developmental toxicants by the US EPA [Given these few epidemiological investigations and the heavy industrial background of southwestern Pennsylvania, the objective of the current study was to conduct an exploratory case–control study in this area to assess if neurotoxic air pollutants, as modeled by NATA, were associated with the risk of ASD. We focused on suspect agents found in the previous three investigations which used NATA data and evaluated whether there was an increased risk of ASD associated with higher exposures to these e US EPA .This study was approved by the University of Pittsburgh Institutional Review Board (IRB number PRO10010240).Cases of ASD for this study were children born between January 1, 2005 and December 31, 2009 in Allegheny, Armstrong, Beaver, Butler, Washington, or Westmoreland County in southwestern Pennsylvania and who were currently residing in the six-county area. Our goal was to enroll approximately half of the prevalent cases among this birth cohort. Based on 23,399 births in 2007 in the six county area  and a prThere is no autism registry in Pennsylvania, and therefore no centralized agency that could be accessed for permission to contact parents of children with ASD for the purposes of conducting a study. Our investigation used an extensive outreach campaign to recruit ASD cases from a combination of 1) ASD specialty diagnostic and treatment centers, 2) private pediatric and psychiatry practices, 3) school-based special needs programs (starting at age 5), and 4) autism support groups. Per our IRB guidelines, we were not allowed to directly contact parents of children with ASD. Therefore, we provided informational packets to these agencies and organizations with a letter, contact sheet and pre-addressed envelope to be returned to our office, and these agencies mailed the information to families with ASD. When a contact sheet was returned, we were permitted to contact the mother to describe the study and request consent to participate.A case of ASD was defined as any child 1) who scored a 15 or above on the Social Communication Questionnaire (SCQ), a positive screen for the presence of autistic features, and 2) for whom there was written documentation, including ADOS or other test results, of a diagnosis of an ASD from a child psychologist or psychiatrist. Cases were not included in the study if the child was adopted, parents were not English speaking, or a parent was not available for interview. A total of 217 cases were consented and interviewed for the study.The study was designed to have two different sets of controls. The first control group (interviewed controls) was recruited from a random selection of 5007 births weighted by sex  from the Pennsylvania Department of Health (PA DOH) state birth registry files for 2005 to 2009 in the six-county area. Interviewed controls were frequency matched to the cases on year of birth, sex, and race. We recruited through a direct letter appeal signed by the Pennsylvania Secretary of Health. The rules for both the PADOH IRB and that of the University of Pittsburgh mandated that there would be no direct contact with potential controls, except for the opportunity to return an envelope and contact sheet indicating refusal to be in the study or an indication that the parent was interested in enrolling his or her child in the study by providing contact information. We requested a postal service return to sender, address correction requested. However, since we used an address from the birth certificate that was several years old, it is likely that many of the letters were never delivered to the intended resident or were simply ignored, making it difficult to determine a true response rate.After we obtained informed consent, parents were screened for inclusion criteria and administered the SCQ for their child. Children with an SCQ >15 or with a reported diagnosis of ASD were not included as controls. Other exclusion criteria were the same as those for cases. The first control group consisted of 226 eligible controls that were consented and interviewed.For each of the cases and the interviewed controls, a personal interview with the mother was conducted by trained interviewers using a structured questionnaire, adapted from the CDC’s Study to Explore Early Development (SEED). The questionnaire included parental demographic and socioeconomic information, a detailed residential history, maternal and paternal occupational history, family history of ASD, smoking history, maternal reproductive and pregnancy history, and child’s medical history. Data was obtained on all residential addresses and the corresponding start and end dates that the mother/child lived at those addresses from three months prior to last menstrual period (LMP) until the child’s second birthday.The second control group (birth certificate or BC controls) consisted of a random sample of births occurring from 2005 to 2009 for the six county area of study, weighted with a male to female ratio of 4:1 and year of birth. Birth certificate information on the cases and controls, consisting of residence at birth, age of mother, smoking history, maternal education, race and other infant characteristics, was then used for the second case–control analysis. Of the total sample of 5,007 birth certificates, 16 were identified as being in our case (ASD) population and were removed from the control group.http://www.epa.gov/ttn/atw/nata2005/tables.html accessed April 16, 2014). Out of the 177 air toxics available through NATA, we examined the distribution, variability, and correlations of 37 air toxics characterized as having neurological, developmental or endocrine-disrupting effects by one of the previous studies [Exposure to ambient hazardous air pollution concentrations was estimated using modeled data from the 2005 NATA assessment. The 2005 NATA estimates are an annual average by census tract and were downloaded from the US EPA website ( studies  or the Uhttp://developer.mapquest.com/web/tools/lat-long-finder). Year 2000 census tracts (11 digit FIPS codes) for each address were assigned using ArcGIS 10.1, linking to 2009 Tiger Line files for the 2000 United States census. We calculated person-specific exposure estimates for each of the air toxic compounds, taking into account the locations of and changes in residence and the time spent at each residence. For each child, average exposure estimates were computed for the time periods of pregnancy, first year of life, and second year of life. Two participants who lived at a residence outside of the United States for which no NATA data was available were excluded from analysis, leaving an analytic group of 217 cases and 224 controls.For the analyses of the interviewed cases and controls, the residential addresses obtained during the interview were geocoded to an X, Y coordinate using ArcGIS  and verified manually. When an address could not be successfully geocoded in ArcGIS, other methods were used, including MapQuest Latitude/Longitude Finder , aromatic solvents , and chlorinated solvents . Index scores were computed for each of the structural groups of metals, aromatic solvents, and chlorinated solvents by summing the quartiles for the compounds in each group. Similar to what was done for the individual compounds, quartile cut points of these scores were calculated based on the distribution of the index scores among the interviewed controls. Logistic regression models comparing highest quartiles to the lowest quartile were conducted for each of the indices for both the interviewed and BC comparisons, controlling for mother’s age, education, race, smoking, child’s year of birth and sex. IBM SPSS Statistics 20 and 22 were used for all analyses. No formal adjustment was made for multiple comparisons.Additionally, we noted a significantly higher number of multiple births reported among cases compared to controls . As there is a high rate of prematurity and other problems associated with multiple births, we conducted a sensitivity analysis with and without the inclusion of multiple births for both case–control comparisons.One of the last steps involved a backward multiple logistic analysis of all agents identified as significant in either case–control comparison with adjustment for mother’s age, race, education, smoking, child’s birth year, and child’s sex. This was done in order to consider the most significant effects of NATA compounds while controlling for the same covariates that were used in the previous logistic regression models for individual pollutants.p < 0.01). Similar to the methodology detailed by von Ehrenstein et al [Finally, air toxics are often correlated with each other, and people are often simultaneously exposed to a complex mixture of air pollutants. In our study, the Spearman correlation matrix revealed that many of the air toxics were highly correlated  were diagnosed from specialty ASD diagnostic and treatment centers/clinics, 47 (21.6 %) were recruited through private pediatric psychology/psychiatry practices/University, 43 (20 %) were recruited through school-based special needs programs, and 11 (5.1 %) were recruited through autism support groups or our website.A total of 299 families returned a contact sheet and were initially consented and screened for this study  . Cigarette smoking at any time from three months prior to pregnancy until birth was higher among mothers of interviewed ASD cases compared to mothers of interviewed controls. Using the birth certificate information, mothers of cases reported smoking less prior or during pregnancy compared to their birth certificate control counterparts. Preterm births among ASD cases were significantly greater compared to both control groups, largely due to a greater percentage of multiple births  interviewed ASD cases and controls during the pregnancy period, and for 2) cases and the BC controls using the residence at the time of birth from the birth certificate. As the exposure was assigned differently for the two groups of cases and controls , we compared the distributions. In the comparison of the two data sources for the cases, we found no significant differences (Mann Whitney test). A comparison between the two control groups (interviewed versus BC), however, showed significant differences in the distributions for selenium, styrene, and cyanide; all were higher for the second control group.Table p < 0.10) for second versus first quartile for lead, PAHs, and diesel PM, and third versus first quartile for benzene.In the unadjusted logistic regression analysis of the interviewed case–control comparison (not shown), there were statistically significant odds ratios for fourth compared to first quartile of styrene and chromium. PAHs and methanol were of borderline significance for fourth compared to first quartile. For the birth certificate unadjusted analyses , associations were statistically significant for toluene third versus first and styrene second versus first quartile. Results were of borderline significance . Chromium was also associated with significantly higher odds of having ASD  when comparing the fourth to the first quartile of exposure, after adjustment for covariates. PAHs and methylene chloride were of borderline significance . Lead exposure, third quartile compared to first, was significant  as well as toluene  third to first quartile. There was a borderline significant effect for benzene  third quartile compared to first. Table p = 0.064).As shown in Table The supplement .A backward stepwise multiple logistic regression analysis was conducted in order to consider the contribution of these seven compounds identified as “compounds of interest” while controlling for important covariates of mother's education, race, age, smoking, child’s birth year and sex. For both the interviewed case–control and BC comparisons, only styrene remained in the final model of the seven air toxics, adjusting for covariates . Also, we applied the NATA concentration estimates for 2005 to the full time period of this study, and they may not have been representative of exposures for other years. In the interviewed analysis, although we had information on changes in residential addresses in the prenatal and postnatal period, we did not have explicit mobility patterns for the mother-child pairs outside of these residential census tracts.Each control group analysis had its unique strengths and weaknesses. We were able to conduct maternal interviews for cases and for the first control group to obtain full residential history information, thereby decreasing exposure misclassification bias. We were also able to examine the association between ASD and estimated exposure to NATA air toxics not only during pregnancy, but also for the first and second years of life—the first study to do so. The second control group, because it was a random sample representative of all births in the six county area , removed the issue of response bias among the controls. However, a limitation of the second set of case–control analyses was the inability to capture residences during pregnancy other than the address reported at the time of birth. We noted that 16.1 % of the case mothers and 12.9 % of the interviewed control mothers reported moving to a new address during the year before the infant’s birth. Based on the sociodemographic characteristics of the birth certificate controls, the percentage that moved during pregnancy may have been even higher among the birth certificate controls, leading to exposure misclassification for the second set of control analyses.th percentile) compared to low pollutant concentrations (20th percentile). Hazardous air pollutants with more precise and elevated OR estimates included methylene chloride, quinoline and styrene, with odds ratios that were between 1.4 and 1.8 [Of the four studies (including ours) that used NATA to assess the risk of ASD associated with air toxics, the Windham et al. and Kalkbrenner et al. studies are the most similar with regard to case selection, and the use of birth certificates for residence and covariates. They identified cases using an existing surveillance system for California  and Nort and 1.8 . ResultsOur interviewed case–control group was most like the Roberts et al. investigation as neither study utilized a surveillance system to identify ASD cases and both relied on personal interview for residential history of the mother during pregnancy and afterwards and other potential risk factors. Roberts et al. was able to identify the offspring of mothers who participated in the Nurses’ Health Study II between 1987 and 2002 diagnosed with ASD . RobertsOur second control was similar to Windham’s investigation because residence and personal risk factors were obtained from the birth certificate in both studies. In general, the four NATA studies noted increased risk of ASD for certain heavy metals, chlorinated solvents (methylene chloride) and specific aromatic solvents (styrene).Each previous NATA study investigated a different geographical area and used NATA assessments from varying years. Windham et al. and Kalkbrenner et al. used the 1996 NATA assessment, while our present study used the most recent NATA data available 2005). Roberts assigned exposure using the assessment closest to each year of birth, so all assessments from 1990 to 2002 were included. The US EPA advises that NATA results from different years should not be compared since there are changes in the methodology and emissions or source inputs for each assessment [05. Rober3 cases, 90 ng/m3 controls), Roberts et al. (60 ng/m3), our present study , and Kalkbrenner et al. . The exposures for the West Virginia participants in the Kalkbrenner study tended to be the lowest, most likely because West Virginia is more rural compared to the regions considered in the other investigations. Both Roberts and Kalkbrenner found relationships with ASD and styrene exposure. Styrene was not entered as an individual pollutant in any of Windham’s models.Nevertheless, we compiled the results for 13 NATA compounds for cases and controls from each of the major NATA/autism studies –19 for cCurrent research points to a variety of cellular, molecular and inflammatory pathways that directly damage brain structure or lead to a predisposition for disease that affects the CNS system through neuroinflammation, oxidative stress and glial activation , 24. DioStyrene emissions come from a variety of sources, including point sources  and on-road sources such as car exhaust , 27. AccChromium is also emitted from a variety of sources, processes, and industries, such as coal and oil combustion, electroplating, leather tanning, cement-producing plants, tobacco smoke, and the metal and textile industries . ChromiuResults of this case–control study in Southwestern Pennsylvania suggest that living in areas with higher ambient levels of styrene and chromium is associated with increased risk of ASD; moreover, there are borderline effects for PAHs and methylene chloride. When considering singleton births only, there were additional significant associations with arsenic, lead and cyanide. Our study was unique in that we were able to utilize two different kinds of control group analyses: the first using personal interviews capturing the period of pregnancy to age two, and the second a random sample of all births (weighted by sex) from the same time period based on birth certificate information. Our dataset enabled us to adjust for other suspected risk factors of ASD .The above compounds represent air toxics of interest which require greater scrutiny to determine individual risk beyond the census tract or group level. Ground level monitoring of these targeted compounds should be conducted for multiple time periods (days of week and hours of the day) at multiple locations, including around major industrial sources. Future work should also include time activity patterns to obtain spatiotemporal estimates of exposure to air toxics, taking into account the dynamic movement of individuals during daily life. In addition, a national or statewide autism registry would enhance access to a greater proportion of all ASD cases and enable greater participation into future research.


Hemorrhage from ruptured pseudoaneurysm is a rapidly progressing and potentially fatal complication after pancreaticoduodenectomy (PD). Stent graft placement for hepatic artery pseudoaneurysm has recently been reported as a valid alternative to transcatheter arterial embolization (TAE). We report a case of pseudoaneurysm of the common hepatic artery (CHA) with distal arterial stenosis treated by stent graft placement for pseudoaneurysm and balloon dilation for arterial stenosis due to pancreatic fistula after PD. A 67-year-old man underwent PD for intraductal papillary mucinous neoplasm with concomitant early gastric cancer. After the operation, pancreatic fistula developed, for which conservative management by drainage was continued. On the postoperative day 30, melena started. Emergency abdominal angiography revealed a pseudoaneurysm in the CHA, as well as distal arterial stenosis extending from the proper hepatic artery (PHA) to bilateral hepatic arteries. The portal vein was also stenotic due to pancreatic fistula, for which TAE was not judged suitable because of the risk of liver failure. Therefore, stent graft placement and balloon dilation were chosen. Three pieces of coronary covered stent were placed in a coaxial overlapping manner followed by balloon dilation of the proper and left hepatic arteries. Balloon dilation of the right hepatic artery failed by technical reasons. Completion arteriography confirmed the patency from the CHA to the left hepatic artery as well as the exclusion of the pseudoaneurysm. A liver abscess that developed in the right hepatic lobe after intervention was successfully treated by percutaneous drainage, and the patient discharged on day 27 after stent graft placement. Non-embolic management with preservation of the liver arterial flow may be an option for complicated pseudoaneurysm after PD. Despite the advancement of surgical techniques, post-pancreatectomy hemorrhage remains one of the most serious complications, occurring in 1–8 % of all pancreatic resections and accounting for 11–38 % of overall mortalities . RecentlA 67-year-old man underwent PD for intraductal papillary mucinous neoplasm of the pancreas head with concomitant early gastric cancer originating from the gastric angle. The gastric lesion was diagnosed as signet ring cell carcinoma, which was suspected of cancer invasion to the submucosal layer. Distal gastrectomy and lymph node dissection with left gastric artery isolation were added for gastric cancer. Reconstruction procedure was performed with the modified Child method, comprising pancreaticojejunostomy, choledochojejunostomy, and gastrojejunostomy. End-to-side pancreaticojejunostomy was accomplished by duct-to-mucosa anastomosis (modified Kakita method) with monofilament absorbable thread. An external stent across the pancreaticojejunostomy has been placed for diversion of pancreatic juice from the pancreatic anastomotic site. A closed suction drain was placed to the ventral part of the pancreaticojejunostomy. On postoperative day (POD) 5, a turbid discharge was observed from the drainage. The drainage juice contained amylase of more than 10,000 IU/ml, which was confirmed as pancreatic fistula based on the criteria of the International Study Group on Pancreatic Fistula , for whiTAE and stent graft placement for delayed hemorrhage from arterial pseudoaneurysm after PD represent a first-line treatment, due to their high success and low morbidity rates as compared with surgical re-laparotomy . TreatmeThe arterial pseudoaneurysm caused by POPF after PD seems to require careful evaluation according to clinical conditions such as the complexity, fragility, and shape of the pseudoaneurysm as well as the bloodstream to the liver. Stent graft placement for a bleeding pseudoaneurysm after PD may replace TAE as the first-line treatment, under selected conditions.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


There has been a renewed interest in the place of birth, including intended home birth, for low risk women. In the absence of adequately-sized randomised controlled trials, a recent Cochrane review recommended that a systematic review and meta-analysis, including observational studies, be undertaken to inform this topic. The objective of this review is to determine if women intending at the onset of labour to give birth at home are more or less likely to experience a foetal or neonatal loss compared to a cohort of women who are comparable to the home birth cohort on the absence of risk factors but who intend to give birth in a hospital setting.We will search using Embase, MEDLINE, CINAHL, AMED and the Cochrane Library to find studies published since 1990 that compare foetal, neonatal and maternal outcomes for women who intended at the onset of labour to give birth at home to a comparison cohort of low risk women who intended at the onset of labour to give birth in hospital. We will obtain pooled estimates of effect using Review Manager. Because of the likelihood of differences in outcomes in settings where home birth is integrated into the health care system, we will stratify our results according to jurisdictions that have a health care system that integrates home birth and those where home birth is provided outside the usual health care system. Since parity is known to be associated with birth outcomes, only studies that take parity into account will be included in the meta-analyses. We will provide results by parity to the extent possible.http://www.crd.york.ac.uk/Prospero/ (Registration number: CRD42013004046).This protocol was registered with PROSPERO at  Today intended birth at home in most well-resourced countries, outside of The Netherlands, accounts for up to only 3% of all births. There are extremes of response and support for women who plan a home birth. Some settings have infrastructure in place to support home birth while in other settings home birth is undertaken in a less supportive or even hostile environment ,2. OtherThus, the objective of our systematic review and meta-analyses is to determine if women intending at the onset of labour to give birth at home are more or less likely to experience a foetal or neonatal loss compared to a cohort of similarly low risk women who intend at the onset of labour to give birth in hospital.We are aware that there are several ways of approaching this research objective, and plan to carefully analyse the research design of each study to ensure that a meta-analysis is only undertaken when the research questions of the included studies are similar. First, information about the study setting taken from the publication, correspondence with authors, and other published literature will inform us about the integration of home birth into the health care system. Studies from locations where home birth is considered well-integrated into the health care system will be analysed separately from studies of places where home birth is a less-acceptable option and not integrated into the health care system. Second, we will consider the criteria used to assemble the intended home birth and intended hospital birth cohorts in each study. One method is to include all intended home births in a given time frame regardless of their eligibility or obstetric risk status and to compare them to a group intending hospital birth and deemed to be at low obstetrical risk. This method reflects a pragmatic approach and will determine the safety of home birth in actual practice. The research question that will be answered using studies taking this approach is:1. Do women who intend at the onset of labour to give birth at home experience a higher or lower incidence of foetal or neonatal loss compared to women at low obstetric risk who intend at the onset of labour to give birth in hospital?A different method of assembling the study cohorts is to include only women who meet local eligibility criteria for home birth regardless of intended place of birth. The result of such a study provides information about place of birth under ideal circumstances where women’s choices align with professional recommendations. The research question that will be answered using studies taking this approach is:2. Do women who intend to give birth at home and who meet their local eligibility criteria for home birth at the onset of labour experience a higher or lower incidence of foetal or neonatal loss compared to women who would have been eligible for home birth but intend at the onset of labour to give birth in hospital?We will address both research questions to increase the applicability of our findings. Furthermore, because we are interested in outcomes within parity groups (nulliparous and multiparous) we will report findings for these sub-groups.To meet the objectives of this review, we will apply the following inclusion/exclusion criteria to studies of home birth:1. The study must have a comparison group of women who intended to birth in hospital, and the women in this “intended hospital birth group” must be at similarly low risk for birth complications, as defined by the authors, as the women in the intended home birth group. In pragmatic study designs, the intended hospital birth group may in fact have been at a lower obstetrical risk than the intended home birth group.2. The cohorts must be defined by the intended location of birth rather than the actual location of birth. Intrapartum transfers from the intended home to hospital should be captured in the intended home birth group, and inadvertent home births occurring in the intended hospital group should be captured in the hospital birth group. Both scenarios, for different reasons, have the potential to increase the risk of poor outcomes, and these outcomes should be analysed according to the intended place of birth.3. We will exclude studies where the intention for a home birth is determined earlier in the pregnancy and not reconfirmed at the onset of labour. When complications of pregnancy arise prior to the start of labour, most women will rightfully plan to give birth in hospital despite previous hopes for a home birth.4. The study must account for parity since outcomes are known to be different for nulliparous women compared to primiparous and multiparous women .5. The study must provide some assurance that the cohort of those intending home birth is complete (no missing cases) within the jurisdiction, in order to eliminate selection bias. Furthermore, the study should indicate if any of the women in the home birth cohort fell outside of the eligibility criteria for home birth in the studied jurisdiction, essentially increasing the risk of complications for that cohort. The authors should indicate how they approached the inclusion or exclusion of these cases in the analyses.6. The study must be published in a peer reviewed journal during or after 1990. There has been a steady decline in perinatal and neonatal mortality, and an increasing rate of Caesarean section and epidural use in the last 20 years . The stuStudies with significantly incomplete outcome data (>10%) will be excluded from the meta-analyses.We will search five electronic databases separately for relevant articles: Embase, Medline, and AMED using the OVID interface; CINAHL using the EBSCOhost interface, and the Cochrane Library. Reference lists from included articles and in particular from any systematic reviews will also be cross-checked.Our search strategy will use a combination of subject headings, keywords and free-text terms related to the specific intervention, such as . Because we anticipate that there may be a variety of study designs that present home birth outcomes, we will not include terms for methodology, as is recommended for reviews of non-randomised studies . Each seTwo reviewers will independently screen the titles and abstracts for full-text retrieval. A full-text screening form has been created, outlining the eligibility criteria for inclusion in the review  that are included in each study, likely using table format. For the meta-analyses, we will attempt to combine the outcomes for the hospital groups, provided that the women in the groups being combined meet the eligibility criteria. Although this approach increases the potential of increasing variance of outcomes among the comparison groups, it also diminishes any potential for selection bias in making the determination of which group(s) to include . If the Two reviewers will independently extract data from each of the included studies using a detailed data abstraction form , neonatal resuscitation (as defined in each study), and Apgar scores of less than seven at five minutes. Definitions  used by the authors will be collected and included in a table that describes each included study. Apgar scores are assigned to neonates at one minute and five minutes after birth, and are meant to serve as a measure of the newborn’s transition to neonatal life. An Apgar score of less than seven at five minutes of age may indicate a problem, so we plan to collect the number of cases that fall below this cut point. Where it is available, we plan to record two components of neonatal resuscitation: the use of positive pressure ventilation and the use of chest compressions.Data on maternal outcomes will include maternal death, postpartum hemorrhage, perineal trauma and infection. Postpartum hemorrhage has varying definitions; we will use the number of cases with estimated blood loss greater than 1,000 ml . When thData on obstetric interventions will be recorded, including the use of oxytocin for augmentation of labour, the use of epidural anaesthesia/analgesia for pain control, episiotomy, assisted vaginal delivery (vacuum or forceps) and Caesarean section. In studies where outcomes are presented as part of a composite, we will make every effort to obtain the data for the relevant components contributing to the composite. Transfer rates will be collected, including from home to hospital and from one hospital to another (or to another department). When available we will collect information about the timing of transfers and whether or not they were emergencies.Two reviewers will assess risk of bias for each of the included observational studies using the Newcastle Ottawa scale adapted for our study purposes . For ranOur primary outcome is any reported foetal or neonatal mortality as a proportion of all births. We anticipate that studies may have used varying definitions of mortality, with differing time periods or exclusion criteria based on malformations. It is unhelpful to exclude studies  because different definitions were used. In addition to reporting any mortality, we will report on outcomes using a more traditional definition of time of death, such as perinatal death. We will report the crude mortality rate as well as the rate excluding malformed infants.The association of intended place of birth with our primary outcome will be estimated using an odds ratio and 95% confidence interval. This approach will be used for all other outcomes measured as proportions. Odds ratios will be used because it is anticipated that at least some of the data for this review will be collected retrospectively, and some of the outcomes may occur relatively commonly, a situation where the odds ratio is the preferred measure .2) will be reported along with confidence intervals. The magnitude and strength of I2 will be interpreted according to the Cochrane Handbook [Data abstracted from studies will be entered into the Review Manager program. When individual case data are not available, effect estimates and their standard errors will be entered using the random effects inverse variance statistical method. Forest plots will be created for the outcomes of interest. Measures of consistency  outcomes than in jurisdictions where home birth is not integrated and supported within the health care system. We will describe variations in defining low risk and in eligibility for home birth.We will provide descriptive analyses of variation among study settings, and plan if possible, to stratify our meta-analyses based on those settings where home birth is an integrated service within the health care system and those where it is less integrated. Our If it is possible, we will report outcomes stratified by parity .We will report our findings in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .We will conduct a systematic review and meta-analysis of studies on births intended at the onset of labour to take place at home compared to hospital, taking into account factors such as parity and integration of home birth into the health care system. Our proposed systematic review and meta-analysis will contribute to the gap in the literature that has been identified by a recent Cochrane review  and willThe authors declare that they have no competing interests.EKH and AR led the study design and drafting of the manuscript. JT, GB and KK contributed to the design of the protocol and manuscript revisions. All authors read and approved the final manuscript.“Search Strategy”. Description: This file indicates the search strategy that will be used to identify studies that are potentially eligible for inclusion in our review.Click here for file“Study Eligibility Form”. Description: This form will be used by two independent reviewers to indicate whether or not each study meets the list of inclusion and exclusion criteria and therefore to determine eligibility for inclusion in our review.Click here for file“Data Abstraction Form”. Description: This form will be used by two independent reviewers to collect information from each included study, including counts and effect estimates for all outcomes of interest that were reported on. Additional sources may be used to complete parts of the form, such as the description of the study setting.Click here for file“Questionnaire for Authors of Included Studies”. Description: This file includes a questionnaire to be sent along with an accompanying cover letter to authors of all included studies to ascertain information about the integration of home birth into the health care system in the region at the time that each study was conducted.Click here for file


The levonorgestrel intrauterine system has: (1) excellent effectiveness, (2) high satisfaction levels, (3) non-contraceptive benefits, and (4) potential to help reinvigorate interest in intrauterine contraception. The time is ripe for ministries and donor agencies to work together to make the product widely available across Africa. The levonorgestrel intrauterine system has: (1) excellent effectiveness, (2) high satisfaction levels, (3) non-contraceptive benefits, and (4) potential to help reinvigorate interest in intrauterine contraception. The time is ripe for ministries and donor agencies to work together to make the product widely available across Africa. Jacobstein.See related article by The contraceptive known as the levonorgestrel intrauterine system (LNG IUS) was developed in the 1970s. The product releases small amounts of progestin into the uterus and improves contraceptive action compared with earlier inert plastic devices. The first commercialized LNG IUS set a high standard for future contraceptive development. Relative to other reversible contraceptives, the LNG IUS has the highest effectiveness levels (combining the highest product continuation rates with over 99% efficacy).,The legacy product was first approved in Finland in 1990, in the rest of Europe in the 1990s, and in the United States in 2000As of 2015, no major international donor agency has issued and executed a tender for purchasing the LNG IUS. Thus, the per unit cost for the public sector is unknown. For drugs to be purchased in large quantities by major international donor agencies, such as the US Agency for International Development (USAID) and the United Nations Population Fund (UNFPA), the products must first be approved by a stringent regulatory authority  or by the World Health Organization (WHO) through its Prequalification Programme. Then, the products must be registered at the national level in recipient countries. Currently, only the legacy product meets these criteria for procurement; hopefully, one or more of the other products will soon be eligible as well. Together, these actions may foster eventual purchase of a low-cost product by an international donor agency.In this paper, I provide a summary of the obstacles to interest in the LNG IUS. Then, I outline 6 main reasons why donor agencies should purchase the LNG IUS and why family planning programs should incorporate the method into their services.Aside from some temporary regulatory obstacles, international donor agencies and foundations have uncertainty over the “value added” with an LNG IUS. The uncertainty involves 3 interrelated issues: (1) high product cost, (2) belief that the current variety of other contraceptive commodities is sufficient, and (3) doubt that an LNG IUS can overcome program barriers to uptake that currently affect the copper intrauterine device (IUD). Each of these real or perceived (current or past) beliefs dampens enthusiasm for taking procurement and program action.High product cost is a relative concept and a major barrier to LNG IUS procurement. The comparison with the copper IUD, which costs donors less than $1 per unit,While both the LNG IUS and the copper IUD are types of intrauterine contraception, they have vastly different characteristics and will thus attract different users.Duration of use also plays into the cost calculations and comparisons. For example, the copper IUD lasts up to 12 years; this fact inappropriately drives perceptions that any new form of intrauterine contraception  needs to match that duration. Of note, the 3-year subdermal implant was not held to the standard of the 5-year implant, yet it has had substantial success and support. Sufficient interest in the LNG IUS may never materialize if donor agencies continue to compare it to the copper IUD or the subdermal implant.Five primary contraceptive commodities currently make up the backbone of international donor support: injectables, pills, condoms, copper IUDs, and subdermal implants. From a donor perspective, this array enables couples to choose a contraceptive delivery system to suit a variety of personal preferences and needs. The subdermal implant is currently in high supply, due to the volume guarantee arrangement associated with the 2013 price reduction. Programs need to expand access to the product for the arrangement to be successful. If donors and foundations continue to view the 5 main contraceptives as sufficient, then the LNG IUS will never reach its full potential.Finally, negative perceptions of the copper IUD and the struggles to establish even moderate levels of use in most African countries naturally dampen interest in another intrauterine product such as the LNG IUS. Many factors contribute to the poor uptake of the copper IUD. Previous failed efforts to stimulate uptake of the copper IUD should only be informative of the challenges for a new product, not predictive of a similar destiny.Previous challenges with stimulating uptake of copper IUDs should inform new product rollout but should not be predictive of a similar destiny.The LNG IUS is a unique type of contraceptive that combines 2 key features: intrauterine placement and use of a proven and safe progestin. It will attract new users and stimulate programs. For the reasons outlined below, the LNG IUS should be procured by the international donor community.WHO recently placed the LNG IUS on the Essential Medicines List.According to WHO, a health care system is not meeting basic needs without the LNG IUS on the formulary.Worldwide, user satisfaction with the LNG IUS is consistently high. A study in 18 different countries in Asia and Europe found that 95% of LNG IUS users were satisfied with the product.,Research in Africa also shows good prospects for the LNG IUS. In Kenya, 16% of family planning clients chose the LNG IUS when given the opportunity; only 3% wanted the copper IUD.No other hormonal method releases progestin directly into the uterus; this results in a predominately local effect with highly efficacious triple-action mechanisms on the cervix, endometrium, and ovaries to prevent pregnancy. Moreover, the level of levonorgestrel released from the LNG IUS is steady and slow, which minimizes side effects. In contrast, short-acting hormonal methods have abrupt dosing effects and higher levels of circulating hormones that create peaks and troughs of systemic levels; for many users, this causes intolerable side effects, leading to high discontinuation rates.The slow and steady release of hormone directly into the uterus with the LNG IUS results in high efficacy and minimal side effects.Non-contraceptive benefits also make the LNG IUS unique; the benefits are linked to how the LNG IUS shrinks the endometrium and minimizes uterine bleeding. The LNG IUS is a proven treatment for heavy menstrual blood loss and is more effective than all other non-hysterectomy approaches.The LNG IUS is a proven treatment for heavy menstrual blood loss.The LNG IUS may help anemic women; this is probably the most important potential non-contraceptive benefit for women in resource-poor countries. Through the mechanism of reducing menstrual blood loss, the LNG IUS can help anemic women retain up to 19 grams of iron each month.By reducing menstrual blood loss, the LNG IUS might increase women’s iron stores.Because of these unique attributes, the LNG IUS is not interchangeable with the copper IUD. In Kenya, nearly a third of LNG IUS acceptors said they would have chosen a short-acting method if the LNG IUS were not available, and only 21% would have chosen the copper IUD.,The best example of rapid uptake of the LNG IUS is from the United States. In this mature contraceptive market, the LNG IUS quickly reinvigorated interest in intrauterine contraception.Ministries of Health recognize the importance of expanding access to long-acting reversible contraception, particularly since sterilization services are more difficult to provide. In the 1980s, many countries put the newly available copper IUD at the center of their family planning programs. Egypt, Mexico, Turkey, and Vietnam experienced tremendous fertility transition in one generation by making the IUD widely accessible. Today, Ethiopia’s Ministry of Health is using health extension workers to make subdermal implants widely available; this may result in similar patterns of uptake that were observed in countries where the copper IUD became popular. Other countries will focus on the LNG IUS when it becomes available. No one can predict which countries will launch the LNG IUS and make it successful, just as nobody predicted which countries would succeed with copper IUDs and implants.The international family planning community is ready to support the LNG IUS. At the biennial International Conference on Family Planning in Ethiopia in 2013, a small survey of 30 conference participants found that 100% of respondents with knowledge of the LNG IUS supported the idea of making the product available in public-sector clinics worldwide . When asked why they would support the introduction of an LNG IUS, responses fell primarily into 2 categories: benefits offered by the method  and to support expansion of the method mix/choice for women.,NGOs consistently show high uptake of IUDs in the same public-sector clientele where ministries fail. The difference is that NGO providers have the knowledge, skills, job expectations, and proper support to make IUD services available. For example, between 2008 and 2012 Marie Stopes International more than tripled the number of IUDs it provided in sub-Saharan Africa, from 69,087 insertions to more than 215,000.Introduction of the LNG IUS is a new opportunity for Ministries of Health and providers in the public sector to establish successful, demand-driven intrauterine contraception services. As demonstrated in the United States, a single intrauterine product with a proven track record and high acceptability can stimulate provision of services, even in the public sector. With a new product such as the LNG IUS, public-sector providers can develop the skills and confidence to insert IUDs and serve the clientele who currently have latent demand for services. Thus, the LNG IUS may be the easiest route to establish consistent access to the copper IUD.WHO lists IUDs (copper IUDs and the LNG IUS) and subdermal implants as the most effective reversible forms of contraception.Intrauterine contraception and implants are the most effective reversible forms of contraception.,Adolescents also need more effective options like the LNG IUS. Preventing unintended pregnancy in this population  can help young women achieve other goals they may have . Consensus is building that long-acting reversible contraceptives should be easily available to sexually active young women.The LNG IUS is not just another, interchangeable contraceptive. This fact should help justify taking procurement and program action for the public sector in sub-Saharan Africa. For many decades, the obstacles to procurement appeared insurmountable. Today, however, international donors have better information and more opportunities to make large-scale procurement a reality. With renewed emphasis and funding for family planning, the timing couldn’t be better. Women in resource-poor countries will benefit tremendously from the LNG IUS; worldwide equity in access to the technology is needed.


Late preterm birth accounts for 70 % of all preterm births. While the impact of feeding problems in very preterm infants has been widely investigated, data on late preterm infants’ feeding issues are scarce. The aim of the present study was to investigate the need of nutritional support during hospital stay in a cohort of late preterm infants and to identify the factors that most contribute to its occurrence.We analyzed the medical records of late preterm infants, born 2011–2013, admitted to a single institution. Neonatal data, the need for nutritional support, defined as the need for parenteral nutrition or intravenous fluids or tube feeding, and the feeding status at discharge were retrieved. The occurrence of respiratory distress syndrome, congenital malformations/chromosomal diseases, cardiac diseases, sepsis, hypoglycemia, poor feeding and the need for surgical intervention were also collected.p < 0.0001), gestational age of 34 weeks , being small for gestational age , having a respiratory distress syndrome  and the need of surgical intervention  were associated with a higher risk of need of nutritional support during hospital stay.A total of 1768 late preterm infants were included. Among the 592 infants requiring a nutritional support, 228 developed a respiratory distress syndrome, two developed a sepsis, one presented with a cardiac disease, 24 underwent a surgical intervention, eight had a chromosomal disease/congenital malformation, 80 had hypoglycemia. In addition, 100 infants required nutritional support due to poor feeding and 149 were born small for gestational age. Birth weight ≤2000 g (adjusted OR = 12.2, 95 % CI 7.5-19.9, Late preterm infants are at relatively high risk of requiring nutritional support during hospital stay, especially if they have a birth weight ≤2000 g, a gestational age of 34 weeks, are born small for gestational age, develop a respiratory distress syndrome and require a surgical intervention. The present findings add to the knowledge of late preterm infants’ feeding issues and may contribute to tailoring nutritional approaches for these infants. Late preterm birth, defined as a birth that occurs between 34 0/7 and 36 6/7 week of gestation, contributes significantly to the premature rate, accounting for 70 % of all preterm births , 2. InciWhile the impact of feeding problems in very preterm infants has been widely investigated , there iWe analyzed the medical records of late preterm infants born 2011–2013, admitted to Authors’ Institution, including level I, II and III of care. The Ethics Committee of the Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico approved the study. Written informed consent was obtained by parents at time of infants’ admission. Inclusion criteria was gestational age 34 0/7 to 36 6/7. Exclusion criteria were newborns transferred to other Institution.According to our internal clinical protocol, late preterm infants with a birth weight ≥1900 g, irrespective of gestational age, were admitted to level I of care, provided that clinical conditions were stable and no nutritional support was required. Infants with a birth weight <1900 grams and/or requiring any type of nutritional support were admitted/transferred to either level II or III of care, according to their clinical conditions.According to our internal nutritional procedure, infants with a birth weight <1500 g qualified for parenteral nutrition. In addition, infants presenting with any clinical condition that could hinder the beginning of enteral nutrition or that could interfere with the ability to feed exclusively by mouth received either parenteral nutrition/intravenous fluids or tube feeding. Provided that infants were in stable clinical conditions, mothers were encouraged to breastfeed their infant. When human milk was unavailable or insufficient, formula feeding was started.The neonatal, medical and feeding data were collected from the patients’ computerized medical charts from birth to discharge. The neonatologists in charge of the infants daily fulfilled the infants’ medical charts after completing their medical visit. Data were then retrieved using a software incorporated into the computerized medical charts . The recorded neonatal data were: gestational age at birth, birth weight, length and head circumference, gender, singleton or multiple pregnancy, length of stay. Gestational age (GA) was based on the last menstrual period and first-trimester ultrasonogram. The infants with a birth weight <10th or ≥10th percentile for gestational age on the basis of Fenton’s growth chart , were re2 test for discrete variables or by the ANOVA or the Mann–Whitney test, when appropriate, for continuous variables. The association between gestational age at birth and the need of nutritional support during hospital stay was tested by computation of odds ratios (OR) and 95 % confidence intervals (CI). In binary logistic regression analysis, the adjusted odds ratios were first calculated for the infants who did not develop comorbidities, adjusting for the following potential confounders: GA (=34 weeks vs >34 weeks), birth weight (≤2000 g vs >2000 g), gender , being twin (twin vs singleton), small for gestational age (SGA vs AGA), and the need of nutritional support (yes vs no) as the outcome variable. The adjusted odds ratios were then calculated for all the enrolled infants, including as potential confounders, in addition to the variables previously entered, the occurrence of respiratory distress syndrome (yes vs no), sepsis (yes vs no), cardiac disease (yes vs no), surgical intervention (yes vs no), chromosomal disease/congenital malformation (yes vs no), hypoglycemia (yes vs no) and the need of nutritional support (yes vs no) as the outcome variable.Descriptive data are shown as means ± standard deviation (SD) or number of observations (percentage). Comparison among groups was performed by the X vs > 34 weeks), and to birth weight (≤2000 g vs >2000 g), due to the increased risk of developing feeding difficulties in infants born with the lowest gestational ages and birth weights [For analysis, infants that had needed either parenteral nutrition, intravenous fluids and/or tube feeding were pooled together and categorized as infants needing nutritional support. Furthermore, infants were grouped according to gestational age .p < 0.0001).Out of the 1768 late preterm infants included, 1176 were admitted to level I of care, 322 were admitted to level II of care and 270 were admitted to level III of care. Basic subject characteristics are shown in Table p < 0.0001), 1.5 % needed a surgery treatment, 0.7 % had a chromosomal and/or a congenital disease, 0.1 % developed a sepsis.Of the enrolled infants, 14 % developed a respiratory distress syndrome  and 18 % were fed exclusive human milk .Need of nutritional support was found in 592 infants. Out of the patients requiring nutritional support, 228 developed respiratory distress syndrome, two developed sepsis, one presented with a cardiac disease, 24 underwent a surgical intervention, eight had a chromosomal disease/congenital malformation, 80 had hypoglycemia. In addition, 100 infants required nutritional support due to poor feeding and 149 infants were born SGA. According to our internal nutritional procedure, all the infants requiring nutritional support were admitted to either level II or III of care.p < 0.0001). Among infants requiring nutritional support, 76 % were fed formula whereas only 24 % were fed any human milk.In Table p < 0.0001), GA of 34 weeks , being born SGA , having developed a respiratory distress syndrome  and having required a surgical intervention  resulted to be independently associated with a higher risk of receiving a nutritional support during hospital stay.Regarding infants who did not develop co-morbidities, at binary logistic regression analysis, birth weight ≤2000 g, GA of 34 weeks and possibly being born SGA were independently associated with a higher risk of nutritional support during hospital stay (Table The findings of this study indicate that the lower the birth weight and the gestational age are, the greater the risk for needing nutritional support during hospital stay. Specifically, the need of nutritional support was registered in 33.5 % of the included late preterm infants.These findings are in agreement with previous data reported in literature. The coordinated sucking ability that allows for the provision of sufficient intake for growth by sucking feeds alone begin to develop at 34 weeks . HoweverAs a consequence, the feeding challenges that the late preterm infants commonly experience lead to a high need for parenteral nutrition and intravenous fluids and place them at risk to be delayed in their discharge to home , 14, 15.At logistic regression analysis, when considering only infants who did not develop co-morbidities, birth weight ≤2000 g, GA of 34 weeks and possibly being born SGA were independently associated with a higher risk of having nutritional support during hospital stay. In addition, when including in the analysis the infants who have developed co-morbidities, not only birth weight ≤2000 g, GA of 34 weeks and being born SGA, but also having developed a respiratory distress syndrome and having required a surgical intervention resulted to be independently associated with a higher risk of receiving a nutritional support. Indeed, out of the infants requiring a nutritional support in the present study, 58 % and 25 % presented a co-morbidity and were born SGA, respectively. Being born SGA is actually a recognized risk factor for very preterm infants for having a prolonged transition period from the beginning of oral feeding to full oral feeding . The greLate preterm infants have been reported to be at risk for inadequate consumption of milk feedings at the breast due to both ineffective breastfeeding behaviors and delayed onset of lactation . AccordiThe present study has limitations. First, the data have been collected from a single institution. Second, a potential bias of the current study could result from the clinical and nutritional protocols used. Hence, given these selection biases, it is not possible to generalize our findings from a single centre study of a cohort of infants to all late preterm infants. Nevertheless, a strength of the study is that it addresses a relatively large number of late preterm infants.Late preterm infants are at relatively high risk of requiring nutritional support during hospital stay, especially if they have a birth weight ≤2000 g, a gestational age of 34 weeks, are born small for gestational age, develop a respiratory distress syndrome and require a surgical intervention. The present findings add to the knowledge of late preterm infants’ feeding issues and may contribute to tailoring nutritional approaches for these infants.