Lethal Malformations Research Articles

Molecular autopsy in maternal-fetal medicine.

PurposeThe application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.MethodsIn this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing.ResultsPathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality (ALPL, GUSB, SLC17A5, MRPS16, THSD1, PIEZO1, and CTSA), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality (INVS, FKTN, MYBPC3, COL11A2, KRIT1, ASCC1, NEB, LZTR1, TTC21B, AGT, KLHL41, GFPT1, and WDR81) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence (MS4A7, SERPINA11, FCRL4, MYBPHL, PRPF19, VPS13D, KIAA1109, MOCS3, SVOPL, FEN1, HSPB11, KIF19, and EXOC3L2).ConclusionOur results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

A Pentanucleotide ATTTC Repeat Insertion in the Non-coding Region of DAB1, Mapping to SCA37, Causes Spinocerebellar Ataxia

Advances in human genetics in recent years have largely been driven by next-generation sequencing (NGS); however, the discovery of disease-related gene mutations has been biased toward the exome because the large and very repetitive regions that characterize the non-coding genome remain difficult to reach by that technology. For autosomal-dominant spinocerebellar ataxias (SCAs), 28 genes have been identified, but only five SCAs originate from non-coding mutations. Over half of SCA-affected families, however, remain without a genetic diagnosis. We used genome-wide linkage analysis, NGS, and repeat analysis to identify an (ATTTC)n insertion in a polymorphic ATTTT repeat in DAB1 in chromosomal region 1p32.2 as the cause of autosomal-dominant SCA; this region has been previously linked to SCA37. The non-pathogenic and pathogenic alleles have the configurations [(ATTTT)7-400] and [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90], respectively. (ATTTC)n insertions are present on a distinct haplotype and show an inverse correlation between size and age of onset. In the DAB1-oriented strand, (ATTTC)n is located in 5' UTR introns of cerebellar-specific transcripts arising mostly during human fetal brain development from the usage of alternative promoters, but it is maintained in the adult cerebellum. Overexpression of the transfected (ATTTC)58 insertion, but not (ATTTT)n, leads to abnormal nuclear RNA accumulation. Zebrafish embryos injected with RNA of the (AUUUC)58 insertion, but not (AUUUU)n, showed lethal developmental malformations. Together, these results establish an unstable repeat insertion in DAB1 as a cause of cerebellar degeneration; on the basis of the genetic and phenotypic evidence, we propose this mutation as the molecular basis for SCA37.

Congenital malformations, palliative care and postnatal redirection to more intensive treatment – a review at a Swiss tertiary center

Purpose: The so-called lethal malformations pose ethical challenges. Most affected fetuses die before or at birth. Live-born neonates commonly receive palliative care. If the postnatal course is better than expected, redirection towards more treatment may occur. We aimed to analyze this in a Swiss patient cohort. Materials and methods: Over 6 years, fetal malformation was suspected in 1113 cases. We identified patients prenatally assigned to palliative care, assessed pre- and postnatal diagnoses, and outcomes. Results: Fourteen neonates received palliative care. Eleven patients received palliative care following late termination of pregnancy, for three, palliative care was planned and the fetus died during delivery, for two, the outcome was unknown (incomplete documentation). Genetic testing was performed in 50%. The predominant diagnostic group was central nervous system malformations (33%), followed by chromosomal aberrations (20%) and renal anomalies (17%). One child assigned to palliative care was resuscitated. Antenatal findings were anhydramnios and pulmonary hypoplasia. Postnatally, respiration was better than expected. The neonate was admitted to intensive care, died on day one. Conclusions: Nervous system malformations seem to be a major criterion for foregoing life-sustaining interventions. Redirection towards more treatment is rare. This may reflect precise prenatal prognostication; a degree of self-fulfilling prophecy cannot be excluded.

In this issue – April 2017

In this issue – April 2017

Cardiac Regeneration: Lessons From Development.

Palliative surgery for congenital heart disease has allowed patients with previously lethal heart malformations to survive and, in most cases, to thrive. However, these procedures often place pressure and volume loads on the heart, and over time, these chronic loads can cause heart failure. Current therapeutic options for initial surgery and chronic heart failure that results from failed palliation are limited, in part, by the mammalian heart's low inherent capacity to form new cardiomyocytes. Surmounting the heart regeneration barrier would transform the treatment of congenital, as well as acquired, heart disease and likewise would enable development of personalized, in vitro cardiac disease models. Although these remain distant goals, studies of heart development are illuminating the path forward and suggest unique opportunities for heart regeneration, particularly in fetal and neonatal periods. Here, we review major lessons from heart development that inform current and future studies directed at enhancing cardiac regeneration.

OP32.10: Survival at one year of age of fetuses diagnosed with lethal congenital malformations: experience of 12 years in a reference centre in Chile

OP32.10: Survival at one year of age of fetuses diagnosed with lethal congenital malformations: experience of 12 years in a reference centre in Chile

Trends in Congenital Heart Disease

Congenital heart disease (CHD) is the most common class of major congenital malformations. Although there is slight variation between many population-based studies, CHD occurs in ≈1% of live births, with similar prevalence throughout world,1–3 and in 10% of aborted fetuses.4 It is also the leading cause of mortality from birth defects.5 Approximately one-quarter of the 40 000 children born with CHD annually in the United States require intervention in the first year of life. In the 60 years since the first successful repair of a congenital heart defect using cardiopulmonary bypass in 1953, the accurate diagnosis and effective treatment of even the most complex congenital heart lesions have become standard practice. Critical CHD is often lethal in the absence of treatment, and effective surgical, catheter, and medical therapies have dramatically extended life expectancy. With advances in the survival of patients with CHD, there have been major demographic shifts, so that adult patients with CHD now outnumber children even with complex forms of CHD.6 The expected surgical outcomes for patients with simpler congenital cardiovascular lesions (eg, typical forms of septal defects) have continually improved7 and have long since reached a very high level of excellence. These procedures can now be reasonably viewed as a commodity, which is widely available in the developed world. In treatment of simpler lesions, research is increasingly focused on methods to increase the safety, efficiency, and value of therapeutic procedures, and to provide high-quality alternatives to children in nations with resource-constrained healthcare infrastructure and budgets, as well. On the other end of the spectrum of disease severity, outcomes continue to improve in patients with more complex lesions (Figure 1).8 Survival through childhood is now common even in the most complex and lethal malformations, such as hypoplastic left heart syndrome. …

Teratogenic Nephrotoxicity induced by aluminium

The intensified growth of the modern industry has been accompanied by an increased utilization of metals in the processing of manufactured goods, foods and drugs. The mobilization of many trace elements has resulted in a growing concern about the effects of these substances on various biological processes especially about their possible effects on early mammalian development Hardness of drinking water has positively been correlated to lethal congenital malformations. Chemical agents and pharmaceutical drugs play a very important role in the teratogenesis. Amongst other trace elements or environmental chemicals, aluminium has been reported to have teratogenic properties in chick and rats. So the present study was carried out to establish the role of aluminium containing compounds in producing intra-uterine growth retardation and defected renal development, when the pregnant mothers use these compounds for various periods during pregnancy.

The Mortality of Extremely Premature Infants and the Impact on the Overall Neonatal Mortality Rate [20C

INTRODUCTION: Live births (LBs) in Ohio include any infant who had a heart rate, or took a breath or had any movement. In some countries infants less than 23 weeks are not counted as LBs. The study objective was to investigate the mortality in infants less than 500 grams (g) and to calculate their impact on the overall Neonatal Mortality Rate (NMR) over a 12-year period. METHODS: NMR data were extracted from the Good Samaritan Mortality Committee, CCHMC Perinatal Outreach Project and Vermont Oxford Network database from 1998–2009. RESULTS: Among 73,547 LBs were 699 deaths. The average NMR per 1,000 LBs was 11.4. The average adjusted NMR per 1,000 LB was 4.9. Overall, 349 LBs weighed less than 500 g and 336 died. The proportion of neonatal deaths less than 500 g, to the total NMR, was 48.6%. Infants' weight reported to the State included: 30–100 g (n=11), 101–200 g (n=40), and 201–300 g (n=63). Gestational age (GA) included: 15–17 weeks (n=35), 18–20 weeks (n=108), and 21–23 weeks (n=155). Causes of death included: GA less than or equal to 23 weeks (88.6%, n=298), lethal malformations (4.7%, n=16), RDS (8.6%, n=29), and sepsis (7.4%, n=25); 297 (88.3%) infants died in the delivery room. CONCLUSION: NMR from extreme prematurity was 96.2% and represented half of the overall NMR. Current LB definition and a reporting system of a 30 gram infant as a neonatal death has placed Ohio and the USA at a significant disadvantage compared with other countries with different reporting systems.

Mortality and Major Morbidity of Very-Low-Birth-Weight Infants in Germany 2008-2012: A Report Based on Administrative Data.

Expectant parents of very preterm infants, physicians, and policy makers require estimates for chances of survival and survival without morbidity. Such estimates should derive from a large, reliable, and contemporary data base of easily available items known at birth. To determine short-term outcome and risk factors in very-low-birth-weight preterm infants based on administrative data. Anonymized routine data sets transmitted from hospital administrations to statutory health insurance companies were used to assess survival and survival free of major morbidities in a large cohort of preterm infants in Germany. After exclusion of infants with lethal malformations, there were 13,147 infants with a birth weight below 1,500 g admitted to neonatal care 2008-2012, of whom 1,432 infants (10.9%) died within 180 days. Estimated 180 days survival probabilities were 0.632 (95% confidence interval 0.583-0.677) for infants with 250-499 g birth weight, 0.817 (0.799-0.834) for 500-749 g, 0.931 (0.920-0.940) for 750-999 g, 0.973 (0.967-0.979) for 1,000-1,249 g, and 0.985 (0.981-0.988) for 1,250-1,499 g. Estimated probabilities for survival without major morbidity (surgically treated intraventricular hemorrhage, necrotizing enterocolitis, intestinal perforation, or retinopathy) were 0.433 (0.384-0.481) for 250-499 g, 0.622 (0.600-0.643) for 500-749 g, 0.836 (0.821-0.849) for 750-999 g, 0.938 (0.928-0.946) for 1,000-1,249 g, and 0.969 (0.964-0.974) for 1,250-1,499 g, respectively. Prediction of survival and survival without major morbidities was moderately improved by adding sex, small for gestational age, and severe or moderate congenital malformation, increasing receiver operating characteristic areas under the curve from 0.839 (0.827-0.850) to 0.862 (0.852-0.874) (survival) and from 0.827 (0.822-0.842) to 0.852 (0.846-0.863) (survival without major morbidities), respectively. The present analysis encourages attempts to use administrative data to investigate the association between risk factors and outcome in preterm infants.

A novel HYLS1 homozygous mutation in living siblings with Joubert syndrome.

The p.Asp211Gly homozygous HYLS1 mutation is so far known to cause only hydrolethalus syndrome, a lethal malformation syndrome. We report living sibling patients with a homozygous no-stop mutation in exon 4 of HYLS1, NM_145014.2:c.900A>C (p.Ter300TyrextTer11) in the second decade of life. The proband has Joubert syndrome (JS). The younger brother also has JS and an enlarged posterior fossa that was initially diagnosed as Dandy-Walker malformation. The present mutation is unique as it affects the stop codon. The product protein HYLS1 plays an essential role in the formation of the primary cilium. This report provides insight into the spectrum of disorders involving midline brain defects closely related to cilium dysfunction or ciliopathy.

Why newborns die? A self-audit

Background: A birth weight specific reduction in neonatal mortality has been noted in babies above 1000 gm. This has been attributed to intensive care management of high-risk pregnancies and new borns. A further decline in mortality can be accomplished by evidence based evaluation of high-risk therapies. This prospective study was conducted to evaluate the postnatal factors correlating with new born mortality. Apgar scores at birth have been correlated with deaths in low birth weight babies. In the present study we tried to correlate the presence of apnea, hyaline membrane disease, necrotizing enterocolitis and sepsis with neonatal mortality. Lethal Congenital malformations were also studied. It is a prospective consecutive enumerative study of all new borns weighing less than 2000 grams.Methods: The post natal course in the hospital including the presence of apnea, seizures, patent ductus arteriosus, intra ventricular hemorrhage, hyaline membrane disease, hyper bilirubinemia, necrotizing enterocollitis, duration of oxygen therapy and ventilator support were noted. Statistical analysis was done using Fisher Exact test. Results: There was a significant increase in mortality if the new born had low Apgar score, necrotizing enterocollitis, hyaline membrane disease, apnoea, sepsis or congenital malformations. Nursery biological risk score is a sensitive tool to predict new born mortality.Conclusions: Nursery biological risk factors can be used to predict the outcome. However the clinical picture is compound with various coexisting pathologies.

Meckel-Gruber Syndrome: Autopsy Based Approach to Diagnosis

Meckel-Gruber syndrome (MGS) is a rare lethal congenital malformation affecting 1 in 13,250-140,000 live births. The classical diagnostic triad comprises multicystic dysplastic kidneys, occipital encephalocele, and postaxial polydactyly. It can variably be associated with other malformations such as cleft lip and palate, pulmonary hypoplasia, hepatic fibrosis, and anomalies of central nervous system. A 20 weeks fetus was diagnosed as MGS with classical features along with many other congenital abnormalities such as microcephaly, microphthalmia, hypertelorism, cleft lip and palate, neonatal teeth, and the right side club foot which were detected only after doing autopsy. This case is reported because of its rarity emphasizing the importance of neonatal autopsy in every case of fetal death, especially where the antenatal diagnosis has not been made previously. A systematic approach to accurate diagnosis of MGS based on autopsy will be described here which can allow recurrence risk counseling and proper management in future pregnancies.

Pharyngeal arch artery defects and lethal malformations of the aortic arch and its branches in mice deficient for the Hrt1/Hey1 transcription factor

The aortic arch and major branch arteries are formed from the three pairs of pharyngeal arch arteries (PAAs) during embryonic development. Their morphological defects are clinically observed as isolated diseases, as a part of complicated cardiovascular anomalies or as a manifestation of multi-organ syndromes such as 22q11.2 deletion syndrome. Although numerous genes have been implicated in PAA formation and remodeling, detailed mechanisms remain poorly understood. Here we report that the mice null for Hrt1/Hey1, a gene encoding a downstream transcription factor of Notch and ALK1 signaling pathways, show perinatal lethality on the C57BL/6N, C57BL/6N×C57BL/6J or C57BL/6N×129X1/SvJ background. Hrt1/Hey1 null embryos display abnormal development of the fourth PAA (PAA4), which results in congenital vascular defects including right-sided aortic arch, interruption of the aortic arch and aberrant origin of the right subclavian artery. Impaired vessel formation occurs randomly in PAA4 of Hrt1/Hey1 null embryos, which likely causes the variability of congenital malformations. Endothelial cells in PAA4 of null embryos differentiate normally but are structurally disorganized at embryonic day 10.5 and 11.5. Vascular smooth muscle cells are nearly absent in the structurally-defective PAA4, despite the appropriate migration of cardiac neural crest cells into the fourth pharyngeal arches. Endothelial expression of Jag1 is down-regulated in the structurally-defective PAA4 of null embryos, which may be one of the mechanisms underlying the suppression of vascular smooth muscle cell differentiation. While the direct downstream phenomena of the Hrt1/Hey1 deficiency remain to be clarified, we suggest that Hrt1/Hey1-dependent transcriptional regulation has an important role in PAA formation during embryonic development.

Early Enhanced Parenteral Nutrition, Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants.

Efforts to optimize early parenteral nutrition (PN) in extremely low-birth-weight (ELBW) infants to promote growth and development may increase hyperglycemia risk. Recent studies have identified an association between early hyperglycemia and adverse outcomes in ELBW infants. To examine the prevalence of early hyperglycemia and clinical outcomes among ELBW infants before (2002-2005) and after (2006-2011) the implementation of an early enhanced PN protocol and to assess the independent effects of early enhanced PN and early hyperglycemia on mortality. Observational cohort study in a level III neonatal intensive care unit. Prospectively collected clinical data in the neonatal intensive care unit's medical database, nutritional information, and blood glucose levels were merged for analysis. All ELBW infants born between January 1, 2002, and December 31, 2011, without lethal malformations and still alive at 12 hours of life were eligible for inclusion in the study. Mortality was the main outcome measure. Severe hyperglycemia was defined as 2 consecutive blood glucose levels exceeding 216 mg/dL at least 3 hours apart. A multivariable logistic regression model was applied to determine the independent effects of early enhanced PN and hyperglycemia on mortality. In total, 343 infants were included in the study, 129 in a historical comparison group before the enhanced PN protocol and 214 in the early enhanced PN group. Baseline characteristics were similar between the study groups. After the introduction of early enhanced PN, the prevalence of severe hyperglycemia during the first week of life was higher in the early enhanced PN group (11.6% [15 of 129] vs 41.6% [89 of 214], P < .001), as was the mortality (10.9% [14 of 129] vs 24.3% [52 of 214], P = .003). When adjusting for background characteristics, treatment, and nutritional data, early severe hyperglycemia remained a strong independent risk factor for death (odds ratio, 4.68; 95% CI, 1.82-12.03), together with gestational age (odds ratio, 0.62; 95% CI, 0.49-0.79). The implementation of an enhanced PN protocol was correlated with an increased prevalence of severe hyperglycemia and higher mortality. In the multivariable analysis, an enhanced PN regimen per se was not predictive of mortality, whereas early severe hyperglycemia remained strongly predictive of death. To avoid detrimental effects on outcomes in ELBW infants, the optimal composition of early PN to avoid postnatal growth failure must be carefully balanced against hyperglycemia risk.

Primary prevention of neural tube defects in Brazil: insights into anencephaly.

Anencephaly is a lethal malformation characterized by the absence of the skull and both cerebral hemispheres caused by deficiency of closure of the neural tube at rostral level between 23 and 25 days of gestation (Bronberg et al. 2011). The occurrence of anencephaly and other neural tube defects (NTDs) such as meningocele and spina bifida are between 50 and 70 % preventable by periconceptional folic acid (FA) administration to reduce their prevalence across populations (Blencowe et al. 2010). The percentage decrease is dependent upon the background prevalence. The percentage of NTDs that are preventable by periconceptional folic acid intake is dependent on the prevalence of folate-sensitive NTDs in the population (Robbins et al. 2006; Bronberg et al. 2011). To prevent anemia due to iron deficiency and the occurrence of NTD, the Brazilian Ministry of Health approved the resolution RDC No. 344 on December 13, 2002, whereby the flour fortification of wheat and maize was regulated. This resolution determined that as of June 2004, wheat and corn flours be supplemented with at least 4.2 mg iron and 150 mcg of FA/100 g flour (ANVISA 2002). As in many South American countries, there are only two exceptions to penalized abortion in Brazil: in case of rape or to save the woman’s life. The Brazilian Criminal Code does not include fetal malformations as a cause of penalized abortion. This limitation was partially overcome in 2004, when the Brazilian Supreme Court of Justice authorized abortion in cases of anencephalic fetuses (Diniz 2007). Termination of pregnancy (TOP) with an anencephalic baby was made legal in 2012, without need of a special judicial authorization (Carvalho 2011). Until 2012, TOP had been legal in Brazil in cases of anencephaly only after special authorization from a judge. A survey performed with Brazilian obstetricians showed that 37 % of women with a pregnancy of anencephalic fetus had successfully obtained authorization for legal abortion (Diniz et al. 2009). About ten South American countries, in most of which abortion for congenital malformations is not authorized by law, primary prevention of anencephaly and other NTDs is managed through mandatory fortification of flour with FA (PAHO 2003). In some of these countries, fortification has proven to be an effective strategy for the primary prevention of anencephaly and NTDs. In particular, Argentina (Bronberg et al. 2011) and Chile (Cortes et al. 2012) have reduced the number of deaths by anencephaly by about 50 % in the post-fortification period compared to the pre-fortification stage. There are dissimilar records in Brazil in terms of fortification results according to NTDs, the type of data used (infant deaths or born alive), and level of spatial and temporal coverage these results are based on (Orioli et al. 2011; Pacheco et al. 2009; Fujimori et al. 2013; Schuler-Faccini et al. 2014). For its lethality, since 99 % of those born with anencephaly die within the first month of life and because the phenotype is well identified, even by non-specialists, anencephaly is a malformation whose epidemiological behavior can be analyzed with some confidence and provide an accurate and precise picture of the effect of flour fortification with FA and other preventive measures. Given the socioeconomic, geographical, ecological, and cultural diversity of Brazil, it is estimated that spatial and temporal variations of infant deaths from this NTD may be present. In this paper, the temporal variation and spatial distribution at different levels of the state organization in Brazil, infant and fetal deaths by anencephaly were analyzed in relation to the different phases that occurred in the process of fortification with FA.

Early Signs and Perinatal Diagnosis of Tracheal Agenesis

A preterm boy of 30 weeks and five days did not breathe spontaneously at birth and despite visualization of the vocal cords, intubation attempts did not succeed, until a tube 2.0 was placed using an Eschmann stylette, mistakenly considered endotracheal. A few hours later, suspicion of tube dislocation arose and renewed intubation attempts failed. The ENT specialist performed a tracheoscopy and found a blind ending of the trachea in the subglottic area. The trachea could not be felt below this area. Retrospectively the ventilation went via the esophagus to the lungs. The clinical presentation, the tracheoscopic and CT-scan findings indicated a tracheal agenesis Floyd type 3. This is a rare congenital and usually lethal malformation. Specific antenatal and clinical findings may indicate and facilitate early diagnosis. We hope that this case presentation will raise the awareness of a tracheal agenesis.

Advances in ultrasound imaging for congenital malformations during early gestation.

With refinement in ultrasound technology, detection of fetal structural abnormalities has improved and there have been detailed reports of the natural history and expected outcomes for many anomalies. The ability to either reassure a high-risk woman with normal intrauterine images or offer comprehensive counseling and offer options in cases of strongly suspected lethal or major malformations has shifted prenatal diagnoses to the earliest possible gestational age. When indicated, scans in early gestation are valuable in accurate gestational dating. Stricter sonographic criteria for early nonviability guard against unnecessary intervention. Most birth defects are without known risk factors, and detection of certain malformations is possible in the late first trimester. The best time for a standard complete fetal and placental scan is 18 to 20 weeks. In addition, certain soft anatomic markers provide clues to chromosomal aneuploidy risk. Maternal obesity and multifetal pregnancies are now more common and further limit early gestation visibility. Other advanced imaging techniques during early gestation in select cases of suspected malformations include fetal echocardiography and magnetic resonance imaging.

Haemoglobin level at birth is associated with short term outcomes and mortality in preterm infants.

BackgroundBlood volume and haemoglobin (Hb) levels are increased by delayed umbilical cord clamping, which has been reported to improve clinical outcomes of preterm infants. The objective was to determine whether Hb level at birth was associated with short term outcomes in preterm infants born at ≤32 weeks gestation.MethodsData were collected retrospectively from electronic records: Standardised Electronic Neonatal Database, Electronic Patient Record, Pathology (WinPath), and Blood Bank Electronic Database. The study was conducted in a tertiary perinatal centre with around 5,500 deliveries and a neonatal unit admission of 750 infants per year. All inborn preterm infants of 23 to 32 weeks gestational age (GA) admitted to the neonatal unit from January 2006 to September 2012 were included.The primary outcomes were intra-ventricular haemorrhage, necrotising entero-colitis, broncho-pulmonary dysplasia, retinopathy of prematurity, and death before discharge. The secondary outcomes were receiving blood transfusion and length of intensive care and neonatal unit days. The association between Hb level (g/dL) at birth and outcomes was analysed by multiple logistic regression adjusting for GA and birth weight (BWt).ResultsOverall, 920 infants were eligible; 28 were excluded because of missing data and 2 for lethal congenital malformation. The mean (SD) GA was 28.3 (2.7) weeks, BWt was 1,140 (414) g, and Hb level at birth was 15.8 (2.6) g/dL.Hb level at birth was significantly associated with all primary outcomes studied (P <0.001) in univariate analyses. Once GA and BWt were adjusted for, only death before discharge remained statistically significant; the OR of death for infants with Hb level at birth <12 g/dL compared with those with Hb level at birth of ≥18 g/dL was 4.1 (95% CI, 1.4–11.6). Hb level at birth was also significantly associated with blood transfusion received (P <0.01) but not with duration of intensive care or neonatal unit days.ConclusionsLow Hb level at birth was significantly associated with mortality and receiving blood transfusion in preterm infants born at ≤32 weeks gestation. Further studies are needed to determine the association between Hb level at birth and long-term neurodevelopmental outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0247-6) contains supplementary material, which is available to authorized users.

Atomic bomb testing and its effects on global male to female ratios at birth.

Fallout from atomic bomb testing may travel great distances before precipitating. Males are born in excess of females in a ratio that approximates 0.515 (M/T: male live births divided by total live births. Radiation increases M/T by causing lethal malformations that affect female more than male foetuses, decreasing total births. This study was carried out in order to ascertain whether the effects of increased background radiation levels from atomic weapon testing had any widespread effects on M/T and births in the Americas, Europe, Asia and Australasia in relation to the Partial Test Ban Treaty of 1963. Annual live births by gender were obtained from a World Health Organization dataset and annual number of atomic bomb tests were also obtained (historical data). Overall, 94.5% of births studied showed a uniform reduction in M/T between the early 1950s to the late 1960s, followed by an increase to the mid-1970s, with a subsequent decline. A negative correlation of M/T with total births was found in 66% of births studied, and these were the regions which exhibited the rising M/T pattern in the 1970s. The birth deficit for countries with significant correlations of total births with M/T (North America, Europe and Asia) was estimated at 10090701. A rising M/T was found in most regions in temporal association with atomic weapon testing. Most of these regions also had an associated decline in total births. Elevated levels of man-made ambient radiation may have reduced total births, affecting pregnancies carrying female pregnancies more than those carrying male pregnancies, thereby skewing M/T toward a higher male proportion.