Previous Sibling Research Articles

Young and vulnerable: Spatial-temporal trends and risk factors for infant mortality in rural South Africa (Agincourt), 1992-2007

BackgroundInfant mortality is an important indicator of population health in a country. It is associated with several health determinants, such as maternal health, access to high-quality health care, socioeconomic conditions, and public health policy and practices.MethodsA spatial-temporal analysis was performed to assess changes in infant mortality patterns between 1992-2007 and to identify factors associated with infant mortality risk in the Agincourt sub-district, rural northeast South Africa. Period, sex, refugee status, maternal and fertility-related factors, household mortality experience, distance to nearest primary health care facility, and socio-economic status were examined as possible risk factors. All-cause and cause-specific mortality maps were developed to identify high risk areas within the study site. The analysis was carried out by fitting Bayesian hierarchical geostatistical negative binomial autoregressive models using Markov chain Monte Carlo simulation. Simulation-based Bayesian kriging was used to produce maps of all-cause and cause-specific mortality risk.ResultsInfant mortality increased significantly over the study period, largely due to the impact of the HIV epidemic. There was a high burden of neonatal mortality (especially perinatal) with several hot spots observed in close proximity to health facilities. Significant risk factors for all-cause infant mortality were mother's death in first year (most commonly due to HIV), death of previous sibling and increasing number of household deaths. Being born to a Mozambican mother posed a significant risk for infectious and parasitic deaths, particularly acute diarrhoea and malnutrition.ConclusionsThis study demonstrates the use of Bayesian geostatistical models in assessing risk factors and producing smooth maps of infant mortality risk in a health and socio-demographic surveillance system. Results showed marked geographical differences in mortality risk across a relatively small area. Prevention of vertical transmission of HIV and survival of mothers during the infants' first year in high prevalence villages needs to be urgently addressed, including expanded antenatal testing, prevention of mother-to-child transmission, and improved access to antiretroviral therapy. There is also need to assess and improve the capacity of district hospitals for emergency obstetric and newborn care. Persisting risk factors, including inadequate provision of clean water and sanitation, are yet to be fully addressed.

A comparison of family and neighborhood effects on grades, test scores, educational attainment and income—evidence from Sweden

This paper compares sibling and neighborhood correlations in school performance, educational attainment and income as a way to learn whether the neighborhood where a child grows up in might explain parts of the sibling similarities found in previous sibling correlation studies. The data are based on a cohort of nearly 13,000 individuals born in 1953 and their siblings, all of whom grew up in the Stockholm area. The results show that neighborhood correlations are in general very small and in particular they are much smaller than the sibling correlations. Living in the same neighborhood does not seem to add much to the sibling similarities.

Antenatal diagnosis of larsen syndrome

We report acase of antenatally diagnosed Larsen syndrome.A 30-year-old consanguineously married women witha pregnancy of 20 weeks of gestation, with history ofprevious child diagnosed as Larsen syndrome on the basisof characteristic clinical and radiological features.With the background history of Larsen syndrome inthe previous sibling, in the present pregnancy Larsensyndrome was diagnosed antenatally on the basis ofmultiple joint dislocations, resulting in abnormal positionof legs and club feet, hypertelorism and depressed nasalbridge on ultrasonography (Fig. 1).Antenatal genetic counseling was done and the coupledecided to terminate the pregnancy. The product ofmedical termination of pregnancy which confirmed theprenatal diagnosis. The abortus was sent for autopsy, andconfirmed the diagnosis.For antenatal diagnosis, targeted ultrasound in a fetusat risk for Larsen syndrome should include evaluation offace, which tends to be flat, depressed nasal bridge, cleftpalate, hypertelorism and prominent forehead. Jointsshould be examined for club feet, multiple jointdislocations at elbow, hips, knee and abnormal jointpositions. Spinal abnormalities include kyphosis andscoliosis. Occasional findings include hydrocephalus,clinodactyly, supernumerary carpal bones and digits.Sonographic diagnosis of the condition before the end ofthe second trimester affords the patient the ability toterminate the pregnancy if she desires, and gives thephysician the chance to recounsel the patient and plan forappropriate management.

Factor XIII Deficiency - A Case Report with Review of Literature

Factor XIII deficiency is a rare disorder and these patients present with bleeding diathesis in the neonatal period. An 18 days old male child was brought with the history of umbilical stump bleeding. Two previous siblings had died in the neonatal period of an unknown cause, possibly because of intracranial haemorrhage and another at the age of 6 years of unknown cause. Investigations revealed Factor XIII deficiency. He was put on Fresh Frozen Plasma (FFP) support as he could not afford Fibrogammin and currently receives 6 weekly FFP and is doing well. J Med Sci 2009;12(2):53-55.

Intracranial Hemorrhage in Alloimmune Thrombocytopenia: Stratified Management to Prevent Recurrence in the Subsequent Affected Fetus.

Abstract 894 Introduction:Fetal and neonatal alloimmune thrombocytopenia (AIT) result from parental platelet-specific antigen incompatibility combined with maternal sensitization. AIT is the most common cause of severe thrombocytopenia and intracranial hemorrhage (ICH) in term newborns; if ICH occurs in 1 child then the next affected sibling has a > 90% chance of developing an ICH. Prevention of recurrent ICH is the primary goal of antenatal management of AIT. Methods:Thirty-three women with 37 separate pregnancies were enrolled in 2 consecutive studies of antenatal management of AIT. All patients had a previous child who had suffered an ICH. They were subdivided into 3 groups (Extremely High Risk (EHR), Very High Risk (VHR) and High Risk (HR)) based on the timing of that child's ICH. Therapy was stratified according to the timing of the sibling ICH. The table below lists risk stratification, treatment and outcomes for each treatment arm. In all arms, if fetal blood sampling (FBS) showed a platelet count < 30,000/mL3 or if FBS was not performed, therapy was intensified with additional prednisone and/or intravenous IVIG. Results:The mean, on-therapy fetal platelet count was greater than the previous sibling birth platelet count (BPC) in all arms. The first EHR fetus, whose mother received IVIG 1g/kg/wk and prednisone 1mg/kg/d beginning at week 12, suffered an ICH at 19 weeks gestation and died. The EHR protocol was changed to IVIG 2g/kg/wk. None of the 7 other EHR fetuses had an ICH, and all had BPC > 50,000/mL3. Two patients in the VHR group had ICHs, but both occurred at BPC > 100,000/mL3. One was a Grade I (of IV) ICH; the other occurred in a 24-week-old premature infant. Fourteen of the 17 VHR fetuses had BPC > 50,000/mL3. Within the HR group, 2 fetuses (therapy started at 20-24 weeks), suffered an ICH. One patient should have been treated in the VHR arm, but could not receive optimal treatment due to late referral. The other ICH was Grade I, although the BPC was low. All HR fetuses, except for 3 receiving IVIG 1g/kg/wk starting at 20-24 weeks, had BPC > 50,000/mL3. Major complications of the study were FBS-related: 1 case of fetal tachycardia and 8 cases of fetal bradycardia; 3 cases lead to emergent cesarean section, one a result of hemorrhaging from the needle insertion site. Discussion:Fetuses of AIT-affected pregnancies with ICH in a previous affected sibling are at very high risk for ICH. The results of this study demonstrate the success of risk-tailored treatment in prevention of recurrent ICH. Although all or almost all 37 of the fetuses in this study would have developed a recurrent ICH, there were only 5 recurrent ICHs and only 2 of 5 occurred due to failure of therapy. Treatment should be stratified based on the timing of the sibling ICH: the highest risk is second trimester antenatal hemorrhage followed by third trimester followed by perinatal. See the table below for recommended treatments for each group. Since complications due to FBS continued to be substantial, FBS should be avoided until after 32 weeks at which time urgent delivery could be performed if a complication occurred. The intensification of treatment at fixed gestational ages rather than relying on the results of FBS further minimizes the need for early FBS.Risk Stratification, Treatment, Outcome and RecommendationsHigh Risk (n=12)Very High Risk (n=17)Extremely High Risk (n=8)DefinitionPerinatal ICH in prior siblingICH 28-36 wk in prior siblingICH prior to 28 wk in prior siblingTreatments1Arm AIVIG 1g/kg/wk (n=6)IVIG 1g/kg/wk (n=15)IVIG 1g/kg/wk + Pred 1mg/kg/d (n=1)Arm BIVIG 2g/kg/wk (n=2)IVIG 2g/kg/wk (n=2)IVIG 2g/kg/wk (n=7)Arm CIVIG 1g/kg/wk + Pred 0.5mg/kg/d (n=4)Mean Sibling BPC (x1,000/mL3)Arm A11.213.34Arm B5.09.521.5Arm C20.3Mean BPC (x1,000/mL3)Arm A47.3120.7NAArm B112.093124.3Arm C137.0ICH221Expected ICH10-1215-178Recommended Treatment21. IVIG 1g/kg/wk + Pred 1mg/kg/d at 20 wk 2. Add 2nd IVIG 1g/kg/wk if FPC at 32 wk < 50,000/mL31. IVIG 1g/kg/wk at 12 wk 2. Add Pred 1 mg/kg/d or 2nd IVIG 1g/kg/wk at 20 wk1. IVIG 2g/kg/wk at 12 wk 2. Add Pred 1mg/kg/d at 24-26 wkICH, intracranial hemorrhage; IVIG, intravenous immunoglobulin; Pred, prednisone; BPC, birth platelet count; FPC, fetal platelet count; FBS, fetal blood sampling1High Risk patients in Study 1 (4 IVIG 1g/kg/wk and 4 IVIG 1g/kg/wk+Pred 0.5mg/kg/d) started therapy at 20-24 weeks. All other patients started therapy at around 12 weeks.2All arms should undergo FBS at 32 weeks. Disclosures:Bussel:Amgen, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Research Funding; Sysmex: Research Funding; Scienta: Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees.

Infant Mortality in Rural Bangladesh: State Dependence vs. Unobserved Heterogeneity

Using longitudinal data of the Health and Demographic Surveillance System (HDSS) in Matlab, Bangladesh, covering the time period 1982–2005, and exploiting dynamic panel data models, we analyze siblings’ death at infancy, controlling for unobserved heterogeneity and a causal effect of death of one child on survival chances of the next child. Matlab is a rural area split into two: a “treatment” area where along with standard government services extensive maternal and child health interventions are available, and a “comparison” area where only the standard government services are available. The observed infant mortality rates are 50 per 1,000 live births in the treatment area and 67.4/1,000 in the comparison area. We use separate models for the two areas and analyze the differences in infant mortality between the two areas using several decompositions. Our model predicts that in the comparison area, the likelihood of infant death is about 30% larger if the previous sibling died at infancy than if it did not, and the estimates suggest that, in the absence of this “scarring” effect, the infant mortality rate among the second and higher order births would fall by 6.2%. There is no evidence of such a scarring effect in the treatment area, perhaps because learning effects play a larger role with the available extensive health interventions. We find that distance to the nearest health clinic can explain a substantial part of the gap in infant mortality between the two areas.

Characteristics of Children Whose Siblings Have Fetal Alcohol Syndrome or Incomplete Fetal Alcohol Syndrome

To describe the clinical features of American Indian children born just before and just after a sibling with fetal alcohol syndrome or incomplete fetal alcohol syndrome. Two retrospective case-control studies were conducted of Northern Plains American Indian children with fetal alcohol syndrome or incomplete fetal alcohol syndrome identified from 1981 to 1993 by using International Classification of Diseases, Ninth Revision, Clinical Modification code 760.71. Compared with the controls, the 39 siblings born just before children with fetal alcohol syndrome (study 1) and 30 siblings born just before children with incomplete fetal alcohol syndrome (study 2) had more facial dysmorphology (23.1% and 16.7%, respectively), growth delay (38.5% and 10.0%), and central nervous system impairment (48.7% and 33.3%). The 20 siblings born just after children with fetal alcohol syndrome (study 1) and 22 siblings born just after children with incomplete fetal alcohol syndrome (study 2) had more facial dysmorphology (20.0% and 9.1%, respectively), growth delay (45.0% and 22.7%), and central nervous system impairment (50.0% and 31.8%) than the control siblings. The "before" siblings had characteristics of fetal alcohol syndrome that could have predicted that the next child was at risk for fetal alcohol syndrome. The "after" siblings had better outcomes than the previous siblings with fetal alcohol syndrome, a finding that was associated with a decrease in maternal alcohol consumption during the after-sibling pregnancy.

Transcobalamin (TC) deficiency—Potential cause of bone marrow failure in childhood

It is unusual for inborn errors of metabolism to be considered in the investigative work-up of pancytopenia. We report a family in which the proband presented with failure to thrive at 2 months of age and subsequent bone marrow failure. A previous sibling had died at 7 months of age with suspected leukaemia. Haematological findings in the proband were significant for pancytopenia, and bone marrow aspiration showed dysplastic changes in all cell lineages. Urinary organic acid analysis revealed elevated methylmalonic acid. The synthesis of transcobalamin II (transcobalamin, TC) by cultured fibroblasts was markedly reduced, confirming the diagnosis of TC deficiency. The proband and his younger asymptomatic sister (also found to have TC deficiency) were homozygous for R399X (c.1195C>T), a novel mutation resulting in the loss of the C- terminal 29 amino acids of TC, a highly conserved region. Response to parenteral vitamin B(12) in the proband was dramatic. At 6 years 3 months of age, physical examination is normal and developmental level is age appropriate. His sister is clinically asymptomatic and is also developing normally. Propionylcarnitine concentrations were not elevated in the newborn screening cards from the proband and sister, but that was for specimens retrieved from storage after 7 years and 5 years, respectively. Inherited and acquired cobalamin disorders should both be considered in the differential diagnosis of bone marrow failure syndromes in young children. Early detection of the metabolic causes of bone marrow failure can ensure prompt recovery in some cases involving the vitamin B(12) pathway.

Outcomes of pregnancies following a birth with major birth defects: A population based study

Background/aim Parents whose first infant had birth defects may worry about a new pregnancy. Our aim was to study pregnancy outcomes among non-malformed second siblings in families where the first birth had a major birth defect. Methods Data were from the Medical Birth Registry of Norway from 1967 to 2004. Births were linked to their mothers through the unique national identification numbers, providing sibship files with the mother as the observation unit. The study was based on 538,669 singleton first and second full siblings. Families were classified as affected families if the first infant had a major birth defect. Pregnancy outcomes for non-malformed second siblings following affected first births were compared with second siblings in families without malformed infants. Subgroup analyses were done for families where first infants had neural tube defects, cleft lip with or without cleft palate, abdominal wall defects, limb reduction defects, pes equinovarus and congenital dysplasia of the hip. Results Second siblings in affected families did not differ from those in unaffected families in risk of perinatal death, small for gestational age, preterm birth, placental abruption or preeclampsia. Second siblings following an infant with limb reduction defects had a higher risk of breech presentation than second siblings in unaffected families, also when stratifying on previous siblings in vertex presentation (stratified OR 2.20 [95% C.I. 1.17–4.15]). Conclusion Parents who proceed to a new pregnancy after a first birth with birth defects may be reassured that, given no recurring defects, there is in general no increased risk of adverse pregnancy outcomes.

Management of alloimmune thrombocytopenia

Fetal alloimmune thrombocytopenia is caused by maternal sensitization to paternally-derived antigens on fetal platelets, most commonly HPA-1a.1 It occurs in approximately 1 in 1000 live births and is the commonest cause of severe fetal and neonatal thrombocytopenia, and of intracranial hemorrhage in neonates born at term.2 Since there is currently no routine screening, first-time cases of fetal alloimmune thrombocytopenia are generally identified following the birth of a markedly thrombocytopenic neonate. Antenatal management is thus only possible in subsequent pregnancies. Intracranial hemorrhage is the most devastating complication of fetal alloimmune thrombocytopenia and often occurs antenatally. Assessment of projected clinical severity is thus based on the development of intracranial hemorrhage in a previous sibling. If there is such a history of intracranial hemorrhage, the chance of this complication occurring again in the next pregnancy is extremely high in an untreated, antigen-positive sibling.3 Administration of intravenous immunoglobulin (IVIG) to the mother, initially given in conjunction with dexamethasone, was first used to prevent recurrence of antenatal intracranial hemorrhage in 1988.4 This approach of providing IVIG-based medical therapy administered to the mother to increase the fetal platelet count has since been extensively investigated in hundreds of maternal-fetal pairs.5 The efficacy of IVIG-based therapy has been supported by numerous studies6–16 (Table 1A) but not by others17–19 (Table 1B). The studies presented in Tables 1A and 1B surprisingly report virtually identical percentages of cases of intracranial hemorrhage: 2.7% versus 2.9%, respectively. However, overall mean birth platelet counts differed markedly between the two groups. While platelet counts are considered to be surrogate markers of intracranial hemorrhage, fortunately, the likelihood of fetal and neonatal intracranial hemorrhage, in the absence of this complication having occurred in a previous sibling, is relatively low.

Risk factors associated with the occurrence of frontoethmoidal encephalomeningocele

Objectives To determine factors associated with the occurrence of frontoethmoidal encephalomeningocele (FEEM), a congenital defect with unique geographical distribution. Methods The subjects of this study were 160 unrelated cases of FEEM. Subjects were recruited between 1999 and 2006 from 15 medical centers throughout Thailand. Data obtained from FEEM cases were analyzed and compared with data from 349 cases of oral clefts studied in the same centers and during the same time and those from the general population (GP) taken in 2003. Results About 52% of FEEM cases had brain anomalies which were not different among types of FEEM. We found familial aggregation reflected by an increased risk to siblings. All of the FEEM cases were of Thai nationality and came from low socioeconomic status. Seven FEEM cases had amniotic rupture sequences. Compared with oral clefts, advanced maternal age (OR: 1.08, 95% CI: 1.02–1.15) was found to be associated with FEEM. In addition, the interpregnancy interval between the FEEM cases and their previous siblings was significantly longer than that of the oral cleft patients and unaffected sibs (OR: 1.17, 95% CI: 1.06–1.28). Conclusions Low socioeconomic status, advanced maternal age, and a long interpregnancy interval may lead to an unfavorable intrauterine environment which, with a certain genetic background such as Thai ethnicity, could contribute to the occurrence of FEEM.

Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G&gt;T mutation: Clinical, pathological, and molecular findings

Otopalatodigital syndrome type 2 (OPD2) is an uncommon X-linked condition characterized by dysmorphic facies, a skeletal dysplasia affecting the axial and appendicular skeleton and extraskeletal anomalies including malformations of the brain, heart, genitourinary system, and intestines. Missense mutations of the FLNA gene, which encodes for the protein filamin A, have recently been shown to cause OPD2 and the allelic syndromes otopalatodigital type 1, Melnick-Needles, and frontometaphyseal dysplasia. Collectively these conditions constitute the otopalatodigital spectrum disorders. We report on two sibs affected by OPD2. The diagnosis was achieved at autopsy of a macerated male stillborn with typical external and skeletal findings of OPD2. A subsequent pregnancy was terminated due to ultrasonographic findings resembling those observed in the previous sibling. Histopathological studies revealed osseus sclerosis and do not support the previously reported membranous ossification defect observed in this condition. Mutation analysis demonstrated a novel mutation, 629G>T, in FLNA that had arisen de novo in the mother. This missense mutation predicts the substitution C210F within the second calponin homology domain of the actin-binding domain of filamin A. The identical substitution has been recently identified in an analogous amino-acid position within the actin binding domain of beta-spectrin leading to hereditary spherocytosis. The observation that phenylalanine is normally present in the same position in other proteins (utrophin, dystrophin) but leads to disease when present in filamin A implies that the function and/or structure of these actin binding domains are not entirely equivalent.

Management of Fetal Alloimmune Thrombocytopenia (AIT): Treatment of 30 Cases in Which the Previous Sibling Suffered an IntraCranial Hemorrhage (ICH).

Prevention of fetal-perinatal ICH is the primary goal of antenatal therapy for AIT. When there was an ICH in a prior pregnancy, these fetuses are at virtually 100% risk for a recurrent ICH. Current antenatal treatments given to the mother are intravenous gammaglobulin (IVIG), oral steroids, or both. Two consecutive studies examined risk-based therapy by tailoring therapeutic interventions according to the course of the previous affected sibling with ICH.Thirty patients with AIT were divided into 4 groups based on the timing of the sibling's ICH (see Figs. 1 & 2, including abbreviations). In the Extremely High Risk (EHR), Very HR (VHR), HR1, and HR2 arms, an adequate initial response was defined as an Fetal Platelet Count (FPC) ≥30 × 109/L at the time of the first Fetal Blood Sampling (FBS). Repeat FBS was done 3–8 weeks later. If the platelet count did not increase, therapy was intensified (“salvage”) by adding prednisone or additiional IVIG. There were 5 ICHs (see Table), 3 of which were failures of antenatal therapy. One ICH occurred in an EHR patient prior to the use of 2g/kg/wk of IVIG as did one of the 2 ICHs in the HR1 study; both of these hemorrhages occurred on IVIG + pred prior to 30 weeks. Both previous siblings had had early antenatal ICHs. The second HR1 patient with ICH was initially on IVIG alone, added pred when repeat FBS was not possible because of premature contractions, and delivered at 35 weeks with a birth platelet count (BPC) of 14 × 109/L; a Grade I intraventricular ICH was noted on the first day of life. The other 2 ICHs occurred in a VHR infant delivered at 24 weeks gestation with a BPC of 248 × 109/L and in a HR2 35.7 week old infant with a BPC of 137 × 109/L. The effectiveness of the treatment strategy was demonstrated because all groups' mean BPC was >50 × 109/L; 3 of 4 groups' mean BPC was >100 × 109/L.The fact that 20 of 30 of the patients required salvage therapy, and that overall, the BPC was greater than the initial FPC in all arms, attests to the need for monitoring of the FPC and for intensification of therapy in these HR patients. Comparing HR1 to HR2, starting therapy earlier than 20–24 weeks in the HR2 arm appeared to substantially increase the BPC. Antenatal therapy with IVIG 1–2g/kg/wk beginning at approximately 12 weeks gestation was effective in preventing ICH in the highest risk pregnancies in 25 of 30 cases. In the future, treatment may start with IVIG 2g/kg/wk and automatically add prednisone at 24–30 weeks for optimal response. This could also allow avoidance of FBS until at least 32 weeks.Summary# of Patients# Requiring SalvageMean FPC at 1st FBS (K)Mean Gestational Age at Birth (weeks)Mean BPC (K)# of ICHs# of Fetal DemisesEHR432332.515511VHR151174.633.612220HR18521.833.168.421HR2315433.212200 [Display omitted]

Risk factors for neonatal mortality in rural areas of Bangladesh served by a large NGO programme

Neonatal deaths account for about half of all deaths among children under 5 years of age in Bangladesh, making prevention a major priority. This paper reports on a study of neonatal deaths in 12 areas of Bangladesh served by a large NGO programme, which had high coverage of reproductive health outreach services and relatively low neonatal mortality in recent years. The study aimed to identify the main factors associated with neonatal mortality in these areas, with a view to developing appropriate strategies for prevention. A case-control design was adopted for collection of data from mothers whose children, born alive in 2003, died within 28 days postpartum (142 cases), or did not (617 controls). Crude and adjusted odds ratios (AOR) were calculated as estimates of relative risk for neonatal death, using 'neighbourhood' controls (241) and 'non-neighbourhood' controls (376). A similar proportion of case and control mothers had received NGO health education and maternal health services. The main risk factors for neonatal death among 122 singleton babies, based on the two sets of controls, were: complications during delivery [AOR, 2.6 (95% CI: 1.5-4.5) and 3.1 (95% CI: 1.8-5.3)], prematurity [AOR, 7.2 (95% CI: 3.6-14.4) and 8.3 (95% CI: 4.2-16.5)], care for a sick neonate from an unlicensed 'traditional healer' [AOR, 2.9 (95% CI 0.9-9.5 and 5.9 (95% CI: 1.3-26.3)], or care not sought at all [AOR, 23.3 (95% CI: 3.9-137.4)]. The strongest predictor of neonatal death was having a previous sibling not vaccinated against measles [AOR, 5.9 (95% CI: 2.2-15.5) and 12.0 (95% CI: 4.5-31.7)]. The findings of this study indicate the need for identification of babies at high risk and early postpartum interventions (40.2% of the deaths occurred within 24 hours of delivery). Relevant strategies include special counselling during pregnancy for mothers with risk characteristics, training birth attendants in resuscitation, immediate postnatal check-up in the home for high-risk babies identified at delivery, advice for mothers on appropriate care-seeking for sick babies, improving the capacity of sub-district hospitals for emergency obstetric and newborn care, and promotion of institutional deliveries.

Prenatal sonographic appearance of cryptophthalmos in Fraser syndrome

Cryptophthalmos (hidden eye) is characterized by the continuous passage of skin from the forehead to the cheek and absence of the palpebral fissure. Cryptophthalmos is the leading feature of Fraser syndrome and has been described in 84 to 93% of affected patients1,2. Cryptophthalmos–syndactyly syndrome or Fraser syndrome is an inherited disorder characterized by variable expression of cryptophthalmos, renal agenesis, laryngeal stenosis, syndactyly, abnormalities of the ears and external genitalia and other minor anomalies. Because of the marked variability of expression in patients with cryptophthalmos, Thomas et al.1 established strict diagnostic criteria (major and minor) for the diagnosis of Fraser syndrome after birth. They outlined the following major criteria: cryptophthalmos, syndactyly, abnormal genitalia and sib with cryptophthalmos syndrome. The minor criteria are malformations of the nose, ears, or larynx, cleft lip and/or palate, umbilical hernia, renal agenesis, skeletal defects and mental retardation. Cases are diagnosed on the basis of at least two major criteria and one minor criterion or on the basis of one major criterion and at least four minor criteria. Because of the difficulty of demonstrating the major criteria, the prenatal diagnosis of the syndrome relies almost entirely on the detection of some of the easily detectable minor criteria like laryngeal atresia and renal agenesis. Many of the reports of prenatal diagnosis of this syndrome have been in the follow-up of a pregnancy with a previous sibling having had the same syndrome3–7. Of all the reports regarding the diagnosis of Fraser syndrome in families with a negative history, the final diagnosis was reached prenatally only in five instances8–11. In four of these reports the prenatal sonographic findings reported were obstructive uropathy8, hydrocephalus8, severe oligohydramnios9 and pulmonary hyperplasia10, but a definitive prenatal diagnosis of Fraser syndrome was not made. Maruotti et al.11 reported the prospective prenatal diagnosis of Fraser syndrome in a fetus at 21 weeks’ gestation based on oligohydramnios, laryngeal atresia, bilateral renal agenesis, bilateral microphthalmos and rhizomelic shortening of bones. In this report we describe the high-resolution sonographic appearance of cryptophthalmos and abnormality of the ocular globes in Fraser syndrome. A 24-year-old woman, gravida 2 para 1, was referred for sonography to rule out fetal anomalies. Her first male child had been delivered normally at term, but died on the second day owing to congenital heart disease. She was in her 26th week of gestation. Sonography was performed using convex 2–5-MHz and 4–7-MHz and linear 5–12MHz probes. Fetal biometry corresponded to a gestational age of 24 weeks, but the amniotic fluid volume was normal. The fetus showed agenesis of the right kidney, a small omphalocele and unilateral microphthalmos. On high-resolution ultrasound examination skin was seen to be continuous over the eyeballs on both sides and the palpebral fissure could not be identified (Figure 1). Echoes from the lens and ciliary apparatus could not be seen within the eyeballs, which revealed a single cavity (Figure 1). The fetus was also found to have bilateral cutaneous syndactyly of all fingers. The ears were small and deformed. The penis was short and lacked preputial cover. A prenatal diagnosis of Fraser syndrome was made and the parents chose to terminate the pregnancy. Externally the fetus showed bilateral cryptophthalmos, low frontal hairline (Figure 2), and bilateral low-set ears with abnormal pinna, broad abnormal nose, micrognathia, normal scrotum, micropenis, imperforate anus and syndactyly of the fingers. On autopsy the right kidney was absent and the left kidney was normal. There was a small omphalocele containing a Meckel’s diverticulum. The right eyeball was smaller than the left. On histopathology the eyeballs revealed only portions of lenses and ciliary bodies, and retinal dysplasia on both sides. These features confirmed the prenatal diagnosis of Fraser syndrome. In the longitudinal scan of the orbit of a normal fetus, the palpebral fissure is seen as a thin gap between the upper and lower eyelids (Figure 1c). In the fetus with Fraser syndrome described here, the cryptophthalmos

Socio‐economic characteristics in children with coeliac disease

To study the relationship between socio-economic factors and coeliac disease. This study was part of a prospective cohort study of 16 286 children born from 1 October 1997-1 October 1999 (the ABIS study; All Babies in Southeast Sweden). Eight paediatric departments recorded all children with coeliac disease in southeast Sweden. Coeliac disease was confirmed through biopsy. Socio-economic characteristics (maternal employment, civil status, whether parents were born in Sweden, parental education, place of living before pregnancy and during pregnancy, crowded living), infant sex, previous siblings, parental age and maternal alcohol consumption during pregnancy were analysed using logistic regression. All data, except for those related to diagnosis of coeliac disease, were obtained through a questionnaire distributed at birth. Coeliac disease in the offspring was less common among mothers who had worked < 3 mo during pregnancy (odds ratio, OR = 0.29; 95% CI: 0.09-0.94; p = 0.039). This risk decrease remained after adjustment for confounders (adjusted OR = 0.28; 95% CI: 0.09-0.92; p = 0.035). No other socio-economic factor was related to coeliac disease. This study indicates that most socio-economic factors are probably of little importance to the development of coeliac disease.

Sudden unexpected infant death: infanticide or SIDS?

A few sudden unexpected deaths in infants are caused by a carer, most often a parent. The issue of how to deal with these deaths has always caused great soul-searching in society. Most unexpected deaths in infants remain unexplained after autopsy and are labelled as sudden unexplained infant death syndrome (SIDS). This term was invented in 1969 to acknowledge that, while unexplained, most of these deaths are natural deaths with no blame accruing to parents already burdened by a recent bereavement. Since then, SIDS parents' groups have been organised in most western countries and have successfully campaigned to promote research and improve the knowledge base of SIDS while improving the support services available to bereaved parents. This highly desirable involvement of parents has had the unintended effect of making it more difficult to discuss the small number of unexpected deaths where infanticide is suspected or proven (perhaps about 5%). The study deals with the issue of whether a repeat unexpected death in a family is natural (SIDS), with or without genuine concerns, or an unnatural (infanticide) death. The data-set is based on the Care of the Next Infant programme, in which families and infants, with a previous sibling dying from a cot death, were enrolled in a support programme facilitated by the Foundation for the Study of Infant Deaths. The strength of the study lies in its prospective nature, and the comprehensive assessment of the repeat unexpected deaths, including interviews with parent(s) and health carers, and an independent assessment of the autopsy, including interpretation of histology slides. The main conclusion is that the recurrence rate of unexpected deaths or SIDS is about 6 per 1000 and that most of these second deaths are from natural causes. So the mere occurrence of a second death is, in itself, insufficient to justify the label of infanticide. Although some families with an unexpected death have worryingly disorganised parenting skills and support structures, Carpenter and colleagues show that unexpected deaths recur, which implies that a diagnosis of infanticide should require more definite evidence.

Association of parental consanguinity with congenital malformations among Arab newborns in Jerusalem.

The aim of this work was to determine the impact of parental consanguinity on congenital malformations in a mixed urban and rural Arab community in Jerusalem, Israel. Arab mothers admitted to four hospitals in west Jerusalem were interviewed after delivery. Demographic and obstetric data were recorded. Neonatal data were extracted from the medical records of the nursery. When malformations were suspected, a 4- to 10-month follow up was achieved for confirming the diagnosis. Of 561 infants, 253 (45%) were born to consanguineous couples. The incidence of major congenital malformations in the offspring was 8.7, 7.1 and 2.6% in cases of first cousins, all consanguineous, and non-consanguineous couples, respectively. No association was found between parental consanguinity and prematurity (p = 0.357) or low birth weight (p = 0.589). Parental consanguinity was also associated with an increased incidence of death in previous siblings (p < 0.000). The increased incidence of congenital malformations and infant mortality in cases of inbreeding prompt the necessity of establishing programs to avoid these complications in the offspring.

10 Severe Neonatal Hyperbilirubinemia: Cause for Concern?

Although severe neonatal hyperbilirubinemia in the term neonate and bilrubin encephalopathy is rare, it is associated with significant morbidity. A number of reports have been published in recent years of bilirubin encephalopathy in term neonates who appeared to be healthy and breast-fed with no evidence of hemolytic disease (Maisels 1995, Ebbesen 2000). Some risk factors are known to be associated with severe hyperbilirubinemia in the newborn and include: jaundice in the first 24 hours of life, previous sibling with jaundice, and gestational age of 35 to 38 weeks (Dennery et al 2001). Additional risk factors include Rh and ABO incompatibility and Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. Attempts to better quantify the frequency, etiologies and risk factors for neonatal hyperbilirubinemia would be of value prior to identifying strategies for risk reduction. Our objective was to obtain epidemiological data about severe neonatal hyperbilirubinemia in order to develop prevention strategies for this condition. Data on term infants 60 days of age or less with unconjugated hyperbilirubinemia was collected from July 2002 to present through the Canadian Pediatric Surveillance Program. Criteria for inclusion in this study included: 1) peak serum total bilirubin >425 μmol/L or 2) neonatal exchange transfusion. Infants who had exchange transfusions for well-documented Rh isoimmunization disease or were less than 36 weeks of gestational age were excluded. After 16 months of surveillance 220 cases of severe neonatal hyperbilirubinemia were reported. Of these, 148 were confirmed, 33 were duplicates or discarded, and 39 are still under review. In only 47 cases was the cause of the hyperbilirubinemia identified. The etiologies included ABO incompatibility (n=28), G6PD deficiency (n=13), other antibodies (n=4), and unstable hemoglobin (n=2). The range of bilirubin reported was from 156 to 731 μmol/L. 37 of the neonates required exchange transfusion, while all neonates were treated with phototherapy. 6 neonates had documented hearing loss and 3 had seizures prior to discharge from hospital. This study shows that severe neonatal hyperbilirubinemia continues to occur in term neonates with significant morbidity. In the majority of cases the underlying etiology could not be identified, which could partly be attributed to incomplete evaluation at the time of presentation. This finding highlights the importance of a complete hematological workup for such children prior to discharge such as a screen for blood group, Coomb's testing, peripheral smear, and a screen for G6PD. Further testing including a hearing assessment and close pediatric follow-up is also likely to be beneficial.

Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G > C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic status

Virtually all patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) are homozygous or compound heterozygous for the 985A > G mutation, which limits the study of a possible genotype/phenotype correlation. A newborn Palestinian infant died suddenly on the second day of life. A previous sibling had also died in similar circumstances aged 3 weeks. Urine organic acid and bloodspot acylcarnitine analysis were consistent with MCADD. He was homozygous for a novel MCAD splice mutation, IVS3-1G > C. This mutation leads to deletion of 7 bp and introduction of a premature termination codon as a result of complete missplicing of MCAD mRNA. This misspliced MCAD mRNA encodes a non-functional protein and is furthermore reduced in amounts due to nonsense-mediated decay, resulting in total lack of functional MCAD enzyme. This is the first molecular identification of MCADD in an Arab patient and the first reported splice mutation in the MCAD gene that has been functionally characterized. The association of homozygosity for a null mutation with lethal neonatal presentation in the index patient and presumably the previous infant suggested a genotype/phenotype correlation. However, a 6-year-old completely asymptomatic sibling also had the characteristic MCADD biochemical phenotype and was homozygous for the same IVS3-1G > C mutation. As a first candidate to modify the disease presentation, by modulating the overlapping enzyme activity, we tested the entire family for the prevalent SCAD gene 625G > A susceptibility variant. Interestingly, all family members were 625G > A homozygous. Additional genetic and/or environmental factors must play a major role in determining the phenotypic diversity of MCADD.