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Importance: Zika virus infection can be prenatally passed from a pregnant woman to her fetus. There is sufficient evidence to conclude that intrauterine Zika virus infection is a cause of microcephaly and serious brain anomalies, but the full spectrum of anomalies has not been delineated. To inform pediatric clinicians who may be called on to evaluate and treat affected infants and children, we review the most recent evidence to better characterize congenital Zika syndrome. Observations: We reviewed published reports of congenital anomalies occurring in fetuses or infants with presumed or laboratory-confirmed intrauterine Zika virus infection. We conducted a comprehensive search of the English literature using Medline and EMBASE for Zika from inception through September 30, 2016. Congenital anomalies were considered in the context of the presumed pathogenetic mechanism related to the neurotropic properties of the virus. We conclude that congenital Zika syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage. Although many of the components of this syndrome, such as cognitive, sensory, and motor disabilities, are shared by other congenital infections, there are 5 features that are rarely seen with other congenital infections or are unique to congenital Zika virus infection: (1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices with subcortical calcifications; (3) macular scarring and focal pigmentary retinal mottling; (4) congenital contractures; and (5) marked early hypertonia and symptoms of extrapyramidal involvement. Conclusions and Relevance: Although the full spectrum of adverse reproductive outcomes caused by Zika virus infection is not yet determined, a distinctive phenotype-the congenital Zika syndrome-has emerged. Recognition of this phenotype by clinicians for infants and children can help ensure appropriate etiologic evaluation and comprehensive clinical investigation to define the range of anomalies in an affected infant as well as determine essential follow-up and ongoing care.

Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings.

BACKGROUND: Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. METHODS: We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. RESULTS: As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. CONCLUSIONS: Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero.

We reviewed studies that reported results of systematic cytomegalovirus (CMV) screening on fetuses and/or live-born infants. The overall birth prevalence of congenital CMV infection was 0.64%, but varied considerably among different study populations. About 11% of live-born infants with congenital CMV infection were symptomatic, but the inter-study differences in definitions of symptomatic cases limit the interpretation of these data. Non-white race, low socioeconomic status (SES), premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection. Birth prevalence increased with maternal CMV seroprevalence. Maternal seroprevalence accounted for 29% of the variance in birth prevalence between study populations. Maternal seroprevalence and birth prevalence were both higher in study populations that were ascertained at birth rather than in the prenatal period. Thus, timing of ascertainment should be considered when interpreting birth prevalence estimates. Birth prevalence was inversely correlated with mean maternal age, but this relationship was not significant when controlling for maternal seroprevalence. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Possible maternal primary infections (i.e. seropositive mother with CMV IgM) resulted in congenital infections about 20% of the time, but are likely to represent a mixture of primary and recurrent infections. In summary, CMV is a common congenital infection worldwide that can lead to permanent disabilities. There is an urgent need for interventions that can reduce the substantial burden of this often overlooked disease.

CONTEXT: Evidence suggests an association between maternal obesity and some congenital anomalies. OBJECTIVE: To assess current evidence of the association between maternal overweight, maternal obesity, and congenital anomaly. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Scopus (January 1966 through May 2008) were searched for English-language studies using a list of keywords. Reference lists from relevant review articles were also searched. STUDY SELECTION: Observational studies with an estimate of prepregnancy or early pregnancy weight or body mass index (BMI) and data on congenital anomalies were considered. Of 1944 potential articles, 39 were included in the systematic review and 18 in the meta-analysis. Data Extraction and Synthesis Information was extracted on study design, quality, participants, congenital anomaly groups and subtypes, and risk estimates. Pooled odds ratios (ORs) comparing risk among overweight, obese, and recommended-weight mothers (defined by BMI) were determined for congenital anomaly groups and subtypes for which at least 150 cases had been reported in the literature. RESULTS: Pooled ORs for overweight and obesity were calculated for 16 and 15 anomaly groups or subtypes, respectively. Compared with mothers of recommended BMI, obese mothers were at increased odds of pregnancies affected by neural tube defects (OR, 1.87; 95% confidence interval [CI], 1.62-2.15), spina bifida (OR, 2.24; 95% CI, 1.86-2.69), cardiovascular anomalies (OR, 1.30; 95% CI, 1.12-1.51), septal anomalies (OR, 1.20; 95% CI, 1.09-1.31), cleft palate (OR, 1.23; 95% CI, 1.03-1.47), cleft lip and palate (OR, 1.20; 95% CI, 1.03-1.40), anorectal atresia (OR, 1.48; 95% CI, 1.12-1.97), hydrocephaly (OR, 1.68; 95% CI, 1.19-2.36), and limb reduction anomalies (OR, 1.34; 95% CI, 1.03-1.73). The risk of gastroschisis among obese mothers was significantly reduced (OR, 0.17; 95% CI, 0.10-0.30). CONCLUSIONS: Maternal obesity is associated with an increased risk of a range of structural anomalies, although the absolute increase is likely to be small. Further studies are needed to confirm whether maternal overweight is also implicated.

Congenital CMV is a major cause of neurological and sensory impairment in children. Reliable estimates of the prevalence of permanent sequelae and mortality associated with congenital CMV are needed to guide development of education and prevention programmes and to gauge the financial costs associated with this disease. To calculate such estimates, this review used data solely from studies in which children with congenital CMV were identified through universal screening. Based on 15 studies with a total of 117 986 infants screened, the overall CMV birth prevalence estimate was 0.7%. The percentage of infected children with CMV-specific symptoms at birth was 12.7%. The percentage of symptomatic children with permanent sequelae was 40-58%. The percentage of children without symptoms at birth who developed permanent sequelae was estimated to be 13.5%. The true burden of congenital CMV infection is unclear because data on important outcomes, such as visual impairment, are lacking and follow-up of infected children has been too short to fully identify late-onset sequelae. Therefore, the estimates of permanent sequelae associated with congenital CMV presented here are likely underestimates. Future studies should extend follow-up of CMV-infected children identified through universal screening and include the evaluation of visual impairment.

The condition of congenital amusia, commonly known as tone-deafness, has been described for more than a century, but has received little empirical attention. In the present study, a research effort has been made to document in detail the behavioural manifestations of congenital amusia. A group of 11 adults, fitting stringent criteria of musical disabilities, were examined in a series of tests originally designed to assess the presence and specificity of musical disorders in brain-damaged patients. The results show that congenital amusia is related to severe deficiencies in processing pitch variations. The deficit extends to impairments in music memory and recognition as well as in singing and the ability to tap in time to music. Interestingly, the disorder appears specific to the musical domain. Congenital amusical individuals process and recognize speech, including speech prosody, common environmental sounds and human voices, as well as control subjects. Thus, the present study convincingly demonstrates the existence of congenital amusia as a new class of learning disabilities that affect musical abilities.

The Baltimore-Washington Infant Study is a regional epidemiologic study of congenital heart disease. Among Infants born in the study area in 1981 and 1982, 664 had a diagnosis of congenital heart disease confirmed in the first year of life by echocardiography, cardiac catheterization, cardiac surgery, or autopsy. The prevalence rate was 3.7/1,000 livebirths for all cases and 2.4/1,000 livebirths for cases confirmed by invasive methods only. Diagnosis-specific prevalence rates of congenital heart disease are compared with those of eight previous case series. Changing diagnostic categorizations in the time span covered and methodological differences resulted in great variation of the data. However, the data of the New England Infant Cardiac Program which used the same case discovery methods showed similar occurrences of major morphologic abnormalities, suggesting that these are stable basic estimates in the eastern United States. For all case series, the rate of confirmed congenital heart disease was approximately 4/1,000 livebirths over the 40-year time span.

We studied the incidence of primary and recurrent cytomegalovirus infection in 3712 pregnant women--2698 of middle to high income and 1014 of low income--to determine whether there were differences in the effects on the fetus. In the higher-income group, 1203 women (45 per cent) did not have antibodies to cytomegalovirus and were therefore susceptible to primary infection, as compared with 179 women (18 per cent) of low income. Congenital infection occurred more often (1.6 vs. 0.6 per cent) in infants in the low-income group. In this group it was associated with recurrent maternal infection more often (in 82 per cent) than with primary maternal infection, whereas in the upper-income group, it was associated with primary maternal infection in half the cases. Altogether, there were 32 cases of congenital cytomegalovirus infection - 16 in each group. Whereas primary maternal infection resulted in fetal infection in only half the cases, it was more likely to ge associated with clinically apparent disease than was recurrent infection. When these cases were combined with 28 cases of congenital infection retrospectively identified at other prenatal clinics, five of 33 infected infants born after primary maternal infection had clinically apparent disease, as compared with none of 27 born after recurrent maternal infection. We conclude that congenital cytomegalovirus infection resulting from primary maternal infection is more likely to be serious than that resulting from recurrent infection, and is more likely to occur in upper socioeconomic groups.

BACKGROUND: Intrauterine transmission of cytomegalovirus (CMV) can occur whether a mother has prior immunity or acquires CMV for the first time during pregnancy. The degree of protection afforded an infected infant by the presence of antibody in the mother before conception is uncertain. METHODS: We compared the outcomes of CMV-infected infants born to mothers who acquired primary CMV infection during pregnancy (primary-infection group) with those of CMV-infected infants born to mothers with immunity (recurrent-infection group). Screening for viruria identified 197 newborns with congenital CMV infection. Stored serum samples were used to categorize maternal infection as either primary or recurrent. We followed 125 infants from the primary-infection group and 64 from the recurrent-infection group. Serial medical, audiologic, psychometric, and eye examinations were used to identify sequelae of CMV infection. RESULTS: Only infants in the primary-infection group had symptomatic CMV infection at birth (18 percent). After a mean follow-up of 4.7 years, one or more sequelae were seen in 25 percent of the primary-infection group and in 8 percent of the recurrent-infection group. Thirteen percent of infants whose mothers had primary infection during pregnancy had mental impairment (IQ less than or equal to 70), as compared with none of those whose mothers had recurrent CMV infections. Sensorineural hearing loss was found in 15 percent of those in the primary-infection group and in only 5 percent of those in the recurrent-infection group. Bilateral hearing loss was identified only among children in the primary-infection group (8 percent). CONCLUSIONS: The presence of maternal antibody to CMV before conception provides substantial protection against damaging congenital CMV infection in the newborn. Primary maternal infection during pregnancy is associated with more severe sequelae of congenital CMV infection.

BACKGROUND: This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. METHODS AND RESULTS: Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with > 4-fold variation between countries. CONCLUSION: Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood.

The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.