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Background: There has been increasing use of hospital discharge data to identify congenital anomalies, with limited information about the accuracy of these data., Objectives: To evaluate the accuracy of hospital discharge data in ascertaining major congenital anomalies in infants., Methods: All liveborn infants with major congenital anomalies born between 2004 and 2009 in New South Wales, Australia were included. They were separated into two study groups: (a) infants identified from the Register of Congenital Conditions with a corresponding record in linked hospital discharge data; and (b) infants with a recorded congenital anomaly in hospital data, but without a register record. For the first group, we assessed agreement (concordant diagnoses) and the proportion of anomalies with discrepant diagnoses in each dataset. For the second group, we determined the number of anomalies recorded only in hospital data and applied specific conditions restricting to those recorded in the birth admission, excluding nonspecific diagnoses, or those with relevant surgical procedures to minimize potential false positives or over-reporting., Results: The first study group included 9,346 infants with an average 84% agreement in the ascertainment of major anomalies between hospital and registry data, and >93% agreement for cardiac, abdominal wall, and gastrointestinal anomalies. Discrepant diagnoses occurred on average in 20% of cases from hospital data and 17% from registry data, and were slightly reduced with the use of diagnoses recorded only in tertiary pediatric hospitals. The second group included 25,893 infants where anomalies were only recorded in hospital data, most commonly skin and unspecified anomalies. Excluding unspecified cases, those only diagnosed at the birth admission and restricting to surgical procedures reduced over-reporting by up to 96%., Conclusions: Hospital discharge data provide an acceptable means to ascertain congenital anomalies, but with variable accuracy for different anomalies. Application of specific conditions and limited to surgical procedures improves the utility of using hospital discharge data to ascertain congenital anomalies., (© 2021 Wiley Periodicals LLC.)

Neonatal "surgical" malformations are associated with higher costs than major "non-surgical" birth defects. We aimed to analyze the financial burden on the Austrian health system of five congenital malformations requiring timely postnatal surgery. The database of the Austrian National Public Health Institute for the period from 2002 to 2014 was reviewed. Diagnosis-related group (DRG) points assigned to hospital admissions containing five congenital malformations coded as principal diagnosis (esophageal atresia, duodenal atresia, congenital diaphragmatic hernia, gastroschisis, and omphalocele) were collected and compared to all hospitalizations for other reasons. Out of 3,518,625 total hospitalizations, there were 1664 admissions of patients with the selected malformations. The annual mean number was 128 (SD 17, range 110-175). The mean cost of the congenital malformations per hospital admission expressed in DRG points was 26,588 (range 0-465,772, SD 40,702) and was significantly higher compared to the other hospitalizations ( n = 3,516,961; mean DRG 2194, range 0-834,997; SD 6161; p < 0.05). Surgical conditions requiring timely postnatal surgery place a significant financial burden on the healthcare system. The creation of a dedicated national register could allow for better planning of resource allocation, for improving the outcome of affected children, and for optimizing costs.

Background: The preconception phase of women's life cycle is critical but comparatively ignored. The presence of health risks is judged as hazardous to the wellbeing of women and their offspring. This study aimed to estimate the prevalence of various pregnancy outcomes and assess the association between certain risk factors and adverse outcomes., Methods: As a part of a preconception care intervention project, a baseline survey was conducted in four blocks of Nashik District, India. In this population-based cross-sectional analytical study, we compared cases in the study group (randomly selected one tribal and one non-tribal block) with those of the control group (one tribal and one non-tribal block). A comparison was also made between the tribal and non-tribal blocks in each group. All women who had a pregnancy outcome in the preceding 12 months (01 April 2017 to 31 March 2018) were interviewed. Trained Accredited Social Health Activists conducted the survey under the direct supervision of Auxiliary Nurse Midwives and Medical Officers. Multivariate analysis was carried out to find the adjusted prevalence ratio of having a particular adverse outcome because of the prespecified potential risk factors., Results: A total of 9307 women participated in the study. The prevalence of adverse pregnancy outcomes was as follows: abortion in 4.1%, stillbirth in 1.7%, preterm birth in 4.1%, low birth weight in 13.2%, and congenital physical defect in 2.8%. Prevalence of parental consanguinity, pre-existing maternal illness at conception, heavy work during the last six months of pregnancy, tobacco consumption, alcohol consumption, direct exposure to pesticides and domestic violence during pregnancy was 18.5, 2.2, 18.7, 5.6, 0.5, 2.3, and 0.8% respectively. Risk factors associated with abortion included pre-existing illness and heavy work in the last six months of the pregnancy. Consanguinity, tobacco consumption during pregnancy and pre-existing illness were identified as risk factors for stillbirth. Significant risk factors of low birth weight were heavy work in the last six months of pregnancy, pre-existing illness and residence in a tribal area., Conclusion: There is a need to emphasize on maternal behaviour, including tobacco consumption, and heavy work during pregnancy, as well as on parental consanguinity and pre-existing maternal illnesses, in order to achieve the best possible pregnancy outcomes., (© 2021. The Author(s).)

Objective: To evaluate the distribution of cases of congenital anomalies in the state of Santa Catarina by health macro-region, to determine the frequency according to maternal and neonatal variables, to estimate the related mortality, and the trends in the period 2010-2018., Methods: An ecological time-series study with secondary data on congenital anomalies and the sociodemographic and health variables of mothers and newborns living in Santa Catarina, from 2010 to 2018. For temporal trend analysis, generalized linear regression was performed using the Prais-Winsten method with robust variance., Results: The average prevalence of congenital anomalies in the period was 8.9 cases per 1,000 live births, being 9.4 cases by 1,000 live births in 2010 and, in 2018, 8.2/1,000. The trend remained stable in the analyzed period. The major malformations were musculoskeletal, hip, and foot malformations, with a proportion ≥30%. There was a higher prevalence of congenital anomalies in low birthweight, preterm, male livebirths with Apgar≤7, born by cesarean section, mothers of older age (≥40 years), and less educated (less than eight years of study). Infant mortality due to congenital malformations was 2.6 deaths/1,000 live births, representing about 25.8% of the total infant deaths in the period., Conclusions: The frequency of congenital anomalies and the mortality with anomalies was stable in the studied period in Santa Catarina. The presence of anomalies was associated with low birth weight, prematurity, and low Apgar score. The highest proportion of congenital anomalies was in the musculoskeletal system.

Background: Fine particulate matter (PM 2.5 ) can easily penetrate blood vessels and tissues through the human respiratory tract and cause various health problems. Some studies reported that particular matter (PM) exposure during pregnancy is associated with low birth weight or congenital cardiovascular anomalies. This study aimed to investigate the correlation between the degree of exposure to PM ≤ 2.5 μm (PM 2.5 ) during pregnancy and congenital anomalies relevant to the field of pediatric surgery., Methods: Mother-infant dyads with registered addresses in the Metropolitan City were selected during 3 years. The electronic medical records of mothers and neonates were retrospectively analyzed, with a focus on maternal age at delivery, date of delivery, gestation week, presence of diabetes mellitus (DM) or hypertension, parity, the residence of the mother and infant, infant sex, birth weight, Apgar score, and presence of congenital anomaly. The monthly PM 2.5 concentration from the first month of pregnancy to the delivery was computed based on the mothers' residences., Results: PM 2.5 exposure concentration in the second trimester was higher in the congenital anomaly group than in the non-congenital anomaly group (24.82 ± 4.78 µg/m 3 , P = 0.023). PM 2.5 exposure concentration did not affect the incidence of nervous, cardiovascular, and gastrointestinal anomalies. While statistically insignificant, the groups with nervous, cardiovascular, gastrointestinal, musculoskeletal, and other congenital anomalies were exposed to higher PM 2.5 concentrations in the first trimester compared with their respective counterparts. The effect of PM 2.5 concentration on the incidence of congenital anomalies was significant even after adjusting for the mother's age, presence of DM, hypertension, and parity. The incidence of congenital anomalies increased by 26.0% (95% confidence interval of 4.3% and 49.2%) per 7.23 µg/m 3 elevation of PM 2.5 interquartile range in the second trimester., Conclusions: The congenital anomaly group was exposed to a higher PM 2.5 concentration in the second trimester than the non-congenital anomaly group. The PM 2.5 exposure concentration level in the first trimester tended to be higher in groups with anomalies than those without anomalies. This suggests that continuous exposure to a high PM 2.5 concentration during pregnancy influences the incidence of neonatal anomalies in surgical respects., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Study Objective: Müllerian (paramesonephric) duct anomalies (MDAs) are associated with several coexisting congenital abnormalities, including renal abnormalities. Although congenital renal abnormalities may remain asymptomatic, the consequences should not be underestimated. In both the literature and clinical practice, it remains necessary to improve awareness of the co-occurrence of different congenital renal abnormalities in women with MDAs. To gain further insight into this co-occurrence and to estimate whether guidelines for women with MDAs should be optimized, this study was performed., Design: A descriptive retrospective analysis., Setting: University Medical Centre Utrecht in the Netherlands., Participants: Women with MDAs diagnosed or treated between 1980 and 2015., Interventions: None., Main Outcome Measures: The prevalence of the co-occurrence of congenital renal abnormalities in women with MDAs., Results: Renal status was recorded in 186 of 255 women (72.9%), and the other women (27.1%) did not have a retrievable renal status. Congenital renal abnormalities were present in 90 of 186 women (48.4%) and were observed most frequently in women having a duplex uterus with obstructed hemivagina. The most common renal abnormality was unilateral renal agenesis, which was observed in 58 of 90 women (64.4%)., Conclusions: MDAs are highly associated with different congenital renal abnormalities, and these results emphasize that women with MDAs should be routinely screened for their co-occurrence. However, these results also highlight that there remains a lack of awareness of this association. Whether all women with congenital renal abnormalities should be routinely screened for MDAs requires further investigation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Our objective was to evaluate the associations with interstitial cystitis during pregnancy using a United States inpatient database., Materials and Methods: We conducted a retrospective cohort study utilizing the Nationwide Inpatient Sample database from the Healthcare Cost and Utilization Project. ICD-9 code number 595.1 was used to extract cases of chronic interstitial cystitis and these pregnancies were compared to pregnancies without chronic interstitial cystitis, using the Chi-squared test to evaluate nominal variables. A multivariate logistic regression model was subsequently used to adjust for statistically significant confounders (p value <0.05)., Results: There were 9,095,995 deliveries during the study period; 793 pregnant women were found to have chronic interstitial cystitis. When controlling for confounding effects in terms of pregnancy outcomes, the diagnosed group had a greater risk of developing pregnancy-induced hypertension (adjusted OR 1.57, 95% CI 1.21-2.05), preeclampsia (adjusted OR 2.06, 95% CI 1.47-2.87), preterm delivery (adjusted OR 1.63, 95% CI 1.23-2.17), preterm premature rupture of membranes (adjusted OR 2.18, 95% CI 1.25-3.79), chorioamnionitis (adjusted OR 2.05, 95% CI 1.24-3.37), delivery via cesarean section (adjusted OR 1.57, 95% CI 1.32-1.88), maternal infection (adjusted OR 2.19, 95% CI 1.40-3.43), and deep venous thromboembolism (adjusted OR 10.56, 95% CI 3.37-33.09)., Conclusions: Interstitial cystitis diagnosis is associated with an increased risk of preeclampsia, preterm birth, and other adverse pregnancy outcomes in this database study. Prospective studies are required to confirm the findings of the correlation between interstitial cystitis and adverse pregnancy outcomes.

Objective: The study aimed to evaluate the association between hemoglobin A1c values and likelihood of fetal anomalies in women with pregestational diabetes., Study Design: Women with pregestational diabetes who delivered at a single institution that serves a nonreferred population from May 1, 2009 to December 31, 2018 were ascertained. Hemoglobin A1c values were obtained at the first prenatal visit. Women who delivered a singleton live- or stillborn infant with a major malformation as defined by European Surveillance of Congenital Anomalies criteria were identified. In infants with multiple system anomalies, each malformation was considered separately. Hemoglobin A1c values were analyzed categorically by using Mantel-Haenszel method and continuously with linear regression for trend for fetal anomalies., Results: A total of 1,676 deliveries to women with pregestational diabetes were delivered at our institution, and hemoglobin A1c was assessed in 1,573 deliveries (94%). There were 129 deliveries of an infant with at least one major malformation, an overall anomaly rate of approximately 8%. Mean hemoglobin A1c concentration was significantly higher in pregnancies with anomalous infants, 9.3 ± 2.1% versus 8.0 ± 2.1%, and p <0.001. There was no difference in gestational age at the time hemoglobin A1c was obtained, 13 ± 8.3 versus 14 ± 8.7 weeks. Hemoglobin A1c was associated with increased probability of a congenital malformation. This reached 10% with a hemoglobin A1c concentration of 10%, and 20% with a hemoglobin A1c of 13%. Similar trends were seen when examining risk of anomalies by organ system with increasing hemoglobin A1c levels, with the greatest increase in probability for both cardiac and genitourinary anomalies., Conclusion: In women with pregestational diabetes, hemoglobin A1c is strongly associated with fetal anomaly risk. Data from a contemporary cohort may facilitate counseling and also highlight the need for preconceptual care and glycemic optimization prior to entry to obstetric care., Key Points: · Infants of diabetic mothers had an 8% major anomaly rate.. · HbA1c of 10% in pregnancy associated with 10% anomaly rate.. · HbA1c of 13% in pregnancy associated with 20% anomaly rate.. · Preconceptual care is important to reduce prevalence.., Competing Interests: None declared., (Thieme. All rights reserved.)

The aim of present study was to assess the karyotypes of amniotic fluid cells and find the frequency of chromosomal abnormalities and their significance in clinical setting. A total of 15,401 pregnant women were assessed from March 2016 to May 2019, and 14,968 amniotic fluid samples were successfully cultured. These fetuses were grouped according to different indications including advanced maternal age, abnormal nuchal translucency (NT) values, positive first/second trimester screening results, high risk NIPT results, very low PAPP-A and free β-hCG multiples of the normal median (MoM) results, abnormal ultrasound findings or previous history of chromosomal abnormalities. Results indicated the presence of normal karyotype in 90.2% (13,497/14,968) of fetuses. Totally, 46.4% (6945/14,968) of fetuses were 46,XX and 43.8% (6552/14,968) had 46,XY chromosome pattern. A total of 1077 abnormal karyotypes were found among 14,968 fetuses, thus the rate of abnormal fetuses was calculated to be 7.2% (1072/14,968). Meanwhile, a total of 394 cases (2.8%) had a normal polymorphism in their karyotype. In other words, abnormal karyotypes were detected in one of 13.9 cases of patients underwent amniocentesis. Down syndrome, Edward's syndrome, abnormal mosaicisms and Patau's syndrome were detected in 4.4% (659/14,968), 0.57% (85/14,968), 0.49% (74/14,968) and 0.24% (36/14,968) of cases, respectively. Sex chromosomal abnormalities including Klinefelter syndrome, Turner syndrome and 47,XXX karyotype were detected in 64 cases (0.43%). In this article, the rates of chromosomal abnormalities are compared between different groups of patients based on the advanced maternal age, abnormal NT values, very low PAPP-A and free β-hCG MoMs results, and positive FTS results. The current investigation provides insight into the most appropriate indications for amniocentesis in Iran., (© 2021. The Author(s).)

Background: Diabetes Mellitus (DM) is a major cause of maternal, fetal, and neonatal morbidities. Our objective was to estimate the effect of both pre-pregnancy and gestational DM on the growth parameters of newborns in the Qatari population., Methods: In this population-based cohort study, we compared the data of neonates born to Qatari women with both pre-pregnancy and gestational diabetes mellitus in 2017 with neonates of healthy non-diabetic Qatari women., Results: Out of a total of 17020 live births in 2017, 5195 newborns were born to Qatari women. Of these, 1260 were born to women with GDM, 152 were born to women with pre-pregnancy DM and 3783 neonates were born to healthy non-diabetic (control) women. The prevalence of GDM in the Qatari population in 2017 was 24.25%. HbA1C% before delivery was significantly higher in women with pre-pregnancy DM (mean 6.19 ± 1.15) compared to those with GDM (mean 5.28 ± 0.43) (P <0.0001). The mean birth weight in grams was 3066.01 ± 603.42 in the control group compared to 3156.73 ± 577.88 in infants born to women with GDM and 3048.78 ± 677.98 in infants born to women with pre-pregnancy DM (P <0.0001). There was no statistically significant difference regarding the mean length (P= 0.080), head circumference (P= 0.514), and rate of major congenital malformations (P= 0.211). Macrosomia (Birth weight > 4000 gm) was observed in 2.7% of the control group compared to 4.8% in infants born to women with GDM, and 4.6% in infants born to women with pre-pregnancy DM (P= 0.001). Multivariate logistic regression analysis demonstrated that higher maternal age (adjusted OR 2.21, 95% CI 1.93, 2.52, P<0.0001), obesity before pregnancy (adjusted OR 1.71, 95% CI 1.30, 2.23, P<0.0001), type of delivery C-section (adjusted OR 1.25, 95% CI 1.09, 1.44, P=0.002), and body weight to gestational age LGA (adjusted OR 2.30, 95% CI 1.64, 2.34, P<0.0001) were significantly associated with increased risk of GDM., Conclusion: Despite the multi-disciplinary antenatal diabetic care management, there is still an increased birth weight and an increased prevalence of macrosomia among the infants of diabetic mothers. More efforts should be addressed to improve the known modifiable factors such as women's adherence to the diabetic control program. Furthermore, pre-pregnancy BMI was found to be significantly associated with gestational DM, and this is a factor that can be addressed during pre-conceptional counseling., (© 2021. The Author(s).)

Objective: To describe infants aged <12 months reported with microcephaly to the Australian Paediatric Surveillance Unit (APSU) following emergence of Zika virus infection internationally., Design, Setting and Patients: National, active, monthly surveillance for microcephaly using the APSU. Microcephaly was defined as occipitofrontal circumference (OFC) of more than 2 SDs below the mean for age, gender and gestation., Main Outcome Measures: Clinical spectrum, aetiology and birth prevalence of microcephaly reported by paediatricians., Results: Between June 2016 and July 2018, 106 notifications were received, with clinical details provided for 96 (91%). After excluding ineligible notifications, 70 cases were confirmed, giving an annual birth prevalence of 1.12 (95% CI 0.88 to 1.42) per 10 000 live births. Of the total number of cases, 47 (67%) had primary microcephaly (at birth); and 25 (36%) had severe microcephaly (OFC >3 SDs). Birth defects were reported in 42 (60%). Of 49 infants with developmental assessment details available, 25 (51%) had failed to reach all milestones. Vision impairment was reported in 14 (26%). The cause of microcephaly was unknown in 60%: 13 (19%) had been diagnosed with genetic disorders; 22 (39%) had anomalies on neuroimaging. No congenital or probable Zika infection was identified. Severe microcephaly was more often associated with hearing impairment than microcephaly of >2 SDs but ≤3 SDs below the mean (p<0.007). Indigenous children and children with socioeconomic advantage were over-represented among children with microcephaly., Conclusion: Novel national data on microcephaly highlight the high proportion of idiopathic cases. This has implications for prevention and management and suggests the need for a standardised diagnostic approach and ongoing surveillance mechanism in Australia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Respiratory diseases are common in children with esophageal atresia (EA), leading to increased morbidity and mortality in the first year. The primary study objective was to identify the factors associated with readmissions for respiratory causes in the first year in EA children., Methods: A population-based study. We included all children born between 2008 and 2016 with available data and analyzed factors at birth and 1 year follow-up. Factors with a P value <.10 in univariate analyses were retained in logistic regression models., Results: Among 1460 patients born with EA, 97 (7%) were deceased before the age of 1 year, and follow-up data were available for 1287 patients, who constituted our study population. EAs were Ladd classification type III or IV in 89%, preterm birth was observed in 38%, and associated malformations were observed in 52%. Collectively, 61% were readmitted after initial discharge in the first year, 31% for a respiratory cause. Among these, respiratory infections occurred in 64%, and 35% received a respiratory treatment. In logistic regression models, factors associated with readmission for a respiratory cause were recurrence of tracheoesophageal fistula, aortopexy, antireflux surgery, and tube feeding; factors associated with respiratory treatment were male sex and laryngeal cleft., Conclusions: Respiratory morbidity in the first year after EA repair is frequent, accounting for >50% of readmissions. Identifying high risk groups of EA patients (ie, those with chronic aspiration, anomalies of the respiratory tract, and need for tube feeding) may guide follow-up strategies., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

The sternal foramen, usually an asymptomatic osteological defect, can lead to catastrophic consequences if not recognized prior to certain medical procedures. This study reports the prevalence of a sternal foramen in two South Amerindian populations compared with other published populations. We evaluated the presence of sternal foramina using thoracic computed tomography scans of 1334 (48% female) participants from two indigenous populations of Bolivia (n = 900 Tsimane, 434 Moseten). The prevalence of sternal foramina was compared to two U.S. populations of similar sex/age distribution (n = 572 Midwest Americans, 131 self-identified Native North Americans) via similar CT scans. A sternal foramen was significantly more common in the two Bolivian populations (prevalence ranging from 12.8 to 13.4%), compared to 4.4-5.1% in the two U.S. groups, consistent with prior estimates in studies from industrialized populations. Males had higher frequency of a sternal foramen compared to females in each of the four groups (OR = 1.904, 95% CI: 1.418-2.568, p < 0.001). Age was not associated with sternal foramen presence. These data show both a higher rate of sternal foramina in the South Amerindian populations versus comparator populations in North America and the highest rate of any studied living population. Although it is not possible to determine from our data the relative contribution of genetics versus early life or environmental causes to the higher rates of sternal foramen, we note that small prior studies have likewise demonstrated a higher prevalence in lower income countries. Further determination of the contributing factors warrants greater investigation and research., (© 2021. Japanese Association of Anatomists.)

The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) is one of the largest case-control data sets of CA-surveillance in the world. We unified all data collected in the HCCSCA between 1980 and 2009 into a new, validated single database that is now open for examination. The details of this unified database are given in this paper. The total number of cases and control newborns is 32,345 and 57,231, respectively. The overall prevalence of CAs recorded in the HCCSCA was 10.7/1000 live-births. Data available for each pregnancy are: CA(s), gender, birth year/month/date, birth weight, gestational age, area of mother's living, maternal age, paternal age, birth order, mother's and father's qualification, employment status and type of employment, mother's marital status, outcome of previous pregnancies, maternal diseases during pregnancy (according to pregnancy months), drug intake during pregnancy (according to pregnancy months), folic acid and/or pregnancy vitamin supplement intake (according to pregnancy months), mother's smoking habits and alcohol consumption patterns. The most frequent anomalies detected were ventricular septal defect (2864), atrial septal defect (1895), polydactyly (1499), hypospadias (1083), and unilateral cleft lip ± palate (961). According to ICD-10, 701 diseases have been found to affect case mothers during pregnancy. Eight hundred and sixteen drugs were identified that had been taken by mothers during pregnancy. The authors are absolutely open for any scientific cooperation based on this database.

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed., Competing Interests: The authors have declared that no competing interests exist.

Background: The worldwide incidence of congenital anomalies (CAs) is estimated at 3-7%, but actual numbers vary widely among countries. Birth defects are the most common causes of infantile mortality, accounting for ~25% of all neonatal deaths., Aims: To determine the prevalence of congenital anomalies in neonates in Fayoum Governorate; to classify malformations; and to clarify the association between congenital anomalies and possible risk factors., Methods: A cross-sectional study was conducted on 1000 infants in the neonatal intensive care unit and outpatient clinics of Fayoum University Hospital and Fayoum General Hospital during August 2017 to April 2018. Detailed history, clinical examination and relevant investigations were performed., Results: The prevalence of CAs was 7.4%. Major malformations accounted for 78.4% and minor malformations 21.6%. The most common CAs involved the cardiovascular system (32.4%), followed by musculoskeletal anomalies (18.9%), chromosomal anomalies (10.8%), anomalies of the central nervous system (9.5%), gastrointestinal tract (6.8%), genital system (5.4%), eyes, head and neck (5.4%), respiratory system (4.1%), multisystems (2 or more) (4.1%), and renal and urinary systems (2.7%). 82.4% of cases were from rural areas, 62.1% were male, 36.5% were female and 1.4% were ambiguous. 85.1% of neonates with malformations were full term., Conclusion: Cardiovascular, musculoskeletal and chromosomal anomalies were the most common CAs in our study. Positive consanguinity, poor attendance at antenatal clinics, rural residence and multiparty were the most common risk factors associated with CAs., (Copyright © World Health Organization (WHO) 2021. Open Access. Some rights reserved. This work is available under the CC BY-NC-SA 3.0 IGO license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo).)

Congenital disorders (CDs), defined as abnormalities in structure or function present at birth, are an important contributor to the disease burden in developing countries. The size and extent of the problem in South Africa (SA) are unknown due to the lack of recent, reliable, observed data on CDs. To address this empirical data gap, this study aimed to measure the birth prevalence of congenital anomalies (a sub-set of CDs) and to describe the pattern of these anomalies at a regional hospital in KwaZulu Natal (KZN), SA. A retrospective, observational, descriptive review of congenital anomalies diagnosed within the neonatal service at Edendale Hospital (EDH), KZN was undertaken between January and December 2018. All EDH in-house live births diagnosed and notified with congenital anomalies by discharge were included. Stillbirths, other pregnancy losses and out-born neonates were excluded. Data were actively collected from the birth register, neonatal admission register, and the individual paper-based surveillance tool developed by the National Department of Health. The in-facility birth prevalence rate for congenital anomalies was 15.57 per 1 000 live births. The most observed system was musculoskeletal (32%) followed by circulatory system anomalies (19%). When the observed birth prevalence rates of key congenital anomalies were compared with previously published, modelled South African data, no significant difference was found. This study responds to the paucity of birth prevalence data on CDs overall and offers evidence that obvious, structural CDs (congenital anomalies) need to be addressed in the SA public health system., Competing Interests: Muhammad Zubayr Saib declares no conflict of interest. Barnesh L Dhada declares no conflict of interest. Colleen Aldous declares no conflict of interest. Helen L Malherbe was the Honorary Chair of Genetic Alliance South Africa (NPO: 001-029) until March 2020 and was appointed as a (Honorary) Director of Rare Diseases South Africa in April 2020 The authors declare that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Higher parental age at childbearing has generated much attention as a potential risk factor for birth disorders; however, previous research findings are mixed. Existing studies have exploited variation in parental age across families, which is problematic because families differ not only in parental age but also in genetic and environmental factors. To isolate the effects of parental age, holding many genetic and environmental factors constant, we exploit the variation in parental age within families and compare outcomes for full siblings. The study data were retrieved from the Medical Birth Registry of Norway, which covers the entire population of births in Norway over an extended period (totaling 1.2 million births). Using variation in parental age when siblings were born, we find large and convex effects of increased parental age on the increased risk of birth disorders. To facilitate comparison with the existing literature, we also estimate the effects of parental age using variation in parental age across families and find that the effects are substantially weaker. We conclude that the existing literature may have underestimated the negative effects of parental aging on adverse offspring outcomes., (© 2021. The Author(s).)

Human health effects of airborne lower-chlorinated polychlorinated biphenyls (LC-PCBs) are largely unexplored. Since PCBs may cross the placenta, maternal exposure could potentially have negative consequences for fetal development. We aimed to determine if exposure to airborne PCB during pregnancy was associated with adverse birth outcomes. In this cohort study, exposed women had lived in PCB contaminated apartments at least one year during the 3.6 years before conception or the entire first trimester of pregnancy. The women and their children were followed for birth outcomes in Danish health registers. Logistic regression was performed to estimate odds ratios (OR) for changes in secondary sex ratio, preterm birth, major congenital malformations, cryptorchidism, and being born small for gestational age. We performed linear regression to estimate difference in birth weight among children of exposed and unexposed mothers. All models were adjusted for maternal age, educational level, ethnicity, and calendar time. We identified 885 exposed pregnancies and 3327 unexposed pregnancies. Relative to unexposed women, exposed women had OR 0.97 (95% CI 0.82, 1.15) for secondary sex ratio, OR 1.13 (95% CI 0.76, 1.67) for preterm birth, OR 1.28 (95% CI 0.81, 2.01) for having a child with major malformations, OR 1.73 (95% CI 1.01, 2.95) for cryptorchidism and OR 1.23 (95% CI 0.88, 1.72) for giving birth to a child born small for gestational age. The difference in birth weight for children of exposed compared to unexposed women was - 32 g (95% CI-79, 14). We observed an increased risk of cryptorchidism among boys after maternal airborne LC-PCB exposure, but due to the proxy measure of exposure, inability to perform dose-response analyses, and the lack of comparable literature, larger cohort studies with direct measures of exposure are needed to investigate the safety of airborne LC-PCB exposure during pregnancy., (© 2021. The Author(s).)

Background: The association between fetal exposure to alcohol and congenital structural disorders remains inconclusive. The present study searched for relationships between maternal alcohol consumption during pregnancy and the risk of congenital malformations., Methods: We evaluated the fixed dataset of a large national birth cohort study including 73,595 mothers with a singleton live birth. Information regarding the alcohol consumption of mothers was obtained from self-reported questionnaires. Physicians assessed for 6 major congenital malformations (congenital heart defects [CHDs], male genital abnormalities, limb defects, cleft lip and/or cleft palate [orofacial clefts (OFC)], severe brain abnormalities, and gastrointestinal obstructions) up to 1 month after birth. Multiple logistic regression analysis was performed to identify associations between maternal alcohol consumption during pregnancy and each malformation., Results: The prevalence of maternal drinking in early pregnancy and until the second/third trimester was 46.6% and 2.8%, respectively. The onset of CHD was inversely associated with mothers who quit drinking during early pregnancy (OR 0.85, 95% CI 0.74-0.98). There was no remarkable impact of maternal drinking habit status on the other congenital malformations after adjustment for covariates., Conclusions: Maternal alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital malformations of interest., Impact: This large-scale Japanese cohort study revealed that no teratogenic associations were found between maternal retrospective reports of periconceptional alcohol consumption and congenital malformations after adjustment for covariates. This is the first nationwide birth cohort study in Japan to assess the effect of maternal alcohol consumption during pregnancy on major congenital malformations. Our finding indicated that maternal low-to-moderate alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital heart defects, male genital abnormalities, limb defects, orofacial clefts, severe brain abnormalities, or gastrointestinal obstructions., (© 2020. The Author(s).)

Background: The prevalence of congenital anomalies in newborns in South Korea was 272.9 per 100,000 in 2005, and 314.7 per 100,000 in 2006. In other studies, the prevalence of congenital anomalies in South Korea was equivalent to 286.9 per 10,000 livebirths in 2006, while it was estimated 446.3 per 10,000 births during the period from 2008 to 2014. Several systematic reviews and meta-analyses analyzing the factors contributing to congenital anomalies have been reported, but comprehensive umbrella reviews are lacking., Methods: We searched PubMed, Google Scholar, Cochrane, and EMBASE databases up to July 1, 2019, for systematic reviews and meta-analyses that investigated the effects of environmental and genetic factors on any type of congenital anomalies. We categorized 8 subgroups of congenital anomalies classified according to the 10th revision of the International Statistical Classification of Diseases (ICD-10). Two researchers independently searched the literature, retrieved the data, and evaluated the quality of each study., Results: We reviewed 66 systematic reviews and meta-analyses that investigated the association between non-genetic or genetic risk factors and congenital anomalies. Overall, 269 associations and 128 associations were considered for environmental and genetic risk factors, respectively. Congenital anomalies based on congenital heart diseases, cleft lip and palate, and others were associated with environmental risk factors based on maternal exposure to environmental exposures (air pollution, toxic chemicals), parental smoking, maternal history (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, and gestational diabetes mellitus), maternal obesity, maternal drug intake, pregnancy through artificial reproductive technologies, and socioeconomic factors. The association of maternal alcohol or coffee consumption with congenital anomalies was not significant, and maternal folic acid supplementation had a preventive effect on congenital heart defects. Genes or genetic loci associated with congenital anomalies included MTHFR , MTRR and MTR , GATA4 , NKX2-5 , SRD5A2 , CFTR , and 1p22 and 20q12 anomalies., Conclusion: This study provides a wide perspective on the distribution of environmental and genetic risk factors of congenital anomalies, thus suggesting future studies and providing health policy implications., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

The objective of this study was to determine whether maternal or paternal ages have any impact on the prenatal incidence of genomic copy number variants (CNV) in fetuses with structural anomalies. We conducted a non-paired case-control study (1:2 ratio) among pregnancies undergoing chromosomal microarray analysis (CMA) because of fetal ultrasound anomalies, from December 2012 to May 2020. Pregnancies with any pathogenic copy number variant (CNV), either microdeletion or microduplication, were defined as cases. Controls were selected as the next two pregnancies with the same indication for CMA but with a normal result. Logistic regression was used, adjusting by use of assisted reproductive technology (ART) and parental smoking. Stratified analysis was performed according to CNV type (de novo/inherited and recurrent/non-recurrent). The study included 189 pregnancies: 63 cases and 126 controls. Mean maternal age in cases was 33.1 (SD 4.6) years and 33.9 (SD 6.0) years in controls. Mean paternal mean age was 34.5 (SD 4.8) years in cases and 35.8 (SD 5.8) years in controls. No significant differences in maternal or paternal age were observed, neither in stratified analysis according to the CNV type. Moreover, the proportion of cases were not significantly different between non-advanced and advanced ages, either considering paternal or maternal ages. The presence of pathogenic CNV at CMA in fetuses with structural anomalies was not found to be associated with advanced paternal or maternal age., Competing Interests: The authors have declared that no competing interests exist.

Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003-2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10 -43 , 2.66 × 10 -15 ). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.

Non-invasive prenatal testing (NIPT) is often erroneously received as a diagnostic procedure due to its high discriminatory power in the field of fetal trisomy 21 diagnosis (wording: "NIPT replaces amniocentesis"). Already a look at the methodology of NIPT (statistical gene dose comparison of a primarily maternofetal DNA mixture information at selected sites of the genome) easily reveals that NIPT cannot match the gold standard offered by cytogenetic and molecular genetic analysis procedures from the matrix of the entire human genome (origin: vital fetal cells), neither in diagnostic breadth nor in diagnostic depth. In fact, NIPT in fetal medicine in its current stage of development is a selective genetic search procedure, which can be applied in primary (without indication) or secondary (indication-related) screening. Thus, NIPT competes with established search procedures for this field. Here, the combined nuchal translucency (NT) test according to Nicolaides has become the worldwide standard since 2000. The strength of this procedure is its broad predictive power: NT addresses not only the area of genetics, but also the statistically 10 times more frequent structural fetal defects. Thus, NIPT and NT have large overlaps with each other in the field of classical cytogenetics, with slightly different weighting in the fine consideration. However, NIPT without a systematic accompanying ultrasound examination would mean a step back to the prenatal care level of the 1980s. In this respect, additional fine ultrasound should always be required in the professional application of NIPT. NIPT can thus complement NT in wide areas, but not completely replace it., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: Microtia is a congenital auricular malformation, often part of a syndromic form (35%-55% of cases). The accurate prevalence of associated malformations remains to be determined with regard to the heterogeneous results of the previous studies. This study aims to describe in a large population cohort the abnormalities associated with microtia and to determine the most suitable assessment for these children., Methods: This is a retrospective and observational cohort study collecting data from the medical records of children affected by microtia, diagnosed or followed-up between 2007 and 2017. Data were collected via a computer database. Clinical data, as well as imaging or genetic results, were noted., Results: Six hundred ninety four children were included, 587 (84.6%) with unilateral and 107 (15.4%) with bilateral microtia. Inner ear malformations were observed in 14.1% of the ears. The main associated anomalies were hemifacial microsomia (29%), velopharyngeal insufficiency (9%), ophthalmologic (6.2%), vertebral (5.9%), cardiac (5.5%) and kidney (3%) abnormalities. Main identified entities were Goldenhar, Treacher-Collins and Guion-Almeida syndromes., Conclusion: A comprehensive clinical assessment must be completed when microtia is diagnosed. Besides screening well-known oculo-auriculo-vertebral spectrum malformations, velopharyngeal insufficiency should be systematically sought. Specialized care must be provided to the very frequently associated hemifacial macrosomia. Mild forms of this last malformation may correspond to Guion-Almeida syndrome, especially in cases of learning disability., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Our study aimed to determine if congenital anomalies are associated with breech presentation at delivery. We conducted a nationwide, retrospective population-based record linkage study and analyzed all singleton births in Finland from 1996 to 2016 using the mandatory health register data collected by the Finnish Institute for Health and Welfare. We compared all major congenital anomalies detected during pregnancy, birth, or the first year of life according to the fetus's presentation at the time of delivery using X 2 -square statistic and Student's t test. We adjusted the results for known risk factors for congenital anomalies to estimate adjusted odds ratios and 95% confidence intervals. Fetuses in breech presentation at delivery had an increased risk for congenital anomalies (6.5%) compared with fetuses in cephalic presentation (3.6%), P < .001. Breech presentation was associated with nearly all types of examined congenital anomalies. The strongest associations were observed with congenital deformities of the hip, the central nervous system, the respiratory system, and the musculoskeletal system. Our study supports the theory that breech presentation is, in many cases, a symptom of a fundamental problem in fetal morphogenesis or function. Neonates born in the breech presentation have a higher risk of congenital anomalies and should undergo a postnatal screening., (© 2021 The Authors. Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

Background: Müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome, occurs in 1 in 4500 to 5000 individuals assigned female sex at birth. Pelvic floor symptoms among individuals with Mayer-Rokitansky-Küster-Hauser syndrome have not been well studied, and it is unknown how vaginal lengthening treatments affect these symptoms., Objective: This study aimed to assess urinary, prolapse, and bowel symptoms in individuals with Mayer-Rokitansky-Küster-Hauser syndrome and to determine whether symptoms vary by vaginal lengthening treatment., Study Design: We conducted a cross-sectional study in 2019 using an online survey distributed by the Beautiful You MRKH Foundation via social media to individuals with Mayer-Rokitansky-Küster-Hauser syndrome. Demographics, age at and timing of diagnosis, information about vaginal lengthening treatment, urinary symptoms (Michigan Incontinence Symptom Index), prolapse symptoms (Pelvic Organ Prolapse Distress Inventory short-form version), and bowel symptoms (Bristol Stool Form Scale) were obtained. The inclusion criteria included self-reported diagnosis of müllerian agenesis and female sex. Respondents with a history of renal transplant or dialysis, completion of <85% of the survey, and non-English survey responses were excluded. Descriptive analyses were used to describe the sample population. Logistic regression, Kruskal-Wallis, and Fisher exact tests were used to compare the prevalence of pelvic floor symptoms and vaginal lengthening treatments. Associations between age and genitourinary symptoms were investigated with Spearman correlations., Results: Of 808 respondents, 615 met the inclusion criteria, representing 40 countries. 81% of respondents identified as white. The median age of the participants was 29 years (interquartile range, 24-36), with a median age at diagnosis of 16 years (interquartile range, 15-17). Among the 614 respondents, 331 (54%) had vaginal lengthening treatment, 130 of whom (39%) had undergone surgical vaginal lengthening. Of individuals with Mayer-Rokitansky-Küster-Hauser syndrome, 428 of 614 (70%) reported having had one or more urinary symptoms, and 339 of 428 (79%) reported being bothered by these symptoms. Urinary symptoms included urinary incontinence (210 of 614 [34%]), urinary frequency (245 of 614 [40%]), urinary urgency (248 of 614 [40%]), pain with urination (97 of 614 [16%]), and recurrent urinary tract infections (177 of 614 [29%]). Prolapse symptoms included lower abdominal pressure (248 of 612 [41%]), pelvic heaviness or dullness (177 of 610 [29%]), and vaginal bulge (68 of 609 [11%]). In addition, constipation was reported by 153 of 611 respondents (25%), and anal incontinence was reported by 153 of 608 (25%) respondents. Beside recent urinary incontinence (P=.003) and anal incontinence (P<.001), the prevalence of pelvic floor symptoms (P>.05) did not differ significantly between those with and without vaginal lengthening. Among those with surgical vaginal lengthening, symptomatic vaginal bulge was highest in individuals who underwent a bowel vaginoplasty procedure., Conclusion: Urinary, prolapse, and bowel symptoms are common among individuals with Mayer-Rokitansky-Küster-Hauser syndrome and should be evaluated in this population. Overall, compared with no vaginal lengthening treatment, having vaginal lengthening treatment is not associated with substantial differences in the prevalence of pelvic floor symptoms, with the exception of recent urinary incontinence and anal incontinence. Our data suggested that bowel vaginoplasty may be associated with greater symptoms of vaginal bulge. More robust studies are needed to determine the impact of various vaginal lengthening treatments on pelvic floor symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy., Methods: We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome., Results: Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia)., Conclusion: This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease.

Objective: The aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes., Design: We performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies., Results: We included 1000 children born to 626 mothers (381 (61%) Crohn's disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population., Conclusion: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies., Competing Interests: Competing interests: JCE: received financial support as advisory board member from Janssen (DEVELOP registry) and Abbvie (CAPE registry; and research support from MSD, NdB: has served as a speaker for AbbVie and MSD. He has served as consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Falk and Takeda, FH: has served on advisory boards or as speaker for Abbvie, Janssen-Cilag, MSD, Takeda, Celltrion, Teva, Sandoz and Dr Falk Funding (Grants/Honoraria) Dr Falk, Janssen-Cilag, Abbvie, Takeda. Consulting Fees: Celgene, Janssen-Cilag, BO grant van Ferring, Falk, Pfizer, Takeda; speakers Fee: Ferring, MSD; advisory board: Janssen, Takeda, Abbvie, Ferring, Takeda, RW: advisory board Janssen pharmaceuticals, CJvdW: has participated in advisory board and/or received financial compensation from the following companies: MSD, FALK Benelux, Abbott laboratories, Mundipharma Pharmaceuticals, Janssen, Takeda and Ferring during the last 3 years., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: The effects of lipid metabolism disorders (LMD) on pregnancy outcomes is not well known. The purpose of this study is to evaluate the impact of LMD on maternal and fetal outcomes., Methods: Using the Healthcare Cost and Utilization Project - National Inpatient Sample from the United States, we carried out a retrospective cohort study of all births between 1999 and 2015 to determine the risks of complications in pregnant women known to have LMDs. All pregnant patients diagnosed with LMDs between 1999 and 2015 were identified using the International Classification of Disease-9 coding, which included all patients with pure hypercholesterolemia, pure hyperglyceridemia, mixed hyperlipidemia, hyperchylomicronemia, and other lipid metabolism disorders. Adjusted effects of LMDs on maternal and newborn outcomes were estimated using unconditional logistic regression analysis., Results: A total of 13,792,544 births were included, 9,666 of which had an underlying diagnosis of LMDs for an overall prevalence of 7.0 per 10,000 births. Women with LMDs were more likely to have pregnancies complicated by diabetes, hypertension, and premature births, and to experience myocardial infarctions, venous thromboembolisms, postpartum hemorrhage, and maternal death. Their infants were at increased risk of congenital anomalies, fetal growth restriction, and fetal demise., Conclusions: Women with LMDs are at significantly higher risk of adverse maternal and newborn outcomes. Prenatal counselling should take into consideration these risks and antenatal care in specialized centres should be considered., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Congenital anomaly is a partial or complete structural and/or functional defect during intrauterine life. Globally, major congenital anomalies account for 6% of all newborns among which about 94% of cases occurred in developing countries. In spite of its public health importance, very limited studies are reported in Ethiopia, and hardly any study in Arsi Zone., Objectives: To determine the predictors of congenital anomalies among newborns in Arsi Zone Public Hospitals, Southeast Ethiopia., Methods: A multi-center institutional-based case-control study was conducted in 418 (105 cases and 313 controls) of newborns in Arsi Zone Public Hospitals. Descriptive analysis, binary and multivariable logistic regressions were implemented., Results: In this study, women who have been drinking alcohol during pregnancy were 3.48 times more prone to have newborns with congenital anomalies than their counterparts (AOR = 3.48; 95% CI: 1.38, 8.74). The likelihood of having a newborn with congenital anomalies was six and four times higher for women who had a maternal illness (AOR = 6.10; 95%CI: 2.39, 15.57) and chewing khat during pregnancy (AOR = 4; 95%CI: 1.49, 10.65), respectively. Moreover, the lack of folic acid supplementation and pesticides during pregnancy were 3.25 and 4.76 times more likely to experience a newborn with congenital anomalies, respectively., Conclusion: Alcohol drinking, maternal illness, khat chewing, and chemical exposure during pregnancy had a significant association with the occurrence of congenital anomalies. While, taking folic acid supplements had a protective effect. Health experts and the community should take these factors into consideration and act accordingly.

Introduction: Congenital anomalies (CAs) are a major cause of infant mortality, childhood morbidity and long-term disability. Over 130 000 children born in Europe every year will have a CA. This paper describes the EUROlinkCAT study, which is investigating the health and educational outcomes of children with CAs for the first 10 years of their lives., Methods and Analysis: EUROCAT is a European network of population-based registries for the epidemiological surveillance of CAs. EUROlinkCAT is using the EUROCAT infrastructure to support 22 EUROCAT registries in 14 countries to link their data on births with CAs to mortality, hospital discharge, prescription and educational databases. Once linked, each registry transforms their case data into a common data model (CDM) format and they are then supplied with common STATA syntax scripts to analyse their data. The resulting aggregate tables and analysis results are submitted to a central results repository (CRR) and meta-analyses are performed to summarise the results across all registries. The CRR currently contains data on 155 594 children with a CA followed up to age 10 from a population of 6 million births from 1995 to 2014., Ethics: The CA registries have the required ethics permissions for routine surveillance and transmission of anonymised data to the EUROCAT central database. Each registry is responsible for applying for and obtaining additional ethics and other permissions required for their participation in EUROlinkCAT., Dissemination: The CDM and associated documentation, including linkage and standardisation procedures, will be available post-EUROlinkCAT thus facilitating future local, national and European-level analyses to improve healthcare. Recommendations to improve the accuracy of routinely collected data will be made.Findings will provide evidence to inform parents, health professionals, public health authorities and national treatment guidelines to optimise diagnosis, prevention and treatment for these children with a view to reducing health inequalities in Europe., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

This Review depicts the evolving role of MRI in the diagnosis and prognostication of anomalies of the fetal body, here including head and neck, thorax, abdomen and spine. A review of the current literature on the latest developments in antenatal imaging for diagnosis and prognostication of congenital anomalies is coupled with illustrative cases in true radiological planes with viewable three-dimensional video models that show the potential of post-acquisition reconstruction protocols. We discuss the benefits and limitations of fetal MRI, from anomaly detection, to classification and prognostication, and defines the role of imaging in the decision to proceed to fetal intervention, across the breadth of included conditions. We also consider the current capabilities of ultrasound and explore how MRI and ultrasound can complement each other in the future of fetal imaging., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Few population-based studies have analyzed patterns of co-occurring birth defects among those with trisomy 13. We evaluated the frequency of all possible combinations of any one, two, three, or four additional co-occurring birth defects among 736 individuals with trisomy 13 using data from the Texas Birth Defects Registry for deliveries during 1999-2014. We calculated the observed-to-expected ratio for each combination, adjusting for the known tendency for birth defects to cluster non-specifically. To address potential ascertainment differences among live births and non-live births, we repeated analyses specifically among live births. The combination of defects with the largest observed-to-expected ratio was microcephalus, reduction deformities of brain (e.g., holoprosencephaly), anomalies of nose, and polydactyly. As expected, most of the highest 30 observed-to-expected ratios involved combinations with documented features of trisomy 13, including defects of the scalp (e.g., aplasia cutis) and heart. Results were similar among sensitivity analyses restricted to live births. Our findings may help further delineate the phenotypic spectrum for trisomy 13 and may inform future research related to improving screening and counseling for the condition., (© 2021 Wiley Periodicals LLC.)

Congenital anomaly is a structural or functional defect which could occur in any organ system. The aim of this study was to determine the prevalence and associated factors of congenital anomalies among newborn babies delivered at Felege-Hiwot Comprehensive Specialized Referral Hospital, Bahir Dar, Ethiopia. A cross-sectional study design was used to review medical records/charts of 11,177 new born babies born at the delivery ward of Felege-Hiwot Comprehensive Specialized Referral Hospital, Ethiopia. The data were collected using an abstraction form. A bivariate analysis was done to assess factors associated with congenital anomalies. Variables whose p-value < 0.2 were included in the multivariable analysis to identify the effects of confounders. P-values < 0.05 were considered statistically significant. A total of 11,177 newborn babies and their mothers were included in the study and the proportion of congenital anomalies was found to be 0.62%. The most (46.4%) prevalent congenital anomaly was neural tube defects. Newborn birth weight < 1.25 kg [AOR, 32.6, 95% CI 11.9-89.0], and newborn weight < 2.5 kg [AOR, 2.67, 95% CI 1.54-4.65], antenatal visits [AOR, 4.0, 95% CI 2.39-6.69] and urban residence [AOR, 2.1, 95% CI 1.28-3.55] were statistically significant factors. In conclusion, neural tube defects were anomalies prevalent in this study. Antenatal visits, birth weight and residence were factors associated with congenital anomalies.

Links between heat exposure and congenital anomalies have not been explored in detail despite animal data and other strands of evidence that indicate such links are likely. We reviewed articles on heat and congenital anomalies from PubMed and Web of Science, screening 14,880 titles and abstracts in duplicate for articles on environmental heat exposure during pregnancy and congenital anomalies. Thirteen studies were included. Most studies were in North America (8) or the Middle East (3). Methodological diversity was considerable, including in temperature measurement, gestational windows of exposure, and range of defects studied. Associations were detected between heat exposure and congenital cardiac anomalies in three of six studies, with point estimates highest for atrial septal defects. Two studies with null findings used self-reported temperature exposures. Hypospadias, congenital cataracts, renal agenesis/hypoplasia, spina bifida, and craniofacial defects were also linked with heat exposure. Effects generally increased with duration and intensity of heat exposure. However, some neural tube defects, gastroschisis, anopthalmia/microphthalmia and congenital hypothyroidism were less frequent at higher temperatures. While findings are heterogenous, the evidence raises important concerns about heat exposure and birth defects. Some heterogeneity may be explained by biases in reproductive epidemiology. Pooled analyses of heat impacts using registers of congenital anomalies are a high priority.

Objective: To understand the risks associated with trisomy 21 in pregnancy in order to inform obstetrical care and improve outcomes., Methods: A population-based retrospective cohort study was undertaken of all pregnancies involving a fetus with trisomy 21 in Nova Scotia, Canada, from 2000 to 2019. Cases were identified from the provincial laboratory genetics database, linked to the Nova Scotia Atlee Perinatal Database for pregnancy outcomes, and compared with the general obstetrical population., Results: A total of 350 pregnancies were identified, of which 23% were ongoing pregnancies in which trisomy 21 was diagnosed prenatally and 24% involved diagnoses made after delivery. Compared with the general obstetrical population, women with ongoing pregnancies affected by trisomy 21 were more likely to be older (mean age 34 vs. 29 y), multiparous (67% vs. 55%), and in a relationship (79% vs. 68%). Trisomy 21 was associated with a significantly increased risk of preterm birth (<37 weeks; 24.1% vs. 8.3%); small for gestational age (<10th percentile; 21.7% vs. 8.2%); cesarean delivery (31.5% vs. 27.1%); and combined perinatal/neonatal mortality (8.0% vs. 0.8%) (P < 0.001 for all)., Conclusion: Trisomy 21 is associated with significant adverse perinatal and neonatal risks. Population screening to identify trisomy 21 can be used to optimize perinatal outcomes with appropriate fetal surveillance in these pregnancies., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objectives: to assess the potential of a new algorithm based on current healthcare databases to identify potential cases of malformation, particularly chromosomal anomalies associated with terminations of pregnancy., Design: retrospective observational study., Setting and Participants: Registry of Congenital Anomalies of Milan, live births, still births, and termination of pregnancies for fetal anomalies from 2012 to 2016, detected by using current healthcare data., Main Outcome Measures: prevalence between 2012 and 2016 of congenital malformations recorded by Milan's Registry of Congenital Anomalies, with particular regard to chromosomal anomaly trends. Variation in the percentage of malformations detected from terminations of pregnancy., Results: prevalence of malformations increased from 270 in 2012 to 283 per 10,000 in 2016; specifically, chromosomal abnormalities increased from 35 to 51 per 10,000 births. The algorithm detected a greater proportion of anomalies associated with therapeutic abortion, especially with respect to chromosomal anomalies, with an increase from 57.7% in 2012 to 75.8% in 2016 (test for trend p=0.002)., Conclusions: the proposed algorithm identified a greater number of chromosomal anomalies that caused termination of pregnancy and may be applied to existing Italian registries to evaluate the quality of healthcare services, in particular with regard to the effectiveness of prenatal trisomy screening policies. The algorithm may also be used where no active surveillance systems are present, as well as in epidemiological studies, to assess environmental impact on congenital anomalies.

Objective: Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy., Design: A retrospective review of clinical case notes., Setting: Two tertiary fetal medicine centres., Population: Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team., Methods: We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient-specific panels and interpreted using American College of Medical Genetics guidelines., Results: A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy., Conclusions: We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES., Tweetable Abstract: Prenatal exome sequencing can aid decision-making in pregnancy management; review ahead of routine implementation in NHS., (© 2020 John Wiley & Sons Ltd.)

Background: The study is aimed at highlighting the pattern of congenital defect in a tertiary care hospital. Congenital anomalies are recognized as a growing cause of neonatal morbidity and mortality in developing countries and a major cause of distress to parents., Methods: This was a prospective descriptive study conducted between September 2019 and August 2020 with the objective to determine the types of congenital anomalies among live born neonates at Manipal Teaching Hospital (MTH), Pokhara and to determine their immediate outcome. Neonatal and maternal characteristics were noted., Results: Twenty four out of 2515 live births had congenital anomalies during the study period, giving an incidence rate of 9.42 congenital anomalies per 1000 live birth per year. Single system involvement was seen in 79.2 % cases, remaining 5 (20.8%) neonates had involvement of more than one system; 54.2% of these newborns were discharged, 33.3% expired, 8.3% left against medical advice and 4.2% were referred out., Conclusions: This study highlights the importance of clinical examination of neonates to detect anomalies in our setting.

Objectives: To compare the differences of epidemiology analysis in population birth defects (BDs) between the rural and urban areas of Hunan Province in China., Methods: The data of population-based BDs in Liuyang county (rural) and Shifeng district (urban) in Hunan Province for 2014-2018 were analyzed. BD prevalence rates, percentage change, and annual percentage change (APC) by sex and age were calculated to evaluate time trends. Risk factors associated with BDs were assessed using simple and multiple logistic regression analyses., Results: The BD prevalence rate per 10,000 perinatal infants (PIs) was 220.54 (95% CI: 211.26-230.13) in Liuyang and 181.14 (95% CI: 161.18-202.87) in Shifeng. Significant decreasing trends in BD prevalence rates were noted in the female PIs (APC = -9.31, P = 0.044) and the total BD prevalence rate in Shifeng (APC = -14.14, P = 0.039). Risk factors for BDs were as follows: rural area, male PIs, PIs with gestational age < 37 weeks, PIs with birth weight < 2500 g, and migrant pregnancies., Conclusions: We should focus on rural areas, reduce the prevalence of premature and low birth weight infants, and provide maternal healthcare services for migrant pregnancies for BD prevention from the perspective of population-based BD surveillance., Competing Interests: The authors declare no competing interests., (Copyright © 2021 Lili Xiong et al.)

Background: Congenital malformations are considered as one of the significant causes of preterm as well as neonatal morbidity and mortality. Literature suggests the association of diverse congenital deformities with maternal exposure to air pollutants. However, the evidence is still inconclusive on the manifestation of these during pregnancy. Thus, systematic review was done on the available epidemiological studies studying the effect of air pollutants on congenital malformations. Furthermore, the meta-analysis was conducted for several combinations of air pollutants and congenital defects., Methods: Twenty six epidemiological studies were extracted from the databases and examined for association of risk of congenital defects with air pollutant concentrations. Metaanalysis was done if the risk estimates of the same anomaly and pollutant group were reported in at least three studies., Results: Each study reported a statistically significant increased risk of congenital malformation with some air pollutant, amid the several tested combinations. Our meta-analysis reported that nitrogen dioxide and PM 2.5 were associated with the risk of pulmonary valve stenosis with OR = 1.74 and OR = 1.42 respectively. The risk of developing tetralogy of Fallot (TOF) was observed to be associated with PM 2.5 with OR = 1.52 . SO 2 exposure was related to a high risk of the ventricular septal defect (VSD) with OR = 1.15 and orofacial defects (OR = 1.27)., Conclusion: It is evidenced that ambient air pollutants have some effect on congenital malformations. Standard case definitions, improved methods of exposure, and better control of confounders will improve future research in this area., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: To describe the major congenital anomalies present in children with postneonatally acquired cerebral palsy (CP), and to compare clinical outcomes and cause of postneonatally acquired CP between children with and without anomalies., Method: Data were linked between total population CP and congenital anomaly registers in five European and three Australian regions for children born 1991 to 2009 (n=468 children with postneonatally acquired CP; 255 males, 213 females). Data were pooled and children classified into mutually exclusive categories based on type of congenital anomaly. The proportion of children with congenital anomalies was calculated. Clinical outcomes and cause of postneonatally acquired CP were compared between children with and without anomalies., Results: Major congenital anomalies were reported in 25.6% (95% confidence interval [CI] 21.7-29.9) of children with postneonatally acquired CP. Cardiac anomalies, often severe, were common and present in 14.5% of children with postneonatally acquired CP. Clinical outcomes were not more severe in children with congenital anomalies than those without anomalies. Cause of postneonatally acquired CP differed with the presence of congenital anomalies, with cerebrovascular accidents predominating in the anomaly group. Congenital anomalies were likely associated with cause of postneonatally acquired CP in 77% of children with anomalies., Interpretation: In this large, international study of children with postneonatally acquired CP, congenital anomalies (particularly cardiac anomalies) were common. Future research should determine specific causal pathways to postneonatally acquired CP that include congenital anomalies to identify opportunities for prevention., What This Paper Adds: One-quarter of children with postneonatally acquired cerebral palsy (CP) have a major congenital anomaly. Cardiac anomalies, often severe, are the most common anomalies. Causes of postneonatally acquired CP differ between children with and without congenital anomalies., (© 2021 Mac Keith Press.)

This cohort study of the International Network on Cancer, Infertility and Pregnancy (INCIP) reports the maternal and neonatal outcomes of 80 pregnant patients diagnosed with non-Hodgkin lymphoma (NHL) between 1986 and 2019, focussing on 57 (71%) patients with diffuse large B-cell lymphoma (DLBCL). Of all 80 patients, 54 (68%) pregnant patients received chemotherapy; mostly (89%) CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens. Four early pregnancies were terminated. Among 76 ongoing pregnancies, there was one stillbirth (1·3%). Overall, there was a high incidence of small for gestational age neonates (39%), preterm delivery (52%), obstetric (41%) and neonatal complications (12·5%), and this could not exclusively be explained by the receipt of antenatal chemotherapy. Half of preterm deliveries (46%) were planned in order to tailor oncological treatment. The 3-year progression-free and overall survival for patients with DLBCL treated with rituximab-CHOP was 83·4% and 95·7% for limited stage (n = 29) and 60·6% and 73·3% for advanced stage (n = 15). Of 36 pregnant patients who received rituximab, five (13%) cases with neonatal complications and three (8%) with maternal infections were reported. In conclusion, standard treatment for DLBCL can be offered to pregnant patients in obstetric centres that cater for high-risk patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Aim: To describe the frequency and types of major congenital anomalies present in children with pre- or perinatally acquired cerebral palsy (CP), and compare clinical outcomes for children with and without anomalies., Method: This multi-centre total population collaborative study between Surveillance of Cerebral Palsy in Europe, Australian Cerebral Palsy Register, and European Surveillance of Congenital Anomalies (EUROCAT) involved six European and three Australian regions. Data were linked between each region's CP and congenital anomaly register for children born between 1991 and 2009, and then pooled. Children were classified into mutually exclusive categories based on type of anomaly. Proportions of children with congenital anomalies were calculated, and clinical outcomes compared between children with and without anomalies., Results: Of 8201 children with CP, 22.8% (95% confidence interval [CI] 21.9, 23.8) had a major congenital anomaly. Isolated cerebral anomalies were most common (45.2%), with a further 8.6% having both cerebral and non-cerebral anomalies. Cardiac anomalies only were described in 10.5% of children and anomalies associated with syndromes were also reported: genetic (8.0%), chromosomal (5.7%), and teratogenic (3.0%). Clinical outcomes were more severe for children with CP and congenital anomalies, particularly cerebral anomalies., Interpretation: This large, international study reports major congenital anomalies in nearly one-quarter of children with pre- or perinatally acquired CP. Future research must focus on aetiological pathways to CP that include specific patterns of congenital anomalies., What This Paper Adds: Congenital anomalies were reported in 23% of children with pre- or perinatally acquired cerebral palsy. A higher proportion of children born at or near term had anomalies. The most common type of anomalies were isolated cerebral anomalies. Clinical outcomes were more severe for children with congenital anomalies (particularly cerebral)., (© 2020 Mac Keith Press.)