An Analysis of Specific Categories of Birth Defects and Developmental Disabilities for Children of Participants of the Air Force Health Study

Background: The Air Force Health Study collected reproductive outcomes for live-born children of male Air Force veterans of the Vietnam War. Methods: Dioxin values for participants were obtained from blood samples. Analyses were conducted of occurrence of 16 specific categories of birth defects and developmental disabilities. Children were categorized as conceived before and after the start of participants’ Vietnam War service. Children conceived before the start of Vietnam War service were treated as being conceived when their fathers had unquantifiable dioxin values. Children conceived after the start of Vietnam War service for participants with missing dioxin values were excluded from primary analyses, but were used to assess the impact of their exclusion on conclusions. Correlation between values for specific categories for multiple children fathered by the same participant was accounted for. The dose-response relationship was treated as a step function increasing for dioxin values larger than adaptively identified individual thresholds changing with the specific category. Results: For 15 of 16 specific categories, the probability of occurrence increased substantially for a sufficiently high dioxin level above identified thresholds. Exclusion of children due to missing dioxin likely did not affect these results. Conclusions: Results supported the conclusion of substantial adverse effects on a wide variety of specific categories of birth defects and developmental disabilities due to sufficiently high exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War. Results may hold more generally, but might also have been affected by a variety of limitations.

Birth defects in pregestational diabetes:Defect range,glycemic threshold and pathogenesis

Currently,60 million women of reproductive age(18-44 years old) worldwide,and approximately 3 million American women have diabetes mellitus,and it has been estimated that this number will double by 2030.Pregestational diabetes mellitus(PGD) is a significant public health problem that increases the risk for structural birth defects affecting both maternal and neonatal pregnancy outcome.The most common types of human structural birth defects associated with PGD are congenital heart defects and central nervous system defects.However,diabetes can induce birth defects in any other fetal organ.In general,the rate of birth defects increases linearly with the degree of maternal hyperglycemia,which is the major factor that mediates teratogenicity of PGD.Stringent prenatal care and glycemic control are effective means to reduce birth defects in PGD pregnancies,but cannot reduce the incidence of birth defects to the rate of that is seen in the nondiabetic population.Studies in animal models have revealed that PGD induces oxidative stress,which activates cellular stress signalling leading to dysregulation of gene expression and excess apoptosis in the target organs,including the neural tube and embryonic heart.Activation of the apoptosis signalregulating kinase 1(ASK1)-forkhead transcription factor 3a(Fox O3a)-caspase 8 pathway causes apoptosis in the developing neural tube leading to neural tube defects(NTDs).ASK1 activates the c-Jun-N-Terminal kinase 1/2(JNK1/2),which leads to activation of the unfolded protein response and endoplasmic reticulum(ER) stress.Deletion of the ASK1 gene,the JNK1 gene,or the JNK2 gene,or inhibition of ER stress by 4-Phenylbutyric acid abrogates diabetes-induced apoptosis and reduces the formation of NTDs.Antioxidants,such as thioredoxin,which inhibits the ASK1-Fox O3a-caspase 8 pathway or ER stress inhibitors,may prevent PGD-induced birth defects.

Correlation Between Birth Defects and Dietary Nutrition Status in a High Incidence Area of China

Objective To investigate the association between birth defects and dietary nutrient intake in a high risk area of China. Methods A dietary survey was performed and serum folic acid was measured in women whose pregnancy was affected by neural tube defects （NTDs） or unaffected by any birth defects （BDs） in Zhongyang and Jiaokou Counties in Shanxi Province of China. ResuIts The local average consumption of foods including dark green vegetables, fruits, fat and meat, and nutrient intake （e.g. energy, protein, retinol, riboflavin, vitamin E, and selenium） were lower than the national average level. In women of childbearing age, these regions, the intake of nutrients was much lower than the recommended nutrient intake （9%-77%）. The case-control dietary nutrition study of women whose pregnancy was affected by BDs （including NTDs and congenital heart defects） demonstrated that, in early pregnancy, adequate nutrition （i.e. eating meat, fresh vegetables, fruit more than once a week） was a protective factor, while eating germinated potatoes was a risk factor. The geometrical mean （pS- p95） of serum folic acid in women with NTD birth defects was 9.6 nmol/L （3.6, 23.03）, which was significantly lower than that in normal women （14.03 nmol/L）. Conclusion Women of childbearing age in the two counties of Shanxi Province, China, have a marked insufficient intake of some nutrients, especially folic acid, zinc, vitamins A and B12. This nutrient deficiency may be an important risk factor for the high prevalence of birth defects in these regions. Therefore, adequate dietary nutrition in early pregnancy can prevent BDs.

Spatiotemporal Property Analysis of Birth Defects in Wuxi,China

Objective To describe the temporal trends and spatial patterns of birth defects occurring in Wuxi, a developed region of China. Methods Wavelet analysis was used to decompose the temporal trends of birth defect prevalence based on the birth defect rates over the past 16 years. Birth defect cases with detailed personal and family information were geo-coded and the relative risk in each village was calculated. General G statistic was used to test the spatial property with different scales. Results Wavelet analysis showed an increasing temporal trend of birth defects in this region. Clustering analysis revealed that changes continued in the spatial patterns with different scales. Conclusion Wuxi is confronted with severe challenges to reduce birth defect prevalence. The risk factors are stable and show no change with spatial scale but an increasing temporal trend. Interventions should be focused on villages with a higher prevalence of birth defects.

Demographic Characteristics and Environmental Risk Factors Exposure of Birth Defects in Pregnant Women: A Population-based Study

Worldwide, the incidence of birth defects in low-income countries is 6.42%, while in middle-income and high-income countries it is 5.57% and 4.72%, respectively;approximately 303, 000 newborns die from birth defects each year. In China, the incidence of birth defects is about 5.6%, and around 8.14 million people have congenital disabilities, accounting for 9.6% of total disabled people[1]. Birth defect remains a major clinical and public health challenge because of its high fatality rate and protracted and severe sequela.

Application Research of “3+1” Mode for Birth Defects Monitoring

Objective To explore the ＂3＋1＂ monitoring mode for birth defects and quality control measures based on the population, and to obtain the related information data for birth defects.Methods With the community population as the basis, adopting the unified monitoring scheme dominant by the leadership and administration of government, with districts （counties） as the monitoring sites, the ＂3＋1 ＂ monitoring mode for birth defects was based on a complete monitoring team with the combination of villages/residents＇ committees, townships （towns）, counties （districts） and the municipality. Demonstration research was carried out in the pilot districts/counties in Chongqing City.Results Birth defects population monitoring system based on population and family planning management and service network was established, and during 2005 and 2006.application research was carried out for the monitoring methods among birth defects population in the pilot districts （counties）, obtaining the relevant information in regional birth defects, with a monitoring coverage of over 99%. Conclusion Fully utilizing the birth management functions of Population and Famlty Planning System and the advantages of service networks, long term, dynamic birth defects monitoring system based on community population was established, with the integration of birth defects monitoring and regular reproductive health services, obtaining overall birth defects occurrence information in details, providing scientific basis for the government to formulate scientific, practical, economic and effective birth defects intervention policy, so as to improve the quality of the population.

A Reassessment of Birth Defects for Children of Participants of the Air Force Health Study

The Air Force Health Study (AFHS), also called the Ranch Hand Study, investigated the impact of exposure to dioxin the toxic contaminant in Agent Orange on health, survival, and reproductive outcomes of male Air Force Vietnam War veterans. It was concluded that available reproductive outcome data did not provide support for an adverse association with paternal dioxin exposure. A more extensive set of AFHS data was used to reassess this conclusion, restricting to the case of birth defects in children fathered after the start of the first Vietnam War tour. Analyses started by repeating published analyses, followed by assessing decisions made in those analyses, for example, of excluding participants with dioxin levels below the detectable limit, using a threshold of 10 parts per trillion for a high dioxin level, and not adjusting for multiple conceptions/children of the same participant. Using data for all participants with measured dioxin levels, both veterans who served in Operation Ranch Hand and other non-Ranch Hand veterans, and after accounting for correlation within children of the same participant, the occurrence for children fathered after the start of the first tour of a major defect, a non-major defect, and multiple defects depended significantly on participants having a high dioxin level. These conclusions were not changed by consideration of covariates. In contrast to prior published analyses, the more extensive AFHS data provided support for an adverse effect of paternal dioxin exposure on birth defects. However, the study had many limitations that could have affected the conclusions.

Observed prevalence and risk factors of birth defects in Shanghai, China

AIM To investigate the prevalence and related risk factors of birth defects in Shanghai. METHODS This report describes a population-based study of all births at the Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China from January 2008 to December 2014. A logistic regression analysis was used to identify the parameters that are independently associated with birth defects. RESULTS A total of 82814 births, including 824 cases of birth defects, were recorded. The rate of birth defects was 0.995 per 100 births. In the multivariable regression analysis, neonatal birth defects were likely to be associated with higher gravidity [odds ratio(OR), 1.099, 95%CI: 1.024-1.178], premature birth(OR = 1.905, 95%CI: 1.501-2.418), low birth weight(OR = 3.844, 95%CI: 3.004-4.919), twin births or higher order multiple pregnancies(OR = 1.477, 95%CI: 1.107-1.969), cesarean delivery(OR = 1.184, 95%CI: 1.016-1.380) and registration as part of a migrant population(OR = 1.380, 95%CI: 1.167-1.632). Female infants were less likely to have birth defects than male infants(OR = 0.710, 95%CI: 0.616-0.818). CONCLUSION Higher gravidity, premature birth, lower birth weight,twin births or higher order multiple pregnancies, and registration as part of a migrant population are independent predictors of birth defects.

Effect of Pathoanatomic Diagnosis on the Quality of Birth Defects Surveillance in China

Objective To provide evidence for more accurate diagnosis of birth defects based on the pathoauatomy of congenital malformations. Methods Data used in this study were obtained fi＇om Luliang City Hospital and three county hospitals of Shanxi province between February 2004 and March 2006. Autopsy and pathological examination of 160 dead fetuses and stillbirths were performed. Photos of dead fetuses and stillbirths were taken, tissues were cut into sections for pathological examination under microscope, all pathological information was recorded, and percentage of birth defects was calculated. Results The proportion of dead fetuses and stillbirths with or without congenital malformations was 84.4% （135/160） and 15.6% （25/160）, respectively. There were 16 categories of major external and internal birth defects in 135 cases of such defects. Congenital heart defects, anencephaly and spina bifida had a higher prevalence rate in the study period. The prevalence rate of non-malformation death and birth defects 〈 28 gestational weeks and internal anomalies ≥ 28 gestational weeks was 14.61% （61/4175） and 17.25% （72/4175）, respectively. A total of 413 in situ anomalies were found in 135 cases of autopsy. Spina bifida, anencephaly, congenital heart defects, aplasia or accessory lobe of lung, renal agenesis and dysplasis and congenital hydrocephaly were more closely associated with severe malformations than with mitis malformations. The cases of dead fetuses and stillbirths with multiple malformations （/〉 2 in situ anomalies） had a higher proportion （74.1%）, whereas those with isolated malformations had a lower proportion （25.93%）. Conclusion The occurrence of congenital malformations in different embryonic developmental stages affects multiple organs. Postmortem examination of internal and multiple malformations of fetal deaths and stillbirths can provide more accurate diagnostic information for birth defects.

Construction of HMI Network System for Individualized Maternity Intervention Service against Birth Defects in Community

The paper expounds the community maternity service system against birth defects, from the viewpoint of individualized service in family planning. We have utilized modern information technology to develop health management information （HMI） network with individualized maternity, and to establish the community service system for intervention of birth dejects. The service system applied the concept of modern health management information to implementing informational management for screening, treatment, following up, outcome monitoring, so as to provide a base for promotion of health, diagnosis, treatment as well as scientific research, with the prenatal screening of Down＇s syndrome as a model. The introduction to informational network during the processes of service has been carried out with regards to its composition, function and application, while introducing the effects of computerized case record individualized in prevention, management and research of Down＇s syndrome.

Risk Factors for Birth Defects: A Conditional LogisticRegression Analysis of a Case-Control Study in Guang-dong Province of China

Information was obtained from the same questionnaire (23 risk factors listed) of cases and controls. We used a multivariate logistic model, which described variables significantly increased risk of birth defects. The risk factors included maternal educational levels, medicine taken during pregnancy and antenatal care. It was suggested to strengthen antenatal care was the main preventive measure against birth defects.

The Relationship between Drug－and Chemical－exposure and Birth Defects during Pregnancy

A case-control study was conducted in 36 hospitals of the urban and suburban areas of shanghai about the relationships between birth defects and drug use and chemical exposures during pregnancy in the period of july 1987-December 1990.The case group was composed if 1,609 subjects,and the control group 3,218 cases.On stall'stical analysl's,it was.found that a correlation ed'sted between birth defects and the intake Of APC and diazepam,and the exposure to pesticides,organic solvents.benzene,synthetic resin and physical.factors(noises)on foe part of foe mother.and the exposure to harmful chemicals and physical factors and the smoking of 20 or more cigarettes a day on the part Of the father.It is also found that foe familial heredilary history of the parents and multigravavidity,malnutrition,common colds,hepatitis and diarrhea during pregnancy may also be relaied to the birth defects.

Clinical study of different fertilization methods of assisted reproductive technology on neonatal birth defects

Objective:To investigate the incidence of neonatal birth defects in assisted reproductive technology(ART)by in vitro fertilization(IVF)and intracytoplasmic sperm injection(ICSI).Methods:The clinical data of 4229 cases of singleton deliver by infertile patients under 35 years old who received IVF/ICSI-ET in our center were analyzed.According to different fertilization methods,they were divided into IVF group(2967 cases)and ICSI group(1262 cases).The general situation of birth,birth defects and the location of defects were compared between the two groups.Results:a total of 38 cases of neonatal birth defects were found,the incidence of birth defects was 0.89%,including 30 cases(1.01%)in IVF group and 8 cases(0.64%)in ICSI group.There was no significant difference in the incidence of birth defects between the two groups(P>0.05).There was also no significant difference in birth weight,gestational age and gender ratio between the two groups(P>0.05).Conclusion:Different fertilization methods in assisted reproductive technology do not increase the incidence of neonatal birth defects.

Adaptive Regression for Nonlinear Interrupted Time Series Analyses with Application to Birth Defects in Children of Vietnam War Veterans

The purpose of this article is to provide an overview of adaptive regression modeling and demonstrate its use in conducting nonlinear analyses of interrupted time series (ITS) data. Adaptive regression modeling is based on heuristic search over alternative models for data controlled by likelihood-cross validation (LCV) scores with larger scores indicating better models. Extended linear mixed models are used for correlated data like ITS data. Power transforms of predictor variables are used to account for nonlinearity. The use of adaptive regression modeling for assessing ITS effects is demonstrated using data on annual proportions of major birth defects in children fathered by male Air Force veterans of the Vietnam War over a 59-year period. The interruption for this ITS is conception after versus before the start of a participant’s first tour in the Vietnam War. Whether the ITS effect is related to dioxin exposure is also addressed. Dioxin is a highly toxic contaminant of the herbicide Agent Orange used in the Vietnam War. The core findings of the reported analyses are that a substantial adverse ITS interruption effect is identified and that this adverse effect can reasonably be attributed to participants having a high dioxin exposure level. Moreover, these results indicate that adaptive regression modeling can identify nonlinear ITS effects in general situations that can lead to consequential insights into nonlinear relationships over time, possibly varying with other available predictors.

出生缺陷与出生体重、胎龄的相关性

目的分析不同出生体重及胎龄围产儿的出生缺陷发生率,为进一步完善出生缺陷监测系统和降低出生缺陷发生率提供新的科学依据。方法对2003年10月1日至2015年9月30日西安市各级开设产科的医疗保健机构出生的孕28周~生后7 d所有围产儿进行出生缺陷监测并收集相关资料。结果2003至2015年共监测围产儿1236937例,其中出生缺陷儿10619例,出生缺陷发生率为8.59‰。2003至2015年西安市出生缺陷医院监测系统共收集出生体重<2500 g出生缺陷患儿3306例,出生孕周≥28周且<37周的出生缺陷患儿3473例,出生孕周≥42周的出生缺陷患儿共224例。2003至2015年低出生体重儿出生缺陷率显著高于正常体重儿(χ^(2)=37097.79,P<0.001)。2003至2015年早产儿(<37周)出生缺陷率显著高于正常产期儿(χ^(2)=24998.24,P<0.001),过期产儿出生缺陷率(≥42周)显著高于正常产期儿(χ^(2)=196.40,P<0.001)。低体重儿出生缺陷常见缺陷类型前5位依次是先天性脑积水、脊柱裂、先天性心脏病、无脑畸形、唇裂合并腭裂。正常体重儿出生缺陷出生结局以活产为主(占68.60%),而低体重儿出生缺陷出生结局以死胎为主(占54.72%),低体重儿出生缺陷与正常体重儿出生缺陷出生结局比较,差异有统计学意义(χ^(2)=647.59,P<0.001)。正常产期儿出生缺陷出生结局以活产为主(占77.38%),过期产儿出生缺陷出生结局以活产为主(占83.93%),而早产儿出生缺陷出生结局以死胎为主(占57.79%)。早产儿与正常产期儿出生缺陷出生结局比较,差异有统计学意义(χ^(2)=2025.08,P<0.001),早产儿与过期产儿出生缺陷出生结局比较,差异有统计学意义(χ^(2)=245.39,P<0.001),正常产期儿与过期产儿出生缺陷出生结局比较差异有统计学意义(χ^(2)=16.28,P=0.001)。结论早产儿、低出生体重儿及过期产儿出生缺陷发生率显著高于正常产期儿,低体重儿与正常体重儿、早产儿与正常产期儿、早产儿与过期产儿、正常产期儿与过期产儿出生缺陷出生结局比较,差异均有统计学意义。

2003至2022年陕西省神经管缺陷发生率下降速率及缺陷儿转归

目的总结2003至2022年陕西省神经管缺陷(NTDs)发生率的流行趋势和下降速率,掌握NTDs诊断时间及缺陷儿转归情况,预测2023至2025年陕西省NTDs发生率,为进一步完善出生缺陷监测系统提供新的科学依据。方法对2003至2022年陕西省各级开设产科的医疗保健机构孕28周至出生后7 d所有围产儿进行出生缺陷监测并收集资料,基于出生缺陷监测系统分析2003至2022年NTDs发生率的分布趋势。结果陕西省2003至2022年共监测围产儿1106483例,NTDs病例共848例,发生率为7.66/万,其中2005年发生率(48.02/万)最高,2022年发生率(0.57/万)最低。NTDs以脊柱裂为主,占55.90%,其次为无脑儿(25.71%)和脑膨出(18.40%),三者发生率均在波动中呈显著下降趋势(P<0.001)。根据Joinpoint分析结果显示,2003至2014年NTDs发生率下降速度较慢,年度变化百分比为-4.04,2014至2022年NTDs发生率下降速度较快,年度变化百分比为-28.05。2003至2022年,陕西省NTDs产前诊断的平均比例为72.88%,出生结局以死胎(61.91%)为主,其次为活产(26.77%)、死产(8.73%)、出生7 d内死亡(2.59%)。经GM(1,1)模型预测,陕西省2023、2024和2025年NTDs率分别为0.49/万、0.41/万和0.35/万。结论2003至2022年陕西省NTDs发生率显著下降,尤其以2014年后下降速率加快。NTDs患儿出生结局以死胎为主,其次为活产。

高龄孕妇MTHFR基因多态性与血清UA、Hcy水平及出生缺陷影响因素分析

目的分析高龄孕妇亚甲基四氢叶酸还原酶(MTHFR)基因多态性及血清尿酸(UA)、同型半胱氨酸(Hcy)水平,探讨出生缺陷的影响因素。方法收集2021年10月至2023年12月青海红十字医院收治的11810例高龄孕妇为研究对象,并根据胎儿是否存在出生缺陷分为观察组(存在出生缺陷,826例)和对照组(未发现明显出生缺陷,10984例),比较两组孕妇的MTHFR基因多态性、血清UA、Hcy水平及临床资料,分析不同民族出生缺陷类型及出生缺陷的影响因素。结果11810例高龄孕妇中,共826例发生出生缺陷,出生缺陷发生率为6.99%;出生缺陷类型中染色体异常发生率最高(2.16%),汉族和回族中的染色体异常发生率均最高(分别为2.21%和1.93%),藏族中神经系统畸形率最高(2.80%)。观察组血清UA及Hcy水平、MTHFR基因C677T位点TT基因型以及总突变T等位基因频率均显著高于对照组(P<0.05)。单因素及多因素分析结果显示,MTHFR基因C677T位点TT基因型、高Hcy水平、高UA水平、常居地为高海拔地区、民族为藏/回族、不良孕产史、孕期未规律服用叶酸、孕早期感冒史、辅助生殖妊娠为出生缺陷的独立危险因素(P<0.05)。结论高龄孕妇MTHFR基因C677T位点TT基因型、高UA及Hcy水平可导致出生缺陷风险增加,需及时关注影响出生缺陷的独立危险因素以采取控制措施,减少高龄孕产妇发生出生缺陷的可能。

关键节点追踪干预对唐筛临界、高风险孕妇实施进一步检测依从性的影响

目的:探讨关键节点追踪干预对唐氏综合征血清学筛查临界、高风险孕妇出生缺陷二级预防措施实施依从性和对产前门诊服务质量满意度的影响。方法:采用便利抽样历史对照的方法,将某医院2020年1月至2020年12月接受检测的173例孕妇设为对照组,将2021年1月至2021年12月接受检测的165例孕妇设为干预组。对照组孕妇接受常规管理方法,干预组接受关键节点追踪干预方法。比较两组孕妇实施产前筛查与诊断技术依从性情况和对产前门诊服务质量满意度情况。结果:两组孕妇检测依从性比较,干预组的临界、高风险孕妇检测实施依从性均高于对照组(χ^(2)=14.449,P<0.001;χ^(2)=4.696,P<0.05);干预组对产前门诊服务质量的满意度高于对照组(χ^(2)=12.736,P<0.05)。结论:关键节点追踪干预可以有效提高唐氏综合征血清学筛查临界、高风险孕妇进一步检测实施依从性和提高孕妇对产前门诊服务质量的满意度。

Perinatal prevalence of birth defects in the Mainland of China,2000–2021:a systematic review and meta-analysis

Background Although birth defects are of great concern globally,the latest national prevalence has not yet been quantified in China.We conducted a systematic review and meta-analysis to estimate the perinatal prevalence of birth defects in the Mainland of China between 2000 and 2021.Methods We performed a systematic literature search of six databases for relevant articles published between January 1,2000,and March 1,2023.We included published studies that reported data on the perinatal prevalence of birth defects in the Mainland of China.The DerSimonian and Laird random-effects models were used to estimate the pooled prevalence and its 95%confidence interval(CI).We also conducted subgroup analyses and univariable meta-regressions to explore differences in prevalence by time period,geographic region,and other characteristics.Results We included 254 studies reporting the perinatal prevalence of birth defects and 86 studies reporting only the prevalence of specific types of birth defects.Based on 254 studies covering 74,307,037 perinatal births and 985,115 cases with birth defects,the pooled perinatal prevalence of birth defects was 122.54(95%CI 116.20–128.89)per 10,000 perinatal births in the Mainland of China during 2000–2021.Overall,the perinatal prevalence of birth defects increased from 95.60(86.51–104.69)per 10,000 in 2000–2004 to 208.94(175.67–242.22)per 10,000 in 2020–2021.There were also significant disparities among different geographical regions.Congenital heart defects(33.35 per 10,000),clefts of the lip and/or palate(13.52 per 10,000),polydactyly(12.82 per 10,000),neural tube defects(12.82 per 10,000),and inborn errors of metabolism(11.41 per 10,000)were the five most common types of birth defects.The perinatal prevalence among males was significantly higher than that among females(β=2.44×10^(−3),P=0.003);a higher perinatal prevalence of birth defects was observed among perinatal births whose mothers were≥35 years(β=4.34×10^(−3),P<0.001).Conclusion Comprehensive and sustained efforts are needed to strengthen surveillance and detection of birth defects,improve prenatal and postnatal healthcare,and promote rehabilitation,especially in underdeveloped areas.