Screening for phenylketonuria in New York City. Threshold values reconsidered

In New York City from 1966 to 1970, almost all 736,469 newborns were screened for phenylketonuria (PKU). Among 1,094 infants with presumptive positive test results, 763 were followed up and 46 of them were judged to require preventive treatment. The considerable annual variation observed in the frequency of values of 4 to 6 mg/100 ml bood phenylalanine suggested low reliability at this level. Screening test results of 4 mg/100 ml, with no cases detected among them, represented 53% of all false positive results; newborns with 6 mg/100 ml results yielded 1 infant in need of treatment and accounted for 40% of the false positive results. The large volume of presumptive positive results generated by these levels presumably contributed to incomplete followup. If the threshold value for followup were raised, the effectiveness and the efficiency of the screening program could be improved. The experiences of other large PKU programs in the United States support these observations.     

Survey of departments of health about PKU screening programs.

Mailed questionnaires were used to examine the success of PKU (phenylketonuria) screening programs that were operated by departments of health and to examine differences between these programs. Of 55 departments, 44 were returned and 42 departments reported they had a PKU detection program. Thirty-eight respondents considered the PKU detection program to be effective, and 31 respondents indicated that the entire program cost $60,000 or less per year. The answers and comments on the questionnaires showed a generally positive view of the effectiveness about the value of the treatment program in general were also positive. However, a few departments indicated that more clinical evidence and experience were needed to fully evaluate the overall merits of PKU detection and screening programs.     

The New England Maternal PKU Project: identification of at-risk women

Young women with phenylketonuria (PKU) are at risk for bearing children with mental retardation, microcephaly, heart defects, and low birthweight. These effects may be prevented if a low phenylalanine diet is maintained prior to and throughout pregnancy. This report describes the procedures of the New England Regional Maternal PKU Project for identifying and locating this population of at-risk women. Newborn screening records, routine umbilical cord blood screening, and PKU Clinic records provided most of the identifying information. We identified 235 women with hyperphenylalaninemia, ages 12 to 44 years. Of these, 183 had PKU or atypical PKU while 52 had non-PKU mild hyperphenylalaninemia. The 235 women represent 88 per cent of the expected number of women with hyperphenylalaninemia in New England. We identified more than the expected number of those with PKU but only 57 per cent of the expected number with mild hyperphenylalaninemia. Developing a national registry, as well as screening women who utilize birth control clinics or prenatal clinics, may be helpful. Implementing routine umbilical cord blood screening programs may be beneficial in efforts to identify women with hyperphenylalaninemia who have had a child and may want more children in the future.     

青岛市四方区1997——2007年新生儿疾病筛查回顾性分析

目的 回顾分析1997-2007年四方区新生儿先天性甲状腺功能低下（CH）、苯丙酮尿症（PKU）的筛查情况．总结经验．使新生儿筛查工作更加正规化、制度化,最大限度地降低智障儿的发生。方法 新生儿出生后72h采足跟血滴于美国进口滤纸上,用荧光法检测血促甲状腺素（TSH）,苯丙氨酸（Phe）浓度。结果 四方区11年来共筛查29814例,确诊CH14例．（男：女=1：2．5）发病率为0．470％。;PKU患儿1例,发病率为0．033％。结论 新生儿疾病筛查是CH,PKU患儿早期诊断的有效方法：政府支持、政策得力、健全妇幼保健三级网络及严格控制实验室质量．保证100％的追访治疗率．是完善新生儿疾病筛查工作．有效降低智障儿发生的有效手段。     

2002～2008年锦州市新生儿疾病筛查分析研究

目的:探讨锦州市2002～2008年新生儿疾病筛查情况,总结经验,采取措施,促进筛查工作。方法:新生儿出生后72h,采足跟末稍血制成滤纸干血片,进行筛查。结果:2002～2008年锦州市新生儿筛查83328例,确诊先天性甲状腺功能减退症(CH)30例,CH发病率1/2777;苯丙酮尿症(PKU)为6例,PKU发病率为1/13888。新生儿筛查率呈逐年上升趋势,由2002年的26.6%上升至2008年的74.6%,平均每年以6.8%的速度上升。结论:锦州市CH及PKU发病率处于稳定水平,在进行新生儿疾病筛查工作中,完善新生儿疾病筛查管理办法和技术规范,加强社会宣传力度,重视筛查工作质量,对CH和PKU患儿早期治疗可避免体格和智能发育障碍,是提高人口素质的重要措施。     

泰州地区新生儿苯丙酮尿症和甲状腺功能减低症筛查分析

目的:了解泰州地区新生儿苯丙酮尿症(PKU)、先天性甲状腺功能减低症(CH)筛查及治疗状况。方法:对泰州地区2003～2011年参加新生儿筛查及治疗情况进行总结。结果:近8年共筛查250 095例新生儿,筛查率呈逐渐上升趋势;共筛查出PKU 15例,发病率0.06‰;CH67例,发病率0.27‰。结论:泰州地区PKU及CH发病率均低于全国平均水平,通过新生儿疾病筛查可以有效对PKU及CH进行早期诊治,减少残疾的发生。     

Prevention of mental retardation in offspring of hyperphenylalaninemic mothers.

Maternal hyperphenylalaninemia constitutes a potential hazard to the fetus for whom the risks of postnatal mental retardation, microcephaly, and congenital malformations are elevated. Preconception and intragestational dietary treatment can apparently improve the outcome of such pregnancies. In the absence of predictive mechanisms for pregnancies at risk and preventive measures involving reproductive counseling and treatment, there could be a rebound in the population frequency of mental retardation related to disorders of phenylalanine metabolism in subsequent generations. We describe a program serving a population of six million that includes screening, diagnosis, treatment, and counseling of the hyperphenylalaninemias. The program has recently added a simple dedicated register for males and females with hyperphenylalaninemia to supplement traditional methods for continuous surveillance of probands. We registered 153 patients: 43 females and 56 males with phenylketonuria, 23 females and 31 males with benign hyperphenylalaninemia, of which 22, 7, 27 and 5, respectively, had reached their 12th birthday in an 1981. Regional centers in the program provided counseling about the consequences of maternal hyperphenylalaninemia and the options to prevent them. No family has rejected the principle or fact of the Register and its goals.     

Trade-off between benefit and harm is crucial in health screening recommendations. Part II: evidence summaries

Evidence on the effectiveness of health screening strategies may be direct (i.e., studies on screening vs. no screening) or indirect (i.e., studies that separately evaluate the screening test[s], the confirmatory test, or the treatment). Critical trade-offs in the balance between harm and benefit for many screening strategies mandate that advocates of health screening adhere to the ethical precepts of nonmaleficence, autonomy, confidentiality, and equity. In our first article, we pointed out five prerequisites to justifying a health screening program: (1) the burden of illness should be high, (2) the screening and confirmatory tests should be accurate, (3) early treatment (or prevention) must be more effective than late treatment, (4) the tests and the treatment(s) must be safe, and (5) the cost of the screening strategy must be commensurate with the potential benefit. As can be gleaned from these criteria, recommendations on screening must be tailored to specific populations. Recommendations in one country, no matter how authoritative, cannot be generalized to apply to all other countries. Although accuracy, effectiveness, and safety data may be global (criteria 2-4), burden of illness and efficiency (criteria 1 and 5) will always vary from country to country. Rather than review various national guidelines, in this last article of our two-part series, we present evidence summaries to illustrate health screening. Our examples were selected to address special issues related to four situations—screening for cancer, risk factors for disease, genetic disorders, and infectious diseases.     

清远市149612例新生儿疾病筛查结果回顾性分析

目的通过回顾性分析清远市149 612例新生儿疾病四项筛查结果,了解清远市新生儿疾病筛查情况及召回率,为进一步提高新生儿疾病筛查的质量提供依据。方法应用芬兰Ani Labsystems公司提供的筛查试剂盒,对149 612份标本进行促甲状腺激素(h TSH)、苯丙酮尿症(PKU)、葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症实验检测,应用法国Sebia Capillarys全自动毛细管电泳仪测定新生儿血红蛋白,从而检测地中海贫血。结果 2016年1月-2018年9月清远市各分娩单位出生新生儿156 323例,接受新生儿疾病筛查的有149 612例,筛查率为95. 71%,其中PKU可疑阳性1 441例,召回1 387例,确诊3例;先天性甲状腺功能减低可疑阳性5 753例,召回3 380例,确诊1 221例;G6PD可疑阳性10 269例,召回4 210例,确诊2 754例;130 669例新生儿中,α地中海贫血可疑阳性11 582例,召回4 272例,确诊3 305例;β地中海贫血可疑阳性8 606例,召回5 463例,确诊1 041例,其中α地中海贫血复合β地中海贫血220例。结论新生儿疾病四项筛查是先天遗传代谢病早期诊断的有效方法,也是现代预防医学的一项重要内容,可有效避免患儿发生体格和智能不可逆的永久性损伤,对地中海贫血防控、优生优育具有重要深远的意义。     

惠州市新生儿PKU、CH、G6PD缺陷筛查结果分析

目的:了解惠州市新生儿PKU、CH、G6PD缺陷的发病率及新生儿疾病筛查的情况。方法:对惠州市2004年度新生儿筛查资料及惠州市各区人口出生情况进行回顾性分析。结果:CH的发病率是4/3157,G6PD缺陷的发病率是415/12629,PKU的检出率是1/12629;惠州市的新生儿总筛查率是27.60%。结论:新生儿筛查是早期发现PKU、CH、G6PD缺陷患儿,使其得到早期诊治,避免发生体格和智能发育障碍的有效手段,是提高人口素质的重要措施。     

新生儿先天性甲状腺功能低下症和苯丙酮尿症筛查

目的　开展新生儿先天性甲状腺功能低下症(Congenital Hypothyroidism ,CH) 和苯丙酮尿症(Phenylketonuria,PKU) 筛查,降低残疾儿童的发生率,提高我国人口素质。方法　应用时间分辨荧光免疫法(TimeResolved Fluorescence Im munoassay ,Tr- FIA) 检测新生儿促甲状腺素(thyroid - stimulating hormone,TSH) 浓度筛查CH;用细菌抑制法(Bacterial Inhibition Assay, BIA) 测定新生儿血苯丙氨酸含量筛查PKU。结果　筛查新生儿CH295991 例,阳性63 例,筛查阳性率为1/4698 ;筛查新生儿PKU 205083 例,筛查阳性率为1/22787 。结论　Tr -FIA 技术是应用于新生儿筛查CH 最为理想的非放射性免疫分析方法;备有严格质量保证的标化枯草杆菌悬液,是做好BIA 筛查PUK 的先决条件;接受国际、国内对新生儿疾病筛查实验室质量监控,是对大批量检测标本质量的有效保证。     

武汉市新生儿苯丙酮尿症筛查11年分析研究

目的:回顾武汉市新生儿苯丙酮尿症11年筛查情况,总结经验、查找不足,促进筛查工作。方法:新生儿出生后72h,采足跟末梢血制成滤纸干血片,检测血片中Phe含量,将Phe值≥240μmol/L(BIA法)或≥120μmol/L(荧光法)的新生儿判为初筛阳性,召回复查确诊。结果:11年来,武汉市筛查新生儿321881例,确诊PKU患儿15例,PKU发病率为0.47/万;PKU发病率无显著上升或下降趋势;用BIA法筛出的PKU发病率与用荧光法筛出的发病率无显著差异。结论:武汉市PKU发病率处于相对稳定的较低水平,用荧光法筛查要优于BIA法,新筛实验室应尽可能使用荧光法,既可降低初筛阳性率,又能提高检出率。要提高筛查覆盖率,加强PKU与BH4的鉴别诊断,研究武汉市PKU患儿家族苯丙氨酸羟化酶基因突变情况,为PKU的产前诊断提供依据。     

广州市1071 203例新生儿苯丙酮尿症筛查结果回顾性分析

目的:回顾性分析广州市1071 203例新生儿苯丙酮尿症(PKU)筛查和召回结果,了解广州地区苯丙酮尿症的发病情况。方法:以2000~2009年广州市所有出生的新生儿为对象,在出生72 h、充分母乳后采集足跟血检测苯丙氨酸含量。筛查结果阳性者及时召回,以血清标本复查确诊并追踪评价治疗效果。结果:共筛查新生儿1071 203例,召回率为96.27%,共检出苯丙酮尿症阳性数35例,发病率为1:30 606。全部阳性患者经早期诊断治疗,患儿的体格和智力等发育无明显异常。结论:新生儿疾病筛查是苯丙酮尿症早期诊断的有效措施之一,也是预防PKU患儿智力和体格发育低下的关键。建立有效的筛查召回网络,规范业务流程,加大宣传力度和加强基层培训能有效提高筛查率和召回率。     

Economics of tandem mass spectrometry screening of neonatal inherited disorders

OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of neonatal screening for phenylketonuria (PKU) and medium-chain acyl-coA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (tandem MS). METHODS: A systematic review of clinical efficacy evidence and cost-effectiveness modeling of screening in newborn infants within a UK National Health Service perspective was performed. Marginal costs, life-years gained, and cost-effectiveness acceptability curves are presented. RESULTS: Substituting the use of tandem MS for existing technologies for the screening of PKU increases costs with no increase in health outcomes. However, the addition of screening for MCAD deficiency as part of a neonatal screening program for PKU using tandem MS, with an operational range of 50,000 to 60,000 specimens per system per year, would result in a mean incremental cost of -pound 17,298 (-pound 129,174, pound 66,434) for each cohort of 100,000 neonates screened. This cost saving is associated with a mean incremental gain of 57.3 (28.0, 91.4) life-years. CONCLUSIONS: Cost-effectiveness analysis using economic modeling indicates that substituting the use of tandem MS for existing technologies for the screening of PKU alone is not economically justified. However, the addition of screening for MCAD deficiency as part of a neonatal screening program for PKU using tandem MS would be economically attractive.     

东莞市新生儿疾病筛查结果分析和随访

目的:分析东莞市10年新生儿疾病筛查和随访结果,评价东莞市新生儿筛查中心开展新生儿疾病筛查的成效和经济效益,以及对提高人口素质的重要性。方法:对2001～2010年东莞市新生儿疾病筛查中心先天性甲状腺功能低下症(CH)、苯丙酮尿症(PKU)、葡萄糖6磷酸脱氢酶(G6PD)缺乏症的筛查结果进行回顾性分析,以东莞市新生儿疾病筛查中心为中心建立东莞市所有产科医院的筛查网络,以所有出生的新生儿为对象,在出生72 h充分母乳后,采集足跟血检测TSH浓度、苯丙氨酸、G6PD活性。筛查结果阳性者,以血清标本复查确诊。结果:2001～2010年东莞市新生儿疾病筛查中心共筛查新生儿771 083例,其中确诊为CH 277例,发病率为1/2 784,回访253例,回访率为91.34%;PKU 30例,发病率为1/25 703,回访25例,回访率为83.33%;G6PD缺乏症26 091例,发病率为1/30,回访23 522例,回访率为90.15%。经早期诊断治疗,CH患儿的体格和智力等发育无明显异常。结论:新生儿疾病筛查是CH、PKU、G6PD缺乏症早期诊断的有效措施之一,建立有效的筛查网络能有效提高筛查率和降低漏诊率,做到早诊早治,有效地防止患儿智力和体格发育低下以及其他器官功能的损害。     

Barriers to dietary control among pregnant women with phenylketonuria--United States, 1998-2000

Newborns in the United States are screened for phenylketonuria (PKU), a metabolic disorder that when left untreated is characterized by elevated blood phenylalanine (phe) levels and severe mental retardation (MR). An estimated 3,000-4,000 U.S.-born women of reproductive age with PKU have not gotten severe MR because as newborns their diets were severely restricted in the intake of protein-containing foods and were supplemented with medical foods (e.g., amino acid-modified formula and modified low-protein foods). When women with PKU do not adhere to their diet before and during pregnancy, infants born to them have a 93% risk for MR and a 72% risk for microcephaly. These risks result from the toxic effects of high maternal blood phe levels during pregnancy, not because the infant has PKU. The restricted diet, which should be maintained for life, often is discontinued during adolescence. This report describes the pregnancies of three women with PKU and underscores the importance of overcoming the barriers to maintaining the recommended dietary control of blood phe levels before and during pregnancy. For maternal PKU-associated MR to be prevented, studies are needed to determine effective approaches to overcoming barriers to dietary control.     

The Cost-Effectiveness of Expanding Newborn Screening for up to 21 Inherited Metabolic Disorders Using Tandem Mass Spectrometry: Results from a Decision-Analytic Model

OBJECTIVES: In 2005, in Ontario, Canada, newborns were only screened for phenylketonuria (PKU) and hypothyroidism. Tandem mass spectrometry (MS/MS) has since been implemented as a new screening technology because it can screen for PKU and many other diseases simultaneously. We estimated the cost-effectiveness of using this technology to expand the Ontario newborn screening program to screen for each disease independently and for hypothetical bundles of up to 21 metabolic diseases. METHODS: We constructed a decision-analytic model to estimate the incremental costs and life-years of survival that can be gained by screening or changing screening technologies. Costs and health benefits were estimated for a cohort of babies born in Ontario in 1 year. Secondary sources and expert opinion were used to estimate the test characteristics, disease prevalence, treatment effectiveness, disease progression rates, and mortality. The London Health Sciences Centre Case Costing Initiative, the Ontario Health Insurance Plan Schedule, and the Ontario Drug Benefits plan formulary were used to estimate costs. RESULTS: Changing screening technologies, from the Guthrie test to MS/MS, for PKU detection had an incremental cost of $5,500,000 per life-year (LY) gained. We identified no diseases for which the incremental cost of screening for just that disease was less than $100,000 per LY gained. The incremental costs of screening ranged from $222,000 (HMG-CoA lyase deficiency) to $142,500,000 (glutaric acidemia type II) per LY gained. Screening for a bundle of diseases including PKU and the 14 most cost-effective diseases to screen for cost less than $70,000 per LY gained, and the incremental cost-effectiveness of adding each of the 14 diseases to the bundle was less than $100,000 per LY gained. The incremental cost of adding the 15th most cost-effective disease was $309,400 per LY gained. CONCLUSIONS: Early diagnosis and treatment of metabolic disease is important to reduce disease severity and delay or prevent the onset of the disease. Screening at birth reduces the morbidity, mortality, and social burden associated with the irreversible effects of disease on the population. Our analysis suggests that the cost-efficiencies gained by using MS/MS to screen for bundles of diseases rather than just one disease are sufficient to warrant consideration of an expanded screening program. It is, however, not cost-effective to screen for all diseases that can be screened for using this technology.     

Intellectual development of patients with phenylketonuria; 15-year national screening in The Netherlands]

OBJECTIVE. To evaluate the intellectual development of patients with phenylketonuria (PKU) or hyperphenylalaninaemia (HPA). DESIGN. Longitudinal follow-up study. SETTING. University Children's Hospitals of Amsterdam, Groningen, Nijmegen, and Rotterdam. METHODS. In September 1974 a nationwide neonatal screening for PKU started in the Netherlands. We obtained data on the intellectual development of 116 patients (101 classical PKU, 15 HPA), all detected and treated in the first 15 years of this screening. The children were tested at 6 ages with different instruments for the assessment of intellectual functions, and the scores were compared with the test norms. Performance and verbal capacities were determined as well as possible sex-related differences. RESULTS. Our data show that the levels of intellectual functioning of PKU and HPA patients do not differ from test norms until the age of 8 yr 6 months. In the older PKU patients there appears to be a trend towards lower IQ scores. We found no sex differences in the mental functioning of PKU patients. CONCLUSION. Continuation of this study is necessary in order to investigate possible negative effects of PKU on cognitive functioning, especially in the older age groups.     

Preventive effectiveness of pre-employment medical assessments.

OBJECTIVE AND METHODS: Health gain, prevention of health loss, and avoidance of financial risk all seem to be driving forces for the use of pre-employment medical assessment. An attempt is made to measure the effect of implementing the pre-employment medical assessment on these end points. The anticipated maximum preventive effect (preventive effectiveness) of selection by means of pre-employment medical assessments for work related risks and the potential for disablement in individual workers can be calculated or estimated. Necessary parameters include test validity characteristics and epidemiological data for both the adverse outcome to be prevented, and risk factors of concern. RESULTS: The preventive effectiveness can be expressed as the effort (number of actions) needed to prevent one adverse event-for example, one case of occupational disease or one case of long term disablement. Actions include: a pre-employment health assessment, rejection of the candidate, individual precautions, adjustments of the job, and adjustments of the job environment. It seems that the preventive effectiveness of many actions can be low, implying that large numbers of actions are needed to prevent one adverse outcome. DISCUSSION: The medical assessment should consist of no more questions and tests than are required relevant to the stated aim. Particularly, when the pre-employment medical assessment is used to reject candidates at risk, the use of tests should be carefully weighed. If the preventive effectiveness is considered to be too low, then the question or test should not be incorporated for selection purposes. The application of a so called "expert judgment" should be based on professional guidelines wherever possible and should be made clear. The benefit of reducing the incidence of a serious adverse event by one may outweigh the costs of rejecting many candidates. CONCLUSIONS: The concept of preventive effectiveness may help to reach evidence based occupational medicine, which starts at the pre-employment medical assessment.     

Importance of diet in maternal phenylketonuria

Diet has long been recognized as the primary treatment modality for individuals with phenylketonuria (PKU) during infancy and childhood. Recent findings from the Maternal PKU Collaborative Study clearly indicate that dietary restriction of phenylalanine is also necessary to prevent the adverse effects of an elevated plasma phenylalanine concentration during pregnancy, which include microcephaly, physical anomalies, and mental retardation.