External Quality Assessment of Maternal Serum Levels of Alpha-Fetoprotein, Free Beta-Human Chorionic Gonadotropin, and Unconjugated Estriol in Detecting Down Syndrome and Neural Tube Defects in the Second Trimester of 87 Maternal Serum Samples, Based on 105-139 Days.

BACKGROUND We aimed to insure the accuracy and reproducibility of alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (free ß-hCG), and unconjugated estriol (uE3) concentrations for the screening for trisomy 21 (T21) and neural tube defects (NTD) in the second trimester. We conducted an external quality assessment of 6 laboratories, using maternal serum specimens. MATERIAL AND METHODS Serum specimens collected from 87 women of singleton pregnancies (4 with T21, 5 with NTD, and 78 with normal fetuses) were divided into 6 equivalent-volume fractions and transported to 6 laboratories (A, B, C, D, E, and F). All laboratories used the time-resolved fluorescence analyzer and supporting reagents to measure concentrations of AFP, free ß-hCG, and uE3. The screening efficacies of T21 and NTD were compared with the certified or accredited status of the participants' quality systems. RESULTS Concentrations of AFP measured by laboratory F were low compared with those determined by the other 5 laboratories, and the differences were significant (P<0.01). There was no statistically significant difference in the free ß-hCG and uE3 concentrations measured by the 6 laboratories (P>0.05). The correlation coefficients for the 3 multiples of the median values were all >0.900. The McNemar paired chi-squared test showed the differences in the positivity and detection rates were not statistically significant (P=1.000). CONCLUSIONS AFP, free ß-hCG, and uE3 values measured by the other 5 laboratories were comparable with those of laboratory A, with good linear correlation. When used in the maternal prenatal screening of T21 and NTD, the test results met the clinical requirements.

Prenatal screening for genetic disorders: Suggested guidelines for the Indian Scenario.

Prenatal testing is the best strategy for reducing the burden of genetic disorders and congenital disabilities that cause significant postnatal functional impairment. Universal prenatal screening is advisable for common genetic disorders and congenital anomalies such as Down syndrome, beta-thalassaemia and neural tube defects. Several prenatal-screening tests are now available for Down syndrome, but knowledge about the appropriate timing of the test and the need for pre- and post-test counselling may not be updated among the primary care physicians. There is also a considerable degree of confusion regarding the prenatal screening test to be chosen in each case, due to the availability of a number of new and advanced screening techniques. At present, there is no nation-wide consensus regarding the nature and timing of these prenatal-screening protocols. Due to the absence of any definite guidelines and the additional lacunae in the awareness regarding the appropriate prenatal screening in the country, the optimum benefits of these screening protocols are not reaching the population. This review focuses on the various prenatal screening and diagnostic tests that are available for common genetic conditions and congenital disabilities and attempts to outline the most cost-effective and gestational age-appropriate strategies for prenatal screening for the Indian healthcare set-up. The recommendations suggested would serve as a source guide for formulating prenatal-screening guidelines for reducing the incidence of common genetic disorders and congenital disabilities in India.

Routine measurement of amniotic fluid alpha-fetoprotein and acetylcholinesterase: the need for a reevaluation.

OBJECTIVE: The objective of the study was to evaluate whether the current screening regimen of measuring amniotic fluid alpha-fetoprotein (AF-AFP) at the time of amniocentesis and reflex acetylcholinesterase testing vs ultrasound alone to detect neural tube and ventral wall defects offers improved diagnostic accuracy and cost benefit. STUDY DESIGN: A retrospective chart review on all patients who had amniocentesis performed at 1 center over the past 11 years was performed. Those with an elevated AF-AFP were compared with those whose AF-AFP was within normal limits. Ultrasound findings and outcomes were reviewed in all cases to assess whether neural tube defects (NTDs) or ventral wall defects (VWDs) were missed by AF-AFP or ultrasound screening. A cost-benefit analysis was then performed. RESULTS: Of 6232 women who underwent amniocentesis between January 2002 and December 2012, 81 had an elevated AF-AFP with or without a positive acetylcholinesterase (AChE). Of these 81 women, 13 had NTDs and 5 had VWDs. The sensitivity of the detailed ultrasound was 100% in detecting NTDs and VWDs, whereas that of the AF-AFP ranged from 22% to 77%, with the inclusion of AChE. The total expenditure for AF-AFP in our sample set (n = 6232 amniocentesis at $76.00 per AF-AFP) was $473,632, and all NTDs and VWDs were detected by ultrasound. Translated to a national laboratory (>42,447 samples/year), the cost savings in 2011 alone would be $3,225,972. CONCLUSION: Given the accuracy of high-resolution ultrasound in the detection of both NTDs and VWDs, measuring AF-AFP and AChE as a reflex-screening test is not a cost-effective approach.

[Assessment of AFP in amniotic fluid: comparison of three automated techniques]. / Dosage de l'AFP dans le liquide amniotique : comparaison de trois techniques automatisées.

Ultrasound scanning is useful to detect neural tube defect (NTD) but scarcely distinguished between closed NTD and open NTD, which had very different prognosis. An amniotic fluid punction is thus mandatory to search for an increase in alpha foeto protein (AFP) levels and for the presence of acetylcholinesterase which identified open NTD. However, AFP levels fluctuate both with the gestational age and the assay used. Our aim was to establish normative values for AFP in amniotic fluid in the second half of pregnancy using three different immunoassays and to improve their clinical relevance. Amniotic fluid punctions were performed on 527 patients from 9 week of gestation (WG) to 37 WG either for maternal age, Trisomy 21 screening, increase in nucal translucency (control group, n = 527) or for suspicion of neural tube defect or abdominal defect (n = 5). AFP was measured using the immunoassay developed for serum AFP on the Access 2 system, the Immulite 2000 and the Advia Centaur. Results were expressed in ng/ml, multiple of the median (MoM) and percentiles. AFP decrease by 1.5 fold between 9 and 19 WG. When NTD was suspected, an increase in anmniotic AFP was observed (from 2.5 MoM to 9.3 MoM) confirming an open NTD. In conclusion, the assay developed on those 3 automates is suitable for the measurement of AFP in amniotic fluid.

Costs and effects of prenatal screening methods for Down syndrome and neural tube defects.

OBJECTIVES: To evaluate prenatal screening methods for Down syndrome and neural tube defects (NTD) with regard to costs per detected case and the number of screening-related miscarriages. METHODS: The screening methods compared were risk assessment tests, i.e. serum tests and nuchal translucency measurement (NT), and invasive testing through chorionic villus sampling (CVS) or amniocentesis. Costs, the number of cases detected and screening-related miscarriages were calculated using a decision tree model. RESULTS: The costs per detected case of Down syndrome ranged from EUR 98,000 for the first-trimester (serum) double test to EUR 191,000 for invasive testing. If NTD detection was included, the (serum) triple test had the lowest costs, EUR 73,000, per detected case of Down syndrome or NTD. The number of screening-related miscarriages due to invasive diagnostic tests varied from 13 per 100,000 women for the (serum) first- and second-trimester combined test to 914 per 100,000 women for invasive testing. CONCLUSIONS: Considering screening for both Down syndrome and NTD favors the triple test in terms of costs per detected case. Compared to invasive testing, risk assessment tests in general substantially lower screening-related miscarriages, which raises the question of whether invasive testing should still be offered in a screening program for Down syndrome.

Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down's syndrome.

OBJECTIVE: To 'map' the current (2004) state of prenatal screening in Europe. DESIGN: (i) Survey of country policies and (ii) analysis of data from EUROCAT (European Surveillance of Congenital Anomalies) population-based congenital anomaly registers. SETTING: Europe. POPULATION: Survey of prenatal screening policies in 18 countries and 1.13 million births in 12 countries in 2002-04. METHODS: (i) Questionnaire on national screening policies and termination of pregnancy for fetal anomaly (TOPFA) laws in 2004. (ii) Analysis of data on prenatal detection and termination for Down's syndrome and neural tube defects (NTDs) using the EUROCAT database. MAIN OUTCOME MEASURES: Existence of national prenatal screening policies, legal gestation limit for TOPFA, prenatal detection and termination rates for Down's syndrome and NTD. RESULTS: Ten of the 18 countries had a national country-wide policy for Down's syndrome screening and 14/18 for structural anomaly scanning. Sixty-eight percent of Down's syndrome cases (range 0-95%) were detected prenatally, of which 88% resulted in termination of pregnancy. Eighty-eight percent (range 25-94%) of cases of NTD were prenatally detected, of which 88% resulted in termination. Countries with a first-trimester screening policy had the highest proportion of prenatally diagnosed Down's syndrome cases. Countries with no official national Down's syndrome screening or structural anomaly scan policy had the lowest proportion of prenatally diagnosed Down's syndrome and NTD cases. Six of the 18 countries had a legal gestational age limit for TOPFA, and in two countries, termination of pregnancy was illegal at any gestation. CONCLUSIONS: There are large differences in screening policies between countries in Europe. These, as well as organisational and cultural factors, are associated with wide country variation in prenatal detection rates for Down's syndrome and NTD.

Routine assessment of amniotic fluid alpha-Fetoprotein in early second-trimester amniocentesis is no longer justified.

BACKGROUND: Open fetal neural tube defects are often followed by an increase in alpha-Fetoprotein concentration in amniotic fluid. For over 25 years there has been a routine to measure amniotic fluid alpha-Fetoprotein in conjunction with early genetic amniocentesis. The efficacy of such a screening test in a low-risk population has been questioned but never evaluated in a Swedish population. METHODS: Data were reviewed retrospectively from all consecutive early second-trimester genetic amniocenteses from two hospitals during the years 1993-2003. Indications for the genetic amniocenteses were maternal age > or = 35 years, maternal anxiety or a history of fetal aneuploidy. A questionnaire was sent to all obstetric clinics in Sweden regarding current common policy and experience of routine amniotic fluid alpha-Fetoprotein measurements, in the detection of open fetal neural tube defects. RESULTS: A total of 1,813 samples were included. In eight cases (0.4%) the amniotic fluid alpha-Fetoprotein concentrations were > or = 3 multiples of median, but five of them were false positive (63%). Out of the three true positive cases, one had clinical relevance. In the other two cases the detection of open fetal neural tube defects was of subordinate importance. In Sweden, during 2004, 91% of the obstetric clinics performed routine assessment of amniotic fluid alpha-Fetoprotein at second-trimester genetic amniocentesis, but only 9% regarded the analysis useful in clinical practice. CONCLUSIONS: According to our results, routine measurement of amniotic fluid alpha-Fetoprotein in early second-trimester genetic amniocentesis, to rule out a risk of open fetal neural tube defects, does not seem justified. The clinical usefulness seems to be limited.

Improving population health or the population itself? Health technology assessment and our genetic future.

The province of British Columbia (BC), Canada is developing its first population-wide prenatal genetic screening program, known as triple-marker screening (TMS). TMS, initiated with a simple blood test, is most commonly used to screen for fetuses with the chromosomal abnormality known as Down syndrome or neural tube disorders. Women testing TMS-positive are offered diagnostic amniocentesis and, if the diagnosis is confirmed, selective second-trimester abortion. The project described in this study was initiated to address the broad range of issues arising from this testing technology and provides an example of the new type of health technology assessment (HTA) contribution emerging (and likely to become increasing necessary) in health policy development. With the advent of prenatal genetic screening programs, would-be parents gain the promise of identifying target conditions and, hence, the option of selective abortion of affected fetuses. There is considerable awareness that these developments pose challenges in every dimension (ethical, political, economic, and clinical) of the health-care environment. In the effort to construct an appropriate prenatal screening policy, therefore, administrators have understandably sought guidance from within the field of HTA. The report authors concluded that, within the restricted path open to it, the role of government is relatively clear. It has the responsibility to maintain equal access to prenatal testing, as to any other health service. It should also require maintenance of medical standards and evaluation of program performance. At the same time, policy-makers need actively to support those individuals born with disabilities and their families.

Social and ethnic inequalities in the offer and uptake of prenatal screening and diagnosis in the UK: a systematic review.

OBJECTIVE: To review studies addressing the question of whether there are social inequalities in either the offer or the uptake of prenatal testing in the UK. METHOD: Systematic review of studies assessing the offer or uptake of prenatal screening or diagnosis according to social class or ethnic origin. Electronic databases were searched using a strategy developed for a review of inequalities in access to maternity care supplemented with terms specific to prenatal testing. Further papers were identified from reference lists, citation searches and key organizations. RESULTS: From over 600 identified papers, 41 were potentially relevant. Twenty met the inclusion criteria. The studies included covered screening and/or diagnosis for Down's syndrome, neural tube defects, haemoglobin disorders and HIV. Many studies were limited by small numbers or poor reporting of data and analysis. Six studies reported data on prenatal testing according to women's social class or educational level. None found any significant social inequalities in testing. Some studies suggested that women of South Asian origin might be up to 70% less likely to receive prenatal testing for haemoglobin disorders and Down's syndrome than White women. A small number of studies suggested that South Asian women might be less likely to be offered testing. CONCLUSIONS: This review provides some evidence of ethnic inequalities in access to prenatal testing. Further research is required to improve our understanding of why testing may not be offered, the reasons for failure to take up testing when offered, and to identify whether there are other social inequalities in access to prenatal testing.

Magnetic resonance imaging and ultrasound in the assessment of the fetal central nervous system.

Ultrasound is the screening modality of choice for evaluation of the fetal central nervous system (CNS). However, in cases of difficult diagnosis further fetal investigation is desirable. Due to ultrafast magnetic resonance imaging (MRI) techniques artifacts from fetal motions are minimized. MRI involves no exposure to radiation and hence appears to be safe. Due to the better soft tissue contrast, additional investigation by MRI may extend the sonographic diagnosis of fetal CNS-anomalies. Ultrasound and MRI are complementary imaging methods in the evaluation of the fetal CNS. The most important indications for ultrasound are screening for CNS anomalies and serial assessment of the dynamic of the disorder. The most important indications for fetal MRI are the "second opinion" and investigation by fetal MRI instead of postpartum MRI (especially in cases of planned postpartum intervention). In this article the indications and limitations of ultrasound and magnetic resonance imaging in the evaluation of the fetal CNS are discussed.

Prenatal screening tests facilitate risk assessment.

Medical technology continues to improve services and testing to provide accurate and timely information for physicians and patients. New screening protocols in which information obtained in the first and second trimesters is integrated to improve detection and lower false positive rates have potential for safer and more effective prenatal care. Families still have difficult choices to make when confronted with the diagnosis of a birth defect. Inherent advantages of early detection are reassurance for low-risk women sooner, and for women with increased risk, more time to consider all options. Without doubt, improvements in risk assessment, diagnosis, and prevention will continue. The advantage offered by laboratory procedures is that the preliminary diagnosis can be made by simple, noninvasive screening tests.

Maternal serum triple analyte screening in pregnancy.

According to the American College of Obstetricians and Gynecologists, it has become standard in prenatal care to offer screening tests for neural tube defects and genetic abnormalities. There have been some changes in the recommended method of prenatal screening over the past few years, and research to improve detection rates with better combinations of maternal serum analytes is ongoing. The issues facing physicians are the sensitivity and specificity of multiple serum analyte combinations. The current maternal serum analytes in use in most areas are alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) and unconjugated estriol. Measurement of AFP alone can detect the vast majority of neural tube defects and a small portion of trisomy 21-affected pregnancies in patients of all ages. Adding hCG and unconjugated estriol to this screen increases the rate of detection of trisomies 21 and 18. Counseling patients about the risks and benefits of such screening is important to provide a balanced discussion of screening issues.

Effect of incorrect gestational dating on Down's syndrome and neural tube risk assessment.

Down's syndrome risks are estimated between 15 and 20 completed weeks' gestation (cGW) using an algorithm involving maternal age and serum alpha-fetoprotein (AFP), chorionic gonadotrophin and unconjugated oestriol levels, each expressed as a multiple of the median level (MoM) at the cGW. The AFP MoM itself is the basis for screening for open neural tube defects (oNTD). Because medians change during this period, gestational dating must be accurate so that appropriate medians are used. A calculated Down's syndrome risk > 1:380 at term is generally considered to indicate a 'high-risk' pregnancy. This study focused on 378 patients with reported risk < or = 1:500 based on physician-supplied cGW (and hence considered at 'low risk' for Down's syndrome) to determine the effect of common 1-2-week dating errors on risk estimates. Using the original analytical data, each patient's risk was recalculated for each week over the 15-20 weeks, and classified into three categories: < 1:380 'low'; 1:380-1:100 'moderate'; and > 1:100 'high'. Advancing originally 'low-risk' patients by one week increased the risk by 1.09-14.1 times (median 3.18, mean 3.60); 46 (12.2%) became 'moderate' and 2 (0.5%) became 'high' risk. Advancing by two weeks increased risks 1.58-60.5 times (median 10.03, mean 12.04); 131 (36.5%) became 'moderate' and 39 (10.9%) became 'high' risk. Predictably, oNTD screening results also were affected. Although 1-2 week differences in AFP medians had little effect on most patients in this study sample, some who originally were oNTD negative became oNTD positive, whereas others who had been oNTD positive became screen negative. Thus, in many cases, a 1-2 week dating error may have only minimal effect on the estimated risks for chromosome or neural tube defects, but in other cases the effect of such an error would be significant.

One stop clinic for assessment of risk for fetal anomalies: a report of the first year of prospective screening for chromosomal anomalies in the first trimester.

OBJECTIVE: To evaluate the introduction of a one stop multidisciplinary clinic for screening for fetal chromosomal abnormalities in the first trimester by a combination of maternal serum biochemistry and ultrasonography providing a risk of chromosomal abnormalities within a one hour clinic visit. DESIGN: One year retrospective review of screening performance. POPULATION: All women attending for routine antenatal care. The population included 4,190 singleton pregnancies in women of all ages screened between 10 weeks and 3 days and 13 weeks and 6 days of gestation between the periods 1 June 1998 and 31 May 1999 in a district general hospital antenatal clinic. METHODS: All women booked into the clinic were offered screening by a combination of maternal serum free beta human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein A (PAPP-A) and fetal nuchal translucency thickness. Women at increased risk of carrying a fetus with trisomy 21 or trisomy 18/13 (> or =1 in 300 at sampling) were offered counselling and an invasive diagnostic procedure. Follow up of the outcome of all pregnancies was carried out. MAIN OUTCOME MEASURES: The detection rate for trisomy 21, trisomy 18/13 and all aneuploides, false positive rate, uptake of screening, uptake of chorionic villus sampling in women identified at increased risk and fetal loss after chorionic villus sampling. RESULTS: Overall 97.6% of the women (4,088/4,190) accepted first trimester screening. The rate of detection of trisomy 21 was 86% (6/7), for trisomy 18/13 100% (9/9) and for all aneuploides 95% (18/19). Fetal death at presentation was found in 1.6% of pregnancies (69/4,088). Of women who accepted screening, 6.1% (257/4,088) presented too late for fetal nuchal translucency measurement and 6.5% of the women (271/4,088) presented too early. The false positive rate was 6.7% (253/3,762). Uptake of invasive testing was 83% (207/253). CONCLUSION: First trimester prenatal screening for chromosomal abnormalities using a combination of maternal serum biochemistry and fetal nuchal translucency thickness can achieve detection rates in excess of 90%. These services can be provided in a one stop multidisciplinary clinic.

Utilisation of medical technology assessment in health policy.

OBJECTIVE: To assess the contribution of medical technology assessment (MTA) to health policy decision making, the question has to be answered whether MTA is actually being used in decision-making processes and what factors are related to its utilisation. DESIGN: We investigated recent Dutch policy decision making concerning four cases, i.e., breast cancer screening, serum alphaprotein (AFP) screening, in vitro fertilisation (IVF) and lung transplantation. METHODS: A search of the international literature yielded 351 articles that reported MTA results concerning the four cases studied. Policy documents, advisory reports and parliamentary discussions were analysed to identify the utilisation of existing MTA knowledge in The Netherlands. Additionally, 23 structured interviews with experts in the field of MTA and/or policy decision-making were conducted. RESULTS: Numerous articles report results of MTA studies of breast cancer screening and in vitro fertilisation. In both cases the Dutch government commissioned MTA studies, but the outcomes of these studies did not substantially affect the decision-making process. MTA knowledge about AFP screening is more limited and studies dealing with lung transplantation are scarce. Nevertheless, policy decisions were made. CONCLUSION: Policy decisions concerning the introduction of (new) technologies in health care are not based on the results of MTA studies. Political arguments and interest groups decide the outcomes. At best, MTA results are used to implement (new) technologies more effectively.

Parent preferences and prenatal testing for neural tube defects.

Previous analyses of prenatal screening for neural tube defects have generally found benefits to exceed costs. The usual screening battery follows an elevated maternal serum alpha-fetoprotein level with high-resolution ultrasound and/or amniocentesis. Current thinking focuses on weighing the risk of a false-negative (an abnormality missed) against the risk of an amniocentesis-induced fetal loss. This thinking neglects the risk of a false-positive (an unaffected fetus labeled abnormal) and individual parents' preferences concerning a false-negative vs a fetal loss. With these risks included, we find that high-resolution ultrasound is appropriate for all women with elevated serum alpha-fetoprotein. Women with moderately elevated serum alpha-fetoprotein who have negative ultrasound scans need no further testing, nor do women with highly elevated serum alpha-fetoprotein and positive ultrasound scans. Further testing using amniocentesis to confirm the ultrasound result is appropriate for women with moderately elevated serum alpha-fetoprotein and positive ultrasound scans, and for women with highly elevated serum alpha-fetoprotein and negative ultrasound scans. The actual cutoffs defining normal, moderately elevated, and highly elevated serum alpha-fetoprotein depend on several parameters, particularly the underlying prevalence of neural tube defects and the parents' preferences.