CLINICAL CHEMISTRY Review Article

Current Issues in Maternal Serum Alpha-Fetoprotein Screening JAY L. BOCK, M.D., PH.D.

its laboratory implementation. The present review outlines current procedures for maternal serum alpha-fetoprotein screening and summarizes recent developments. (Key words: Alpha-fetoprotein; Neural tube defect; Spina bifida; Down's syndrome; Pregnancy; Birth defects; Screening; Genetic counseling) Am J Clin Pathol 1992;97:541-554

Originally established to detect fetal neural tube defects (NTD), the measurement of maternal serum alpha-fetoprotein (MSAFP) has become a standard part of prenatal care. Its implications extend beyond NTD screening to detection of other anatomic malformations, multiple pregnancy, Down's syndrome (DS) and other aneuploidies, and placental disease. Although laboratory measurement of MSAFP is now straightforward, issues pertaining to reporting, interpretation, and follow-up are much less so, partly because of the complex pathophysiology of MSAFP and partly because of the general context of prenatal testing. Maternal serum alpha-fetoprotein testing is relatively centralized and often is done outside of usual clinical laboratory settings, which unfortunately may limit participation of pathologists and clinical chemists in this important area. Literature on alpha-fetoprotein is voluminous and several reviews related to obstetric applications appeared recently.1"10 The present article therefore will not be comprehensive but will outline current laboratory and clinical procedures for MSAFP screening and review recent publications in selected areas. Several topics remain controversial, and the discussion will necessarily reflect the personal biases of the author.

BIOCHEMISTRY

Discovered in 1956," alpha-fetoprotein (AFP) is the predominant protein in mammalian embryonic serum. It has been characterized extensively, as recently reviewed by Deutsch.7 It is a single-chain globular peptide of molecular weight approximately 70,000. From cDNA, a 590amino acid sequence was deduced,12 having about 40% homology to that of albumin. More recently, direct sequencing by fast atom bombardment mass spectrometry was partially completed, largely confirming the earlier sequence but revealing an extra arginine at the N terminus, for a total of 591 amino acids in the mature protein.13 The genes for albumin, AFP, and the vitamin D binding protein (also known as group-specific component) comprise a gene family residing on the long arm of chromosome 4. 14 Complete sequencing of the AFP gene has shown that it spans 19,489 base pairs, including 15 exons and 14 introns. 15 Unlike albumin, AFP is a glycoprotein. Heterogeneity in AFP glycation can be demonstrated by electrophoretic separation and differential binding to lectins. 1617 Alphafetoprotein formed in fetal liver during later stages of pregnancy has increased glycoid content compared to the earlier yolk-sac product, and exhibits increased binding to concanavalin A (con A). Measurement of the con Areactive fraction of AFP has been applied diagnostically From the Department of Pathology, State University of New York, to amniotic fluid but has not proved useful for maternal Stony Brook, New York. serum.16 Received September 27, 1991; manuscript accepted for publication Specific physiologic functions of AFP still have not been October 31, 1991. delineated. Like albumin, it can bind multiple ligands Address reprint requests to Dr. Bock: University Hospital L3-532, Stony Brook, New York 11794-7300. and may serve some transport function. It also has been 541

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Measurement of maternal serum alpha-fetoprotein originated in the early 1970s as a means to screen for fetal neural tube defects, a relatively common and devastating class of malformations. Since that time, assay methods have improved, interpretation has been refined, follow-up testing for neural tube defects has advanced, and many other disease associations have been uncovered. It is a unique test, both in its clinical application and

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Review Article shown to have immunoregulatory properties, but the biologic significance of these remains controversial.7 PATHOPHYSIOLOGY

Although frequent mention is made in the literature of "unexplained elevations" in MSAFP, elevated MSAFP generally can be explained in pathophysiologic terms. It is expected whenever there is any compromise either in the feto-amniotic fluid barrier (causing increased AFAFP) or in the placental barrier. Neural tube defects are usually "open" defects with relatively close contact between amniotic fluid and the fetal integument, allowing increased diffusion of AFP into the fluid. A similar circumstance occurs in ventral wall defects (omphalocele and gastroschisis) and certain other disorders, such as cystic hygroma, congenital skin defect, teratoma, and congenital amputation. Because the AFP concentration in fetal blood is so much higher, even a small amount of fetal bleeding will significantly elevate AFAFP, as will fetal demise with resultant autolysis. Markedly increased AFAFP also can result from a lethal nephrotic syndrome, inherited as an autosomal recessive trait, which is most prevalent in Finland (so called "Finnish nephrosis"). 21-24 More commonly, elevated MSAFP relates not to elevated AFAFP but rather to increased transport across the placenta. Due to the very large concentration gradient between fetal and maternal serum, only a slight compromise of placental integrity is required. Maternal serum

An unusual cause for increased placental transfer of AFP is impairment of the fetus' urinary elimination of AFP, as with renal agenesis or urethral obstruction, leading to increased concentration in the fetal serum.42,43 A recent report described sonographic detection of mild, benign fetal uropathy in many pregnancies with increased MSAFP, postulating that a similar mechanism may be operative in these cases.44 Fetal hypothyroidism was implicated as a cause of elevated fetal serum AFP and MSAFP,45 but this was disputed.46,47 Average MSAFP concentrations are higher in black women and in small women, but results reported as multiple-of-median (MoM) are usually adjusted to account for these variables (see section entitled Median Adjustments and Special Situations). In multiple pregnancy, MSAFP is elevated roughly in proportion to the multiplicity (see Median Adjustments and Special Situations), making the test useful as a detector of unsuspected multiple pregnancy. Elevated MSAFP may, of course, arise from the maternal rather than the fetal compartment; for example, if the mother has an AFP-producing tumor. 48 In practice, this is a very unusual circumstance. In contrast to elevated MSAFP, the pathophysiology of decreased MSAFP remains poorly understood. Chance observation led to the finding that in DS pregnancies MSAFP concentration averages about 25% lower, independent of maternal age (see section entitled Down's Syndrome Screening).49,50 Amniotic fluid AFP and cord serum AFP also are reportedly decreased, implying that DS causes a slower rate of synthesis.51 A recent study tended to support this mechanism, showing no difference in the structure of mRNA transcripts or AFP polypeptides in DS, but finding lower amounts of AFP relative to total protein in the fetal liver.52 However, Seller53 reported normal levels of AFP in DS fetal serum before 20 weeks

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Alpha-fetoprotein is synthesized initially by the yolk sac and later predominantly by the fetal liver. Its concentration in fetal blood reaches a maximum of a few grams per liter at 10 to 13 weeks gestation, after which it declines to less than 100 /tg/L at term, and to adult levels of less than 5 jtg/L by 2 years of age.18 The pathophysiology of elevated MSAFP has been reviewed by Thomas and Blakemore.5 Alpha-fetoprotein can migrate from fetal to maternal circulation by two mechanisms: diffusion across the placenta or leakage across the kidney into amniotic fluid, followed by diffusion across the amnion. The quantitative contribution of each of these routes never has been measured definitively and different estimates have been given, but it is likely that the placental route normally predominates. 918 " 20 However, the placental barrier is evidently quite strong because AFP concentration is five orders of magnitude lower in maternal than in fetal blood. The proportional contribution of the amniotic fluid route may increase when its AFP concentration is abnormally elevated. During the second trimester, MSAFP increases by about 15% per week, although amniotic fluid AFP (AFAFP) and fetal blood concentration decrease at this time. This seems to be due more to increasing permeability of the placenta than to its increasing size.18

alpha-fetoprotein is a more sensitive indicator of fetomaternal hemorrhage than staining of fetal red cells by the Kleihauer-Betke technique, and is increased in about 10% of patients after amniocentesis.25 Elevated MSAFP frequently is seen with placental disease such as tumor, infarction, thrombosis, or inflammation; with cystic changes that are observed sonographically (placental "lakes"); and simply with a placenta that is large for gestational age.6'26"36 Elevation can be massive in cases of triploidy, in which the placenta tends to be large and cystic.37"39 Even when changes are not demonstrable sonographically, elevated MSAFP evidently may occur with placental disease that contributes to increased risk of preeclampsia or fetal death.6,32'40,41 Thus, although elevations due to placental disease are false-positive results in the context of NTD screening, they may have significant implications for obstetric management (see the section below entitled Follow-up).

BOCK Issues in MSAFP Screening gestation, followed by a faster than normal decline. In trisomy 18, unless there is an associated NTD, MSAFP averages about 40% lower.54,55 Low MSAFP also can occur with severe fetal distress or fetal demise, but generally even markedly decreased levels are associated with favorable pregnancy outcome.40,56'57 ASSAY METHODS

QUALITY CONTROL, PERFORMANCE GUIDELINES, AND REGULATION As with most clinical chemistry assays, the mainstay of quality control for MSAFP is monitoring results on control materials by standard procedures. Because

MSAFP results undergo additional "processing" to generate MoMs (see Follow-up Testing), these also must be quality controlled. The median MoM should remain close to 1.00, and the fractions of elevated and low results should remain within acceptable limits.10,64,65 This is more relevant to detection of long-term drift than to daily quality control. Median MoMs can be used only to assess individual runs in a very high-volume laboratory, but lowvolume laboratories can achieve analytic excellence through usual control procedures66,67; a recent survey found no correlation between analytic accuracy and laboratory test volume. 68 External proficiency testing is also essential. Programs are currently provided by New York State, the College of American Pathologists, and the Foundation for Blood Research, Scarborough, Maine (the latter two have merged into a single program as of 1992). Although many laboratories demonstrate good analytic accuracy in these surveys, it has been observed that interpretive reporting varies widely and tends to be more sophisticated at the larger centers.68"70 This consideration makes continued centralization of MSAFP testing desirable. Guidelines and regulations have been promulgated in efforts to improve the quality of MSAFP testing. Guidelines have been issued by the American Society for Human Genetics,71,72 the Canadian Society of Clinical Chemists,73 and the Laboratory Accreditation Program of the College of American Pathologists. In the United States, the federal government does not specifically regulate MSAFP testing (other than to license test kits). As of 1987, four states had adopted specific regulations: California, New York, Maryland, and Iowa.74 Iowa restricts testing to one stateapproved laboratory, whereas California employs contractual arrangements with eight centers that provide both screening and complete follow-up services. New York and Maryland regulate and license MSAFP testing as a special category of clinical laboratory testing. Further national efforts to achieve better uniformity in MSAFP testing appear warranted. It should be remembered, however, that some issues remain controversial, local needs and resources may vary, and excessive regulation may hinder beneficial innovations. NTD SCREENING: OUTLINE OF PROTOCOL The major NTDs are anencephaly, which is lethal, and spina bifida, or meningomyelocele, which is variably, but often severely, disabling.75 Anencephaly and about 90% of cases of spina bifida are "open" defects, with complete exposure of neural tissue to amniotic fluid, or separation by only a thin, transparent membrane. Liveborn incidence of NTD varies geographically and among different ethnic groups, and has been declining during the last two decades.

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As with other protein assays, a significant advance has been the introduction of immunometric technology, which commonly uses a solid-phase and an enzyme-labeled monoclonal antibody directed to different epitopes on the AFP molecule.58"61 These assays have advantages over classical radioimmunoassay in terms of speed, sensitivity, linearity, precision, suitability for automation, and lack of radioactive waste. Their low-end accuracy, in contrast to the documented poor performance of some radioimmunoassay methods,2,62 may be particularly important in the context of DS screening. Immunoenzymetric kits, licensed in the United States at the time of this writing for NTD screening, include the Tandem-E monoclonal bead method by Hybritech, Inc. (San Diego, CA), which can be automated on their Photon Era analyzer, a polyclonal bead method by Abbott Laboratories (Abbott Park, IL), and a microparticle method by Abbott that is automated on their IMx analyzer. Alpha-fetoprotein assays are calibrated relative to established national and international reference preparations, and concentrations often are reported in International Units per milliliter (IU/mL). Although mass units are more comprehensive and a conversion of 1.126 ng/ IU has been specified for the United States Standard,623 routine use of mass units has been controversial. Despite improved standardization in recent years, some bias among methods is still present. It has been noted that MoM calculations (see NTD Screening: Outline of Protocol) correct only for proportional bias among methods— fixed bias can still substantially affect results.58,63 At the time of this writing, test kits for AFP were licensed by the Food and Drug Administration for application to tumor marker testing (specifically as an aid in diagnosis and management of nonseminomatous testicular cancer), NTD screening, or both. Application to DS screening has not been licensed, putting more obligation on individual laboratories to select assay kits with sufficient low-end accuracy for this purpose.

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Review Article

Patient

Sampling

The patient should first be informed about the nature and purpose of the test, and consent (or lack thereof) should be documented. The American College of Obstetricians and Gynecologists has recommended that all prenatal patients be offered an MSAFP test for NTD screening,82 but for various reasons many still are not tested.78,83 Blood is preferably drawn at 16 to 18 weeks gestation, where the best discrimination of NTDs has been documented,81 and in any case between 14 and 23 weeks. The specimen is forwarded to the laboratory with a requisition that includes the patient's name, age, race, and weight at

TABLE 1. CLINICAL SITUATIONS ASSOCIATED WITH ALTERED MSAFP CONCENTRATIONS MSAFP (MoMft Clinical Situation Trisomy 18 Trisomy 21 Maternal diabetes Normal Caucasian Normal black Normal twin pregnancy Open spina bifida Anencephaly Gastroschisis Omphalocele Congenital nephrosis

Liveborn Incidence* 1:3,500 1:1,000

— — — 1:100 1:2,000 1:2,000 1:10,000 1:6,000 1:50,000

Median

Range

0.60 0.72 0.80 1.00 1.10 1.90 3.79 6.52 7.83 4.54

0.15-3.4J 0.29-1.82 0.30-2.12 0.38-2.65 0.41-2.92 0.68-5.32 1.12-12.8 1.67-17.2 3.45-17.8 0.57-36.0 ~2-~20§



MSAFP = maternal serum alpha-fetoprotein. MoM = multiple-of-median. * Approximate figures for the general American population. Incidence may vary widely depending on geographic and ethnic factors. t Except as noted, range is given as limits of the 95% confidence interval, based on published parameters for a log-Gaussian distribution.92,97,136,187 For blacks, the median and limits are assumed to be 10% higher, and for diabetic mothers. 20% lower."•»"'. % Median and range for a series of 38 cases not associated with open malformations.55 § Range for a total of nine reported cases.21,24

time of testing; date of testing; date of first day of last menstrual period; gestational age estimated by ultrasound, if available; family history of NTD, if any; presence of insulin-dependent diabetes mellitus; multiplicity of pregnancy, if known; and any other relevant information, such as previous MSAFP result or previous amniocentesis (MSAFP may be falsely elevated if tested immediately after amniocentesis25). Alpha-Fetoprotein

Measurement

The absolute concentration of AFP is measured by immunoassay (see Assay Methods). Multiple-of-Median

Calculation

The absolute concentration is converted to a MoM, which relates it to the median in normal pregnancies at the same gestational age. The MoM is calculated from the formula:

MoM

measured AFP(/ug/L) median AFP for gestational age (/ig/L) X adjustments

Medians are determined by measuring MSAFP in 100 or more normal pregnancies at each of 14 to 23 completed weeks of gestation. The measurements may be fit to a loglinear curve to give a smooth increase (about 15% per gestational week) and allow interpolation to individual days if desired. It is commonly advised that individual laboratories determine their own medians. However, it

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Maternal serum alpha-fetoprotein testing undoubtedly has played some role in that decline, but other factors appear to be involved. The overall incidence of anencephaly and spina bifida in the United States are each roughly 1 per 2,000 live births.75 (Good estimates of mid-trimester prevalence, which is more relevant to MSAFP screening, are unfortunately difficult to ascertain.) Neural tube defects have been associated with certain teratogens, such as valproic acid, thalidomide, and carbamazepine, and recent studies have confirmed an association with maternal folate deficiency.76"78 Another recent study has shown that caesarean section before the onset of labor improves motor function in infants with spina bifida.79 Hence prenatal detection has important implications beyond the option of abortion. The major ventral wall defects, omphalocele and gastroschisis, have a combined liveborn incidence of about 1 in 5,000, and a relatively favorable prognosis when uncomplicated. Omphalocele, however, is often associated with other anomalies, including NTD and aneuploidy. Again, prenatal detection is helpful in obstetric management.75 The utility of MSAFP for prenatal detection of NTD was first noted by Brock in 197380 and later confirmed by a large collaborative study in the United Kingdom,81 where NTD has had higher prevalence than in the United States. The United Kingdom Collaborative Study showed that, at 16 to 18 weeks gestation, MSAFP approximately follows a log-Gaussian distribution in both unaffected and NTD pregnancies. Median MSAFP was 6.5-fold higher with anencephaly and 3.8-fold higher with open spina bifida (OSB). There was, however, considerable overlap among the three populations, indicating the necessity for confirmatory tests. Table 1 summarizes the changes in MSAFP seen with NTD, ventral wall defects, and other conditions. Programs for NTD screening vary in many details, but the following is generally in accord with common practice and recent recommendations:

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Issues in MSAIFP Screening

Interpretive

Reporting

The complexity of MSAFP and the need for rapid, consistent follow-up places an unusual demand on the laboratory to provide interpretive reports with specific recommendations. Again, however, testing centers will vary in certain details. Selection of an upper cutoff, for example, involves the usual tradeoff between sensitivity and specificity, with 2.00 and 2.50 MoM being commonly used values. Based on the United Kingdom Collaborative Study,81 the former gives a sensitivity rate of about 90% (for anencephaly or OSB) and a specificity rate of 92.3%;

the latter a sensitivity rate of 83% and specificity rate of 96.4%. Studies in this country have yielded comparable results. Placental pathology and increased risk of fetal demise may be associated with MoM elevations as low as 2.040'4' (see Follow-up: Other Follow-up for Elevated MSAFP). The increasing accuracy and availability of ultrasound as a noninvasive follow-up procedure may favor use of the lower cutoff value. When a patient's MoM is greater than the cutoff value selected, the laboratory report should indicate that followup is necessary (see Follow-up). As an aid in decision making and patient counseling, the laboratory may provide a quantitative risk estimate. Risk of OSB as a function of MoM was tabulated by the United Kingdom Collaborative Study based on prevalence in that country in the 1970s.92 Current risks in the United States are probably at least twofold lower, but as indicated above depend on many patient factors and cannot be specified very accurately. Some laboratories recommend that moderate elevations (for example, as much as 3.5 MoM) be followed up with repeated blood sampling. If the second test is normal, the risk for NTD is not substantially elevated and further testing may be avoided.1 However, repeated testing consumes precious time, and it is reasonable to proceed directly to the next step, which is to verify gestational age by ultrasound examination. If ultrasound indicates more advanced gestational age than that predicted by the date of the last menstrual period (or multiple gestation), recalculation of the MoM may give a normal result. Otherwise, definitive diagnostic testing for NTD is required, as discussed in Follow-up: Definitive Diagnosis of NTD below. DOWN'S SYNDROME SCREENING Use of MSAFP testing for DS risk assessment is not as well established as its application to NTD screening. Testing kits are not licensed by the FDA for this purpose, which has been regarded as experimental.93 MSAFP has poor discriminatory power for DS because of the large overlap between unaffected and affected pregnancies. Nevertheless, because of the paucity of other noninvasive markers for DS (but see below), and the fact that MSAFP measurement is routinely performed for NTD screening, many laboratories have felt obliged to provide risk assessments for DS. A survey revealed that such assessments were performed on about one million pregnancies in the United States in 1988.94 To estimate DS risk, the MSAFP concentration generally is expressed as an adjusted MoM, as described above. This assumes that the factors used in the MoM adjustment are unrelated to DS, which is consistent with present data. The MoM could then be compared to a

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has never been shown that geographic variations in medians are important, and manufacturers' medians, if they are carefully determined, actually may have a benefit in terms of interlaboratory uniformity.68 In any case, it is important that whatever medians are used be periodically checked, e.g., by monitoring the median MoM (see Quality Control, Performance Guidelines, and Registration). Because of the steep increase in median with advancing gestational age, accuracy in determining the latter is critical. It is usually calculated from the patient's report of the first day of her last menstrual period. If that is not available, it is preferable to use ultrasound dating rather than an estimate by size. Ultrasound dating from the biparietal diameter is probably optimal for NTD screening because NTD is associated with lower biparietal diameter, which decreases the estimated age and elevates the calculated MoM, thus enhancing the likelihood of detection.84 Because of the imprecision of ultrasound dating, however, it is sometimes simply regarded as confirming the gestational age based on the last menstrual period when there is agreement to within some number of days (range, 4 to 10 days). Otherwise, the gestational age based on ultrasound is used. The "adjustments" term in the MoM calculation, also known as the "expected median," is usually included to account for several factors that affect MSAFP concentration but do not seem to affect NTD risk, or affect it in the opposite manner.85"91 These include maternal weight, race, presence of insulin-dependent diabetes mellitus, and multiple pregnancy (see Median Adjustments and Special Situations). Multiple-of-median calculations generally are reported to two decimal places. This may exaggerate their accuracy because uncertainty of the gestational age is a substantial source of error, in addition to that associated with the chemical measurement and the other adjustment factors. Imprecision of the MoM has a greater effect in DS screening than in NTD screening because of the much greater overlap between affected and unaffected populations (see Down's Syndrome Screening).

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fixed cutoff, for example 0.4, to select women younger than 35 years at increased risk for DS. However, this test would have poor predictive value because it would ignore the fact that the prior risk depends on maternal age. More commonly, information from age and MSAFP are combined, with the lower cutoff for MSAFP increasing with increasing maternal age. In this way, women are selected whose risk is at least equal to that of an average 35 year old woman, in whom it is now standard practice to recommend amniocentesis. (Women older than 35 years with decreased risk, for whom amniocentesis would not be recommended, could also be selected, but this is generally not done because of the tradition of offering amniocentesis to all women older than 35 years).95'96

Recently there has been considerable interest in improving the biochemical risk assessment for DS by combining AFP with other serum markers. The most important of these is choriogonadotropin (hCG). It has been found that maternal serum hCG concentration averages about twice as high in effected pregnancies, 108 "" 2 making it a better individual predictor than MSAFP. As with AFP, the hCG concentration appears to be independent of maternal age." 3 A third marker is unconjugated estriol, the usefulness of which has been more controversial. The bulk of published experience indicates approximately a 20% lower maternal serum concentration in DS pregnancies and suggests some addition to screening efficiency when combined with AFP and hCG. 109114 " 119 The mathematics for combining risks from age, AFP, hCG, and unconjugated estriol is rather complicated because correlations among the biochemical variables must be taken into account, but software for personal computers is available. Trisomy 18 must be considered separately because this syndrome is associated with low hCG as well as low MSAFP." 2 ' 120 Retrospective studies, and early prospective experience, suggest that the "triple screen" approach detects about 60% of DS pregnancies in women younger than 35 years if approximately 5% are selected for amniocentesis." 7 "" 9 Although this is much better performance than provided by MSAFP alone, the cautions mentioned above still apply. Other problems are the additional cost of two extra tests, and the fact that most commercial kits are not optimized for analysis of second trimester serum. Additional biochemical markers that have been explored include the free a- and /?-subunits of hCG, pregnancy-specific ^-glycoprotein, and placental alkaline phosphatase.121"125 A significant advantage from

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Tables giving DS risk estimates based on maternal age and MSAFP have been published.2-97,98 The risks are generally calculated by multiplying the age-related risk, determined from population studies, by a risk ratio calculated from the MSAFP. The risk ratio is equal to the ratio of the heights of the normalized log-Gaussian distributions for the unaffected and DS populations.97 It only can be calculated when the MoM is in the range of 0.4 to 2.5, where a good fit to the log-Gaussian distribution has been demonstrated. Note that when age-dependent cutoffs are used, MSAFP may be "low" even when it is not in a very low percentile. For example, a result of 0.65 MoM in a 34-year-old could put her in the high-risk group, although it is only about one standard deviation below the mean for unaffected pregnancies. Furthermore, it is also below the mean for affected pregnancies. Therefore it is not recommended that any low results be retested because many true-positive results will be negative on retesting simply because of statistical variation and "regression to the mean." 2 If retesting has been performed, however, risk assessment can take both values into account.99 Before recommending amniocentesis it is desirable, as with NTD screening, to verify the gestational age by ultrasound. It is preferable that the femur length not be used in the ultrasound age assessment because these tend to be shorter in DS fetuses'00 and therefore would decrease the sensitivity of screening. Prospective studies have verified efficient detection of Down's syndrome when age- and MSAFP-related risks are combined. The first published study,101 which used a slightly different formula for risk calculation than described above, selected 1,451 of 34,354 women younger than 35 years (4.2%) for amniocentesis. Twelve of the selected women (1 of 121) had a pregnancy affected by DS or trisomy 18, accounting for one quarter to one third of all cases. In the more recent New England Collaborative Study,102 77,273 women younger than 35 years were screened and 2.7% were classified as high risk. Of these, 76% had amniocentesis, resulting in identification of 18

fetuses with DS and 4 with trisomy 18, or a yield of 1 of 72 procedures. An estimated 25% of all fetuses with DS were identified. The yield of amniocentesis in both studies compares well to the risk of fetal loss from the procedure, which is not precisely known but is frequently quoted as about 1 in 200.103 Although the studies therefore demonstrated benefit to the population as a whole, it must be stressed that an MSAFP result usually is not of great help to the individual patient—it modifies the age-related risk, but typically by a modest factor. Personal values may play a greater role in how a particular patient weighs the risk of amniocentesis (fetal loss) compared to its benefit (prenatal detection of a trisomy), which are of such a different nature that they should not be directly compared104"106 (see Follow-up: Patient Counseling). It also should be noted that the inherent imprecision of a MoM value (see Follow-up Testing) translates to a very large uncertainty in the DS risk estimate. The drawbacks and concerns related to this application of MSAFP have been summarized eloquently by Pueschel.107

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Issues in MS/[FP Screening any of these is uncertain.126 Biochemical screening in the first trimester, which would allow follow-up by chorionic villus sampling instead of amniocentesis, also is being explored. Early results suggest that testing may have lower efficiency than in the second trimester but may still usefully detect a large portion of trisomies. 123124127 "' 30 MEDIAN ADJUSTMENTS AND SPECIAL SITUATIONS

I Q O . 2 6 5 8 - 0.00188 X maternal weight in pounds

w hJQV.

r e s u l t s i n nO

adjustment at 141 pounds, a 60% upward adjustment at 250 pounds, and a 16% downward adjustment at 100 pounds. At weights greater than 250 to 280 pounds, no further adjustment is generally applied. For 143 diagnosed cases of OSB, this adjustment increased sensitivity from 80% to 84% at a cutoff value of 2.0, and from 68% to 69% at a cutoff value of 2.5. Confidence intervals for these small changes were not indicated, but the data support continued use of weight adjustment. Drugan and coworkers,133 however, reported that this factor causes too great an adjustment for women weighing more than 200 pounds, generating a small excess of false-positive results. They recommend that the adjustment be applied only up to 200 pounds. A collaborative study also examined the effect of race on MSAFP in pregnancies effected with OSB.134 In uneffected pregnancies it has been found that black women have 10% to 15% higher MSAFP levels than white women.87,89 Because their risk for NTD is actually lower, it has been common practice to adjust their MoM values downward by this amount, and sometimes to use a higher cutoff value for recommending further NTD evaluation. In the collaborative study there were 12 black mothers whose fetuses had OSB, and their median MoM was 4.37, compared to 3.10 in white mothers (P = 0.02). Because this difference is even larger than the difference seen in uneffected pregnancies, the authors concluded that downward adjustment of MoMs and upward adjustment of the cutoff values is justified for NTD screening. Other racial differences in MSAFP probably exist but are not

In pregnancies in which the mother has preexisting, insulin-dependent diabetes mellitus, it has been found that MSAFP levels are 20% to 40% lower, whereas risk for NTD and other malformations is substantially higher.88,90 Again, MoM values and cutoffs may be adjusted (a common practice is to include a factor of 0.8 in the adjustment), but it is better to consider these pregnancies in a separate category. Greene and Benacerraf37 demonstrated that ultrasound examination in diabetic gravidas has better positive and negative predictive value for anatomic malformations than MSAFP. Therefore they questioned the utility of MSAFP screening in this setting, where the increased prior risk makes it reasonable to perform an ultrasound examination in all cases, rather than only as a follow-up to elevated MSAFP. Similar reasoning may apply to multiple pregnancies: in view of the decreased efficacy of MSAFP136 and the many complications associated with twins, routine ultrasound examinations are reasonable. In such settings the utility of also measuring MSAFP for NTD screening may be questioned.' 38 On the other hand, elevated MSAFP may prompt the sonographer to look harder139 and may indicate greater risk (see sections Follow-up: Definitive Diagnosis of NTD and Other Follow-up for Elevated MSAFP). Furthermore, expert "level 2" ultrasound is expensive and not readily available in some locations. The effect of blood glucose control in diabetic pregnancies has been controversial. Baumgarten and coworkers140"142 reported a negative correlation between MSAFP levels and glycohemoglobin, but this was contradicted by Greene and colleagues.143 Martin and associates144 recently studied this problem, finding again a negative relationship between glycohemoglobin and MSAFP, but with some different temporal relationships than reported by Baumgarten and co-workers.140"142 To resolve, at least partially, these discrepancies, they sug-

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As mentioned earlier, MoM calculations and risk reporting must account for a number of maternal variables affecting MSAFP. The most significant is maternal weight. Heavier mothers tend to have lower MSAFP, presumably because the dose of AFP absorbed from the fetus is diluted in a greater blood volume.85"87 Earlier data indicated that specificity of MSAFP screening was improved when MoM results were adjusted for maternal weight, but effects on sensitivity were not studied and were thought by some possibly to be adverse.131 A collaborative study, drawing data from 14 screening programs nationwide, recently addressed this issue.132 The adjustment factor tested was

usually accounted for, nor is it entirely clear who should be considered "black." Maternal serum AFP is increased in multiple pregnancy, roughly in proportion to the multiplicity. Although this effect on the MoM can be nullified by including an adjustment factor equal to the multiplicity, it is better to consider multiple pregnancy as a separate entity. Johnson and associates135 studied 138 twin pregnancies, most without anatomic malformations, finding poorer outcome associated with MoM more than 4.00. Cuckle and associates'36 reported on 46 twin pregnancies affected by NTD, finding median MoMs for anencephaly and OSB of 7.50 and 4.40, respectively. Open spina bifida detection was not as efficient as in singleton pregnancies: a cutoff of about 3.00 to 3.50 MoM would give yield a similar sensitivity rate but a lower specificity rate of only 80% to 85%.

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gested a nonlinear relationship between the variables, with significant depression of MSAFP only when glycohemoglobin is markedly elevated. Effects of MoM adjustments on sensitivity of DS screening have not been closely examined to date. Applicability of MSAFP for DS screening in twin or diabetic pregnancies has not been established. FOLLOW-UP Patient

Counseling

Several reports have concerned counseling and the psychological aspects of MSAFP testing. Using the State-Trait Anxiety Inventory, Burton and co-workers146 showed that women and their partners experience substantial anxiety after an elevated MSAFP result. This anxiety was not diminished by counseling but did abate after follow-up testing was normal, and was not so severe as to induce depression, marital discord, negative attitudes to pregnancy, or problems at work. Evans and colleagues147 found that women referred for amniocentesis because of low MSAFP tend to be more anxious than women referred because of advanced maternal age. Again, however, the level of anxiety was not severe enough to suggest that it should be a deterrent to MSAFP screening. Keenan and associates148 found that anxiety about low MSAFP was ameliorated by counseling. Marteau and colleagues149 reported that a normal result from MSAFP screening had a demonstrable beneficial effect in terms of diminished patient anxiety during the second and third trimesters of pregnancy. Sikkink150 noted that the acceptability of MSAFP testing to patients has received scant attention. In a group of 45 patients who received an educational session about MSAFP, he found that only 31% elected to have the test. Those who did elect to have the test tended to be older and to have spent a longer time discussing the test with a physician. Earley and co-workers151 found that negative feelings about the MSAFP test were expressed frequently by women who previously had a false-positive result (either high or low). Forty-one percent of these women stated

Definitive Diagnosis of NTD Amniocentesis and ultrasound examination have played complementary roles in the definitive diagnosis of NTD. Measurement of AFAFP initially was the most important follow-up test. It has a high sensitivity rate for anencephaly and OSB, but only a moderate specificity rate because many other causes for elevated AFAFP exist (see AFP Measurement). Accordingly, further confirmatory tests are needed. These have generally included qualitative analysis of the fluid for fetal hemoglobin, to rule out a fetal bleed as the cause; and qualitative detection of acetylcholinesterase, an enzyme specific for neural tissue. 152153 Acetylcholinesterase is commonly analyzed by an electrophoretic procedure that separates it from nonspecific esterase,154'155 although immunoassay methods recently have been described.156'157 In ventral wall defects, probably because of some exposure of neural tissue, acetylcholinesterase is also usually positive, but with notably lower intensity than typically seen with NTD. 158 Acetylcholinesterase also may be positive due to a fetal bleed, making interpretation ambiguous when the fetal hemoglobin result is also positive.159 False-positive acetylcholinesterase results have been reported in other circumstances, especially when amniocentesis is performed before 15 weeks.160 In most cases, however, correct diagnosis or exclusion of NTD can be based on the biochemical analysis of amniotic fluid. Chromosome analysis always should be performed with amniocentesis because of increased MSAFP, because these patients are at increased risk for an abnormal karyotype.161 In recent years ultrasonography has become so advanced that the necessity of amniocentesis in the usual follow-up of elevated MSAFP has been questioned. Sonographic follow-up of high MSAFP levels requires a "level 2" procedure, which means that a high-resolution scan is performed by an operator experienced in identifying congenital anomalies. A group at the University of North Carolina initially published a report in 1988 on a policy of revising the NTD risk 10 times downward after a normal level 2 ultrasound (i.e., 90% sensitivity of ultrasound was assumed).162 All patients were then offered amniocentesis but were informed of the revised risk. Under this policy, 67% of patients refused to have amniocentesis. Ultrasound detected all 12 cases of anencephaly but only 8 of 10 cases of OSB in this series, for a sensitivity rate of 91% overall and 80% for OSB. In the past few years, however, ultrasound detection of OSB has improved further, mainly as a result of the recognition of associated intra-

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Counseling is a critical part of the MSAFP screening process.145 The physician must endeavor to minimize patient anxiety while providing the essential information to make choices regarding follow-up. Patient anxiety is a significant negative feature of MSAFP testing because screening will identify more than 5% of patients as "high risk" for NTD or DS, but most of these patients will have healthy babies. A decision regarding amniocentesis may be agonizing for parents. An interesting approach to guiding patients in this choice, based on formal decision analysis, has been presented by Pauker and Pauker.104

they would not have the test in a subsequent pregnancy, compared to only 9% of women with a true-negative test result.

BOCK Issues in MSAFP Screening cranial signs. These include deformity of the frontal bone (the "lemon sign") and cerebellar compression due to the Arnold-Chiari malformation (the "banana sign"). 163164 Several series recently were reported, with 100% detection of OSB. 164 ' 167 Detection of ventral wall defects also has been excellent, as has avoidance of false-positive results, although some scan results of course may be ambiguous. Summarizing published experience from several centers, the North Carolina group found detection of 232 of 234 cases of OSB, for a sensitivity rate of 99.1% (99% confidence interval, 99.0% to 99.9%).103 They now adjust NTD risk downward by 95% after negative results of ultrasound, and have an even smaller fraction of patients choosing to have amniocentesis.

Other Follow-up for Elevated MSAFP As has been emphasized in this review (see Pathophysiology), NTD and other fetal malformations are an

uncommon explanation of elevated MSAFP. Some elevated MSAFP results may properly be regarded as "false positives," simply because they fall at the upper end of the distribution in normal pregnancies. Elevated results may also, however, indicate some degree of breakdown in the placental barrier, which may be associated with complications later in the pregnancy. Association of elevated MSAFP with low birth weight was noted as early as 1977 by Brock.177 In recent published series, complications with increased incidence have included intrauterine growth retardation, maternal hypertension, fetal distress or death, placental infarction or abruption, and premature labor.32-41178"182 Although the highest concentrations of MSAFP are most ominous, 179183 even modest elevations of 2.0 to 2.5 MoM seem to be associated with these complications.41 Katz and associates6 reviewed studies including more than 225,000 screened pregnancies overall. Remarkably, they found that 20% to 38% of unexplained MSAFP elevations were associated with poor pregnancy outcome. Additional strong evidence comes from a recent case-control study comparing 612 California women whose pregnancies ended in fetal death with 2,501 women who gave birth to live infants.40 Only pregnancies that were without MSAFP-associated malformations and were viable at the time of MSAFP testing were included. It was found that MoM values greater than 3.0 were associated with a 10-fold higher risk of fetal death, whereas values in the range 2.0 to 2.9 were associated with a 2.4fold higher risk, which was still statistically significant. The increased risk was related mainly to placental infarction and maternal hypertension. Aristidou and associates181 found that adverse outcomes in pregnancies with elevated MSAFP frequently are associated with abnormal Doppler studies of uterine artery flow. Because of these findings, many workers believe that elevated MSAFP should be taken as an indication of a high-risk pregnancy, warranting increased surveillance. Lenke and co-workers,41 for example, recommended following up all cases with a repeated ultrasound at 30 weeks to evaluate fetal growth, a fetal movement index at 26 weeks, and nonstress testing beginning at 34 weeks. Katz and associates6 argued for a more individualized approach, noting additional tests that may be useful in selected instances: a Kleihauer-Betke test in an Rh-factor-negative woman to test for a fetal-maternal bleeding episode; evaluation for possible drug (cocaine) abuse that may be associated with placental abruption; viral titers to rule out an infection that might cause villitis; and a test for lupus anticoagulant, which might be associated with placental thrombosis. Simpson and co-workers,184 on the other hand, have questioned the wisdom of undertaking expensive surveillance based on elevated MSAFP. They argued that the published series may be affected by ascertainment

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Others have argued that the true sensitivity rates of ultrasound may be lower than suggested by these reports. Substantially lower sensitivity rates were reported by Drugan and associates,168 Whitehead and colleagues,139 and several studies worldwide summarized by Wald and co-workers.169 Lindfors and colleagues,'70 reporting on experience from 1986 to 1989 at the University of California, Davis, reported a 90% sensitivity rate, with three false-negative results for OSB. Many of these reports included scans performed before improved sensitivity was achieved through use of the intracranial signs. On the other hand, published data may be skewed toward better results, and it cannot be assumed that all centers, even with comparable equipment and training, achieve the same results. It also was noted that the incidence of abnormal karyotypes is greater in pregnancies with MSAFP. 57161170171 The response was made that ultrasound often can detect anatomic features associated with aneuploidies and that elevated MSAFP together with a normal ultrasound may not indicate a sufficient risk to justify amniocentesis. 103172 It is clear that ultrasonography has achieved impressive accuracy in the diagnosis of NTDs and other malformations, and that it should now be regarded as the primary follow-up technique for elevated MSAFP. It is difficult for individual centers to know how good their sensitivity rates are, but many centers across the country probably achieve 90% or better. It would be prudent to continue to offer the option of amniocentesis to all women with elevated MSAFP, but also to fully apprise them of the downward revision in risks afforded by a normal ultrasound examination.173"175 Thornton and co-workers176 recently published calculations and tables that may be useful for this purpose.

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bias (although this would not seem to apply to the casecontrol study of Waller and colleagues40), and have not shown whether other predictors of high risk (such as preeclampsia or preexisting maternal illness) might apply in most of these patients. No management protocols have been evaluated in a prospective study, and it is fair to conclude that none can be regarded as a standard of care. 683 If elevated MSAFP in the midtrimester indicates high risk, a logical question is whether follow-up measurements might help to reevaluate that risk. Recent studies, however, have failed to establish usefulness of serial MSAFP tests.182'184-186

Maternal serum AFP is an effective screening test for NTD and other open malformations of the fetus. A stateof-the-art ultrasound examination usually can establish or rule out the diagnosis of NTD with great confidence, diminishing the need for amniocentesis. In the absence of a malformation, elevated MSAFP indicates a higher risk of pregnancy complications and warrants closer fetal surveillance, although a general protocol for following such pregnancies has not been established. Maternal serum AFP, especially when combined with other biochemical markers, can allow substantial detection of DS in women younger than 35 years by selecting about 5% of the population for amniocentesis. However, the sensitivity and specificity of biochemical DS screening are far from optimal, making this application problematic. In the future we may expect continued improvement in laboratory technology for MSAFP testing and greater uniformity in screening programs across the country. Better understanding of the etiology of NTDs, along with the excellent prenatal detection afforded by MSAFP and ultrasound, should lead to a continued decrease in their incidence. Prospective studies may establish recommended follow-up for "unexplained" elevations of MSAFP. For trisomy screening, AFP probably will be supplemented increasingly with other biochemical markers. However, a reliable noninvasive test may have to await newer technology, such as a means for harvesting fetal cells from the maternal circulation.188 REFERENCES 1. Burton BK. Elevated maternal serum alpha-fetoprotein (MSAFP): Interpretation and follow-up. Clin Obstet Gynecol 1988; 31:293305. 2. Knight GJ, Palomaki GE, Haddow JE. Use of maternal serum alpha-fetoprotein measurements to screen for Down's syndrome. Clin Obstet Gynecol 1988;31:306-327. 3. Burton BK. Maternal serum alpha-fetoprotein screening. Pediatr Ann 1989;18:687-92, 694-697.

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CONCLUSIONS AND FUTURE PROSPECTS

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Current issues in maternal serum alpha-fetoprotein screening.

Measurement of maternal serum alpha-fetoprotein originated in the early 1970s as a means to screen for fetal neural tube defects, a relatively common ...
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