Prenatal screening tests facilitate risk assessment. (Cover Story).
Knowledge often provides the power to positively influence outcomes. One of our nation's health goals for the new millennium as articulated in the document Healthy People 2010 is improved maternal, infant and child well-being.(1) There are many ways to accomplish this goal; one means is by increasing maternal understanding of testing available during pregnancy. Informed mothers can hope to have healthier babies. The development and application of new assays and technologies for prenatal screening provide more accurate assessment of risk for birth defects. Integration of screening results from first and second trimester testing offers a higher detection rate, with much lower false positive rate, for Down syndrome (DS).(2) A clearer understanding of the extent to which certain birth defects are preventable may result in more women of childbearing age modifying dietary practices or taking a folic acid supplement to reduce the risk for an affected pregnancy.
The laboratory as part of a prenatal screening can measure a variety of maternal biochemical markers. Although the routine specimen for assay is maternal serum, in some instances maternal urine is also acceptable. Interpretation of data provided by various configurations of screening tests has significantly reduced the need for follow-up with the more costly, risky diagnostic procedures of amniocentesis amniocentesis (ăm'nēō'sĕntē`sĭs), diagnostic procedure in which a sample of the amniotic fluid surrounding a fetus is removed from the uterus by means of a fine needle inserted through the abdomen of the pregnant woman (see , and chorionic villus sampling chorionic villus sampling (CVS) or chorionic villus biopsy (CVB) (kōr'ē-ŏn`ĭk, kôr'–), diagnostic procedure in which a sample of chorionic villi from the developing placenta is removed from the (CVS (1) (Concurrent Versions System) A version control system for Unix that was initially developed as a series of shell scripts in the mid-1980s. CVS maintains the changes between one source code version and another and stores all the changes in one file. ). Procedure-related risks of amniocentesis include miscarriage, fetal puncture, bleeding, and possible infection.(3) If the rate of miscarriage might be expected to be 2 percent to 3 percent, the procedure of amniocentesis carries with it an additional increase in risk of 0.5 percent to 0.8 percent.(4) For CVS, in which a small amount of tissue is taken from the placenta for karyotyping Karyotyping
A laboratory test used to study an individual's chromosome make-up. Chromosomes are separated from cells, stained, and arranged in order from largest to smallest so that their number and structure can be studied under a microscope. , the fetal loss rate is increased by 1 percent to 2 percent for an overall miscarriage risk of 3 percent to 5 percent.(5)
A positive test result can have profound consequences for expectant parents. The potentially adverse psychological impact of prenatal screening test results requires that any facility undertaking such testing have an experienced counseling staff available to work with families. Currently the most common benefit of prenatal diagnosis is better counseling for prospective parents and family members.
There are already tangible benefits from prenatal screening, and even more are likely in the future. Neural tube defects Neural tube defects
A group of birth defects that affect the backbone and sometimes the spinal chord.
Mentioned in: Birth Defects (NTDs) are classified as open if neural tissue is exposed because of openings in the skull and spine.(6) Fetal surgery to repair open NTDs is relatively new and is risky for both mother and child. It has been successful, though it is available only on a very limited basis.(7) Such early surgical repair protects the fetus' previously exposed neural tissue from additional damage by contact with the amniotic fluid (AF) and intrauterine intrauterine /in·tra·uter·ine/ (-u´ter-in) within the uterus.
Within the uterus.
Situated or occuring in the uterus. movement, and from trauma during passage through the birth canal. There is even evidence that certain fetal brain malformations may "correct" themselves following surgery. There is a 30 percent to 50 percent reduction in the need for surgical shunting to reduce hydrocephalus hydrocephalus (hī'drəsĕf`ələs), also known as water on the brain, developmental (congenital) or acquired condition in which there is an abnormal accumulation of body fluids within the skull. , a common condition in newborns with spina bifida. Corrective surgery on newborns is far less problematic and more widely available. In the future, in utero or neonatal corrective gene ther apy may be feasible.
Primary prevention is preferable to remediation. Healthy People 2010 includes specific objectives to reduce the occurrence of developmental disabilities and neural tube defects. One objective is to increase the proportion of pregnancies begun with optimal levels of the B vitamin folic acid.(1) Recent federal initiatives in food fortification with synthetic folic acid are already showing positive results.
Since Jan. 1, 1998, when the U.S. Food and Drug Administration required all enriched cereal grains to be fortified with 140 [micro]g of synthetic folic acid per 100 g of grain, the birth prevalence of NTDs has declined by 19 percent.(8) Continued health education efforts to raise public awareness regarding the beneficial effects of folic acid supplementation by women capable of childbearing remain critical.(9)
Second trimester screening
About 30 years ago, elevated alpha fetoprotein (AFP (1) (AppleTalk Filing Protocol) The file sharing protocol used in an AppleTalk network. In order for non-Apple networks to access data in an AppleShare server, their protocols must translate into the AFP language. See file sharing protocol. ) levels in maternal serum and in amniotic fluid were first linked to the occurrence of fetal NTDs.(10) In 1977, findings of a large collaborative study in the United Kingdom confirmed the value of measuring maternal serum AFP (MSAFP MSAFP Maternal Serum Alpha-Fetoprotein ) in screening for NTDs.(11) Prior to that, unless a woman or a close female relative had had a previous NTD-affected pregnancy, there was essentially no way to predict how likely she was to be carrying an NTD-affected fetus.
In the early 1980s the Food and Drug Administration (FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. ) first licensed an AFP kit, and maternal serum AFP measurements became best practice in this country for detecting NTDs. By the mid-1980s, the merit of MSAFP use in screening for Down syndrome among women younger than 35 had been recognized. By the end of that decade, two additional biochemical markers, human chorionic gonadotropin human chorionic gonadotropin (HCG): see gonadotropic hormone. (hCG) and unconjugated estriol estriol /es·tri·ol/ (es´tre-ol) a relatively weak human estrogen (q.v.), being a metabolic product of estradiol and estrone found in high concentrations in urine, especially during pregnancy. (uE3), had been identified as providing valuable information on the developing fetus.
Prenatal screening in the early 1990s had evolved into the classic triple test of maternal serum markers during the second trimester.(12) What are the origins of these and other recently identified biochemical markers, and what patterns are discernible in their levels during normal and affected pregnancies?
In the fetus, primarily the developing liver produces alpha fetoprotein (AFP). AFP is present in fetal plasma. By means of fetal urination urination
Process of excreting urine from the bladder (see urinary system). Nerve centres in the spinal cord, brain stem, and cerebral cortex control it through involuntary and voluntary muscles. The need to void is felt when the bladder holds 3. , it is also present in the amniotic fluid, although at much lower concentrations. If a developmental defect, such as failure of the neural tube to close, exists, more AFP escapes into the amniotic fluid. Fetal AFP enters the maternal circulation by placental transfer and by diffusion across placental membranes.
Fetal AFP peaks between 10 weeks to 13 weeks gestation, then declines during second and third trimesters. Maternal serum AFP levels rise gradually and peak between 28 weeks and 32 weeks of gestation. After that time, MSAFP declines until delivery. A variety of situations can lead to elevation of maternal serum AFP, including fetal open NTD NTD Neural tube defect, see there , underestimation of gestational age, the presence of multiple fetuses, racial background, placental changes, fetal abdominal wall defects Abdominal Wall Defects Definition
Abdominal wall defects are birth (congenital) defects that allow the stomach or intestines to protrude.
Description , congenital nephrosis nephrosis (nəfrō`səs), kidney disease characterized by lesions of the epithelial lining of the renal tubules, resulting in marked disturbance in the filtration function and the consequent appearance of large amounts of protein (albumin) , and fetal death.
Lower than expected MSAFP levels are seen when fetal gestational age is overestimated, in maternal Type 1 diabetes type 1 diabetes
See diabetes mellitus. , fetal Trisomy trisomy /tri·so·my/ (tri´so-me) the presence of an additional (third) chromosome of one type in an otherwise diploid cell (2n + 1). See also entries under syndrome. triso´mic
n. 21 (Down syndrome) or Trisomy 18 (Edward's syndrome), and in pseudopregnancy pseudopregnancy /pseu·do·preg·nan·cy/ (-preg´nan-se)
1. false pregnancy.
2. the premenstrual stage of the endometrium; so called because it resembles the endometrium just before implantation of the blastocyst. (e.g. caused by tumor or endocrine dysfunction). Depending upon the cutoff thresholds used by the laboratory, measurement of MSAFP detects most NTDs - 70 percent to 80 percent of open spina bifida (OSB OSB
Order of Saint Benedict ) and 95 percent to 98 percent of anencephaly anencephaly /an·en·ceph·a·ly/ (an?en-sef´ah-le) congenital absence of the cranial vault, with the cerebral hemispheres completely missing or reduced to small masses.anencephal´ic
n. .(13) The sensitivity of MSAFP for Down syndrome is low, even when maternal age is considered, but it is a simple test that is widely available.
Cells of the placenta synthesize human chorionic gonadotropin (hCG). hCG consists of two subunits - an alpha and a beta. The single chain of 145 amino acids that comprises the beta subunit is unique to hCG; the alpha subunit is common to other members of the family of glycoprotein glycoprotein (glī'kōprō`tēn), organic compound composed of both a protein and a carbohydrate joined together in covalent chemical linkage. hormones to which hCG belongs, including LH, FSH FSH follicle-stimulating hormone.
Facioscapulohumeral muscular dystrophy (FSH) , and TSH TSH thyroid-stimulating hormone; see thyrotropin.
Thyroid-stimulating hormone (TSH) .
hCG is present in two forms: intact hCG, containing both the alpha and beta subunits; and free beta hCG, containing only the beta subunit. Both subunits are required for biological activity, but it is the beta subunit that determines molecular specificity.(14) Less than 1 percent of the beta subunit exists in the free form. hCG appears in the maternal circulation shortly after implantation and increases rapidly until about eight weeks gestation. The concentration of maternal serum hCG then declines slowly to plateau at about 18 weeks to 20 weeks gestation, and then remains fairly constant.
Multiple hCG-related molecules can be measured in both maternal serum and urine.(15) hCG and its related molecules have been found to be sensitive maternal screening markers for detection of Down syndrome. Clinical results may be reported as multiples of the median (MoM) or in conventional units of measure. Human chorionic gonadotropin elevation of at least 2.5 MoM is associated with a DS fetus. Measurement of hCG levels is not useful in predicting the occurrence of a neural tube defect neural tube defect
Congenital defect of the brain or spinal cord from abnormal growth of their precursor, the neural tube (see embryology), usually with spine or skull defects. (NTD).
Hyperglycosylated hCG, also known as invasive trophoblast trophoblast /tro·pho·blast/ (tro´fo-blast) the peripheral cells of the blastocyst, which attach the blastocyst to the uterine wall and become the placenta and the membranes that nourish and protect the developing organism. antigen (ITA ITA
initial teaching alphabet
ITA initial teaching alphabet: a partly phonetic alphabet used to teach reading
ITA n abbr (BRIT) (= initial teaching alphabet) → ), is a large oligosaccharide oligosaccharide: see carbohydrate.
Any carbohydrate with a few (between 3 and about 6 to 10) units of simple sugars (monosaccharides). A wide variety of oligosaccharides are made by partially breaking down polysaccharides. variant of hCG. It is the main form of hCG produced in the weeks following implantation and can be measured in the expectant mother's urine as well as her serum.(16) In Down syndrome cases, the median hyperglycosylated hCG (H-hCG) value has been reported to be 9.9-fold higher than in unaffected pregnancies.(17) Regular serum hCG detects about 40 percent of DS pregnancies at a false positive rate of 5 percent. (15) Measurement of H-hCG alone is reported to detect 80 percent of DS cases at a 5 percent false positive rate.(17) Testing for this marker began in January 2000 using ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.
Early in the second trimester, the fetus, through a complex series of enzymatic reactions involving the fetal adrenal glands, liver and placenta, synthesizes large amounts of unconjugated estriol (uE3). A portion of the uE3 diffuses across the placenta and can be measured in the maternal serum. Concentration of uE3 in the maternal circulation rises progressively throughout gestation. A decreased level early in the second trimester is an independent predictor for NTD. Elevated MSAFP and low MSuE3 concentrations are highly predictive for neural tube defects.
The enzyme acetylcholinesterase acetylcholinesterase /ac·e·tyl·cho·lin·es·ter·ase/ (AChE) (-ko?li-nes´ter-as) an enzyme present in the central nervous system, particularly in nervous tissue, muscle, and red cells, that catalyzes the hydrolysis of acetylcholine to (AchE) catalyzes hydrolysis hydrolysis (hīdrŏl`ĭsĭs), chemical reaction of a compound with water, usually resulting in the formation of one or more new compounds. of the neurotransmitter acetylcholine acetylcholine (əsēt'əlkō`lēn), a small organic molecule liberated at nerve endings as a neurotransmitter. It is particularly important in the stimulation of muscle tissue. . Acting in the synaptic gap to promote neurotransmitter degradation, it permits timely repolarization repolarization /re·po·lar·iza·tion/ (re-po?ler-i-za´shun) the reestablishment of polarity, especially the return of cell membrane potential to resting potential after depolarization. of the neuron for subsequent impulse conduction. AchE is detectable in the amniotic fluid when nerve tissue or cerebrospinal fluid is directly exposed to AE. Such a situation occurs in cases of open spina bifida (OSB). An open NTD that might be missed by level II ultrasound examination could still be discovered if AchE were found in the amniotic fluid obtained during amniocentesis.
Inhibins are glycoprotein hormones secreted by the ovaries Ovaries
The female sex organs that make eggs and female hormones.
Mentioned in: Choriocarcinoma
ovaries (ō´v in nonpregnant women and by the placenta. Bioactive inhibin in·hib·in
A peptide hormone secreted by the follicular cells of the ovary and the Sertoli cells of the testis that inhibits secretion of follicle stimulating hormone from the anterior pituitary. contains an alpha and a beta subunit. Two forms of inhibin, inhibin A and inhibin B, along with molecular precursors and free subunits, are present in the circulation. The proposed activity of this hormone is to inhibit secretion of follicle stimulating hormone Follicle stimulating hormone (FSH)
A hormone that stimulates the growth and maturation of mature eggs in the ovary.
Mentioned in: Polycystic Ovary Syndrome, Premature Menopause (FSH) from the anterior lobe of the pituitary gland. Dimeric inhibin A (DIA) can be measured by ELISA.
Maternal serum DIA increases during the first trimester until 10 weeks gestation. The DIA concentration changes only slightly until about 25 weeks, when it increases to its peak value at term.(5) A study conducted in Scotland found an elevated inhibin A serum level as early as 11 weeks gestation in women whose fetuses were affected by DS.(18) Because of the substantial increase of levels in DS pregnancies, measurement of DIA provides an important addition to the screening protocol. Significantly, a 22 percent increase in the rate of detection of Down syndrome occurred when DIA was added to the established triple screen. Screening programs have reportedly used DIA as a fourth marker to increase DS detection to 75 percent, while holding the false positive rate at about five percent.(19) About 90 percent of open neural tube defects can be identified using DIA.(20)
USES AND REPORTING - SCREENING FORMATS
To enhance the discriminatory power of tests, combinations of procedures, including multiple marker screening and high-resolution ultrasonography ultrasonography /ul·tra·so·nog·ra·phy/ (-so-nog´rah-fe) the imaging of deep structures of the body by recording the echoes of pulses of ultrasonic waves directed into the tissues and reflected by tissue planes where there is a change in , are recommended. Although useful with low risk patients, single marker analysis, e.g., AFP level, provides only limited information on fetal defects. The detection rate for NTDs is good with MSAFP alone, but only about 25 percent to 33 percent of DS pregnancies are detected if MSAFP, along with maternal age, is measured. (21) The combination of two markers such as AFP and hCG, or the free beta subunit, yields substantially more clinically useful data.
Outside the United States, double tests - AFP and free beta hCG - are quite popular. While some studies have reported a higher detection rate for the free beta subunit, not all findings are in agreement. (22) Based upon information published in 2000, in the United Kingdom 85 percent of the country's neonatal screening laboratories used a double test. (23)
In this country, laboratories customarily provide a triple screen - AFP, uE3, and hCG. Using these three biochemical markers, about 60 percent of DS cases are detected, with a false positive rate of 5 percent. (17) If the beta subunit rather than intact HCG is measured as part of a triple screen, sensitivity for detection of DS pregnancies may approach 85 percent. The combination of urine hyperglycosylated hCG, beta-core fragment (the degradation product of the hCG beta-subunit), serum AFP, and maternal age-related risk brings the detection rate for DS pregnancies to 96 percent, at a false positive rate of 5 percent. (17)
Preference is shifting to use of a quadruple screen in which four serum biochemical markers - AFP, uE3, hCG, and inhibin A - are assayed. Positive biomarker screens must be confirmed by examining fluid and fetal cells obtained by amniocentesis or CVS, and by diagnostic ultrasound.
Because the concentrations of biomarkers in both the mother and the fetus fluctuate over the course of the pregnancy, it is absolutely essential that the laboratory obtain personal information about the patient to ensure a correct interpretation of the complex biochemical changes. Sometimes this is actually the most challenging aspect of the protocol for the laboratory.
Patient variables the laboratorian MUST KNOW
* Maternal birth date
* Gestational age at time of specimen collection
* Maternal weight at time of specimen collection
* Maternal insulin dependent diabetes status prior to pregnancy
* Multiple fetuses, e.g. twins, triplets
To understand how personal information can impact test interpretation, consider the following examples. There is an inverse relationship between maternal weight and serum marker levels. A dilutional effect is noted as maternal blood volume increases. Biomarker concentration tends to be less in larger women and slightly greater in women of less weight.
Maternal weight, racial background, maternal diabetic status, and an accurate estimate of gestational age can impact test interpretation.
No similar dilution effect is noted for amniotic fluid AFP. The concentration of unconjugated estriol in the maternal circulation shows a much smaller dilutional effect, perhaps due to the short half-life of this molecule. MoM values are weight adjusted using standard methods.
Racial and sometimes ethnic background information must be ascertained. African-American women have slightly - 10 percent to 15 percent - higher MSAFP concentrations in comparison to Asian or Caucasian women. Hispanic women tend to have higher APP levels. To take this into account, a median correction factor based upon race is applied to the MSAFP raw data. For African-Americans, the racial correction factor is 1.10. However, for both African-American and many Hispanic women, risk for NTDs is lower. The prevalence of open spina bifida among African-Americans is half that within the general population. While APP requires an adjustment, not all markers appear to differ significantly by race. An hCG correction factor of 1.07 is sometimes applied for African-Americans based upon 7 percent higher hCG levels.
Maternal diabetic status requires risk adjustment of raw data. Patients with Type 1 (insulin dependent) diabetes mellitus have lower MSAFP levels, but a three-times to five-times greater risk for an NTD pregnancy than nondiabetics. Gesrational diabetics are not at increased risk for NTDs. (24) Correction factors for maternal diabetic status must be applied to concentrations of APP, hCG and uE3. For Type 1 diabetic mothers, the MSAFP median correction factor is 0.8. Levels of hCG are 5 percent lower, and the correction factor applied to the MoM is 0.95. Concentrations of uE3 are 8 percent lower among Type 1 diabetics, and the MoM is adjusted by dividing by 0.92.
Accurate estimation of gestational age is essential for valid interpretation of laboratory results. This is more difficult than might be expected. Because between 25 percent and 45 percent of women cannot provide a reliable menstrual cycle history, the prospective mother may inaccurately estimate gestational age. Ultrasound examination is recommended to verify gestational age. How much difference can inaccurate estimate of gestational age make in the meaningfulness of laboratory findings? A difference of 10 days or more between the estimated gestational age estimated gestational age
n. Abbr. EGA
The estimated age of a fetus, usually reported in weeks and based on the date of the last menstrual period. based on patient recollection of her last menstrual period last menstrual period Gynecology The most recent time that a ♀ notes menstruation, a datum recorded in a chart during a routine gynecologic visit. See Menstruation. and ultrasound dating requires the laboratorian to recalculate re·cal·cu·late
tr.v. re·cal·cu·lat·ed, re·cal·cu·lat·ing, re·cal·cu·lates
To calculate again, especially in order to eliminate errors or to incorporate additional factors or data. MoMs and modify the previous interpretation of laboratory results.
Even fetal gender appears to influence the maternal serum markers, AFP and hCG. In pregnancies with an unaffected female fetus, MSAFP has been reported to be significantly lower (3 percent) than in the presence of a male fetus; free beta hCG levels are higher (7 percent) if the fetus is female. (25)
Optimal time for measuring AFP is between 16 weeks and 18 weeks gestation. Before that time, maternal serum concentration of AFP is negligible. Beyond 22 weeks, there is limited discriminatory power between affected and unaffected populations. Biomarker concentrations may be reported either as actual values, i.e., IU/mL or [micro]g/L, or as multiples of the median. MoM values are determined by dividing the patient's biomarker serum concentration by the marker's median concentration in matched, unaffected controls. The median value is the midpoint mid·point
1. Mathematics The point of a line segment or curvilinear arc that divides it into two parts of the same length.
2. A position midway between two extremes. -- as many patients have values greater than the median as have values less than the median. One hundred data points are viewed as the minimum to establish a median value. This requires a laboratory to amass a considerable amount of data to permit meaningful screening for each week of gestation or to make use of a commercially available database.
Facilities select a screening cutoff of either 2.0 MoM or 2.5 MoM, above which a test is considered "positive," meaning that there is increased risk for a birth defect. If an AFP MoM cutoff of 2.0 is used, about 3 percent to 5 percent of screening tests will be identified as abnormally high or "positive." If the cutoff for a medical decision is raised to 2.5, about 2 percent to 3 percent of tests will be positive. Selecting a higher cutoff value reduces the rate of false positives, caused by e.g., twins or incorrect gestational age, but could also increase the number of false negatives. A lower threshold could mean fewer false negatives, but more false positives that would require subsequent testing by invasive diagnostic procedures, i.e., amniocentesis or CVS. Patients need to be reminded that an initial positive test does not mean the fetus has a birth defect, nor does a negative test completely eliminate that possibility. The goal of a screening test is to identify individuals at sufficient risk for a dis order that they would benefit from further examinations. To ensure testing accuracy, participation in proficiency testing and external quality control programs are essential. The first external quality control program for multiple marker screening in the U.S. was developed by the Foundation for Blood Research (FBR FBR Friedman, Billings, Ramsey Group, Inc. (investment firm)
FBR Fast Breeder Reactor
FBR Federal Benefit Rate
FBR Foundation for Biomedical Research
FBR Foundation for Blood Research
FBR Fluidized Bed Reactor ). FBR continues to manage this program with the College of American Pathologists This article or section needs sources or references that appear in reliable, third-party publications. Alone, primary sources and sources affiliated with the subject of this article are not sufficient for an accurate encyclopedia article. . (20)
Commercial diagnostic services and screening program software for interpretive reports are especially helpful in characterizing a patient's risk. To provide the most precise and meaningful estimate of risk, raw data is adjusted for patient variables (see Table 1) and subjected to sophisticated statistical analysis. (20) The quality of screening programs can be increased by the use of improved statistical models. Among the statistical parameters required to calculate screening test performance are coefficients for the correlation between markers within the same trimester trimester /tri·mes·ter/ (-mes´ter) a period of three months.
A period of three months.
The first third or 13 weeks of pregnancy. . (26) When Bayesian and multivariate analyses are applied to clinical, biochemical, and sonographic information, there is improved risk assessment. Manual calculation of these complex statistical correlations is unwieldy and impractical in a clinical situation. Various software programs have been marketed to provide metanalysis of median values from large populations. Laboratories can input biomarker values obtained from testing and patient i nformation. The software will calculate total risk factor based upon the parameters entered. Users are able to choose from a variety of multilingual text and/or graphic formats to provide physicians with a clear interpretive report. As useful as these programs are, some discrepancy may be noted attributable to laboratory-related variation as well as software design. Even when the same maternal serum markers were utilized for Down syndrome risk calculation, comparison of six software packages showed variation in mean detection rate from 54.4 percent to 66.4 percent, with a false positive rate ranging from 2.4 percent to 6.8 percent. It has been suggested that by increasing the number of biomarkers included in the risk assessment, the differences will be diminished. (27)
Neural tube defects
Neural tube defects arise very early in pregnancy. Within 18 days to 20 days after fertilization, critical events occur in the development of the fetal neural tube. The two most common NTDs, spina bifida and anencephaly, affect about 4,000 pregnancies annually in the U.S. (6,28) In about one-half of NTDs, the infant's brain is totally or partially absent -- a condition called anencephaly. In the other one-half of NTDs -- spina bifida -- the neural tube, which ultimately becomes the spinal cord, is not enclosed within the protective vertebral column. To minimize damage to the exposed neural tissue, surgical intervention is necessary as early in life as possible. Individuals with spina bifida often experience paralysis, bowel and bladder incontinence, sexual dysfunction, and varying degrees of learning disabilities. Healthy People 2010 objectives for reducing birth defects call for a 50 percent reduction in NTDs. (1) The baseline for spina bifida and other NTDs is six cases per 10,000 live births.
Risk factors for NTDs include ethnicity, genetic mutations, environmental agents, and dietary status. Some populations are presently at significantly greater risk of NTDs. Much of the early research linking NTD pregnancies with maternal folic acid status was conducted in the United Kingdom. This is not surprising, given that the highest risk for NTDs is among Caucasians of Celtic Irish, Scottish, and Welsh descent. (29)
Other groups have been identified in which risk of NTD pregnancies is high. A study of women in 14 Texas-Mexico border counties from 1993-1998 by the Texas Department of Public Health, with support from the Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center. , reported an overall NTD rate of 13.4 per 10,000 live births, largely reflecting the rate among Hispanic women. (30) The rate of NTDs among African-Americans is about one-third the rate for the U.S. Caucasian population. (31)
The 2010 target is to reduce the overall NTD rate in the U.S. to three per 10,000 live births. Daily intake of folic acid, at least a month before conception as well as during pregnancy, has been shown to reduce the risk for neural tube defects by as much as 50 to 70 percent. (31) British researchers and clinicians in the mid-1960s suspected the benefit of folic acid in preventing NTDs. (32) A decade ago, the U.S. Public Health Service recommended the consumption of 0.4 mg of folic acid daily by all women capable of becoming pregnant. (33) Folic acid antagonists folic acid antagonists
Modified pterins, such as aminopterin and amethopterin, that interfere with the action of folic acid and produce the symptoms of a folic acid deficiency. , primarily antiepileptic drugs, e.g., valproic acid, carbamazepine carbamazepine /car·ba·maz·e·pine/ (kahr?bah-maz´e-pen) an anticonvulsant and analgesic used in the treatment of pain associated with trigeminal neuralgia and in epilepsy manifested by certain types of seizures. , phenytoin phenytoin /phen·y·to·in/ (fen´i-toin?) an anticonvulsant used in the control of various kinds of epilepsy and of seizures associated with neurosurgery.
n. , and phenobarbital phenobarbital /phe·no·bar·bi·tal/ (fe?no-bahr´bi-tal) a long-acting barbiturate, used as the base or sodium salt as a sedative, hypnotic, and anticonvulsant.
n. increase NTD risk. Likewise dihydroreductase inhibitors, e.g., sulfasalazine sulfasalazine /sul·fa·sal·a·zine/ (-sal´ah-zen) a sulfonamide used in the treatment and prophylaxis of inflammatory bowel disease and the treatment of rheumatoid arthritis. , methotrexate methotrexate, drug used in halting the growth of actively proliferating tissues. Introduced in the 1950s, it is used in the treatment of leukemia, psoriasis, and non-Hodgkin's lymphoma. , triamterene, and aminopterin aminopterin: see metabolite. , that block conversion of folate folate /fo·late/ (fo´lat)
1. the anionic form of folic acid.
2. more generally, any of a group of substances containing a form of pteroic acid conjugated with l-glutamic acid and having a variety of substitutions. to its more active metabolites, are known to cause NTDs. (34) While folic acid supplementation may decrease the risk of NTDs associated with use of dihydroreductase inhibitors, it may not modify the risk ofNTDs associated with certain antiepileptic drugs. (34) Although 10 years have now passed since the original P1-IS recommendation, overall public awareness of folic acid prophylaxis for NTDs is still not encouraging, despite numerous public and private educational campaigns. (35,36)
Dietary deficiency of folate may not be the sole risk factor for NTDs. Alterations in folate metabolism are also linked to NTD development and may contribute to the occurrence of chromosomal abnormalities. (37-39) Research is ongoing into the genetic basis for abnormal folate metabolism and NTDs. A specific mutation (677 C[right arrow]T) at nucleotide 677 in the 5,10- methylenetetrahydrofolate reductase (MTHFR MTHFR Methylenetetrahydrofolate Reductase (gene mutation) ) gene may be the cause of abnormal levels of homocysteine Homocysteine Definition
Homocysteine is a naturally occurring amino acid found in blood plasma. High levels of homocysteine in the blood are believed to increase the chance of heart disease, stroke, Alzheimer's disease, and osteoporosis. in serum and amniotic fluid. (38) This variant of the enzyme is thermolabile thermolabile /ther·mo·la·bile/ (-la´bil) easily affected by heat.
Subject to destruction, decomposition, or great change by moderate heating. and has about one-half the activity of the unaltered enzyme, thus leading to mild hyperhomocysteinemia. Elevated levels of the amino acid homocysteine have been reported in mothers of children with neural tube defects and, more recently, in mothers of children with Down syndrome. Folate is required as a cofactor cofactor
An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may for the enzyme-catalyzed remethylation of homocysteine to methionine methionine (mĕthī`ənēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the L-stereoisomer appears in mammalian protein. by a one-carbon transfer reaction. A defect in this pathway, whether due to low folate intak e or altered enzyme activity, leads to elevated circulating levels of homocysteine. Whatever the cause, there is significant association of abnormal amniotic fluid homocysteine levels and defective neural tube closure. (40) Methyl groups are also donated by the folate-derivative (methyl-tetrahyrofolate) to other acceptor acceptor - Finite State Machine molecules, including DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. . Deficient methylation methylation,
n a phase-II detoxification pathway in the liver; methyl groups combine with toxins to rid the body of various substances.
(meth´ of DNA leads to breaks in the strands and increased risk of chromosomal abnormalities arising during cell division. Folate deficiency and increased risk for NTDs can occur because of inadequate dietary intake or because a specific genetic alteration has increased folate requirements to maintain normal metabolism. (41)
The biomarker pattern associated with increased risk of NTD is an elevated concentration of MSAFP and a decreased level of unconjugated estriol. Measurement of hCG is not informative. Amniocentesis permits measurement of AFAFP and acetylcholinesterase.
The risk for abnormalities due mainly to nondisjunction nondisjunction /non·dis·junc·tion/ (-dis-junk´shun) failure either of two homologous chromosomes to pass to separate cells during the first meiotic division, or of the two chromatids of a chromosome to pass to separate cells during of chromosomes during meiosis increases with increasing age. The most common chromosomal disorder is Trisomy 21 or Down syndrome. Affected individuals exhibit mental retardation, delayed development, and increased risk for childhood leukemia, congenital heart disease congenital heart disease, any defect in the heart present at birth. There is evidence that some congenital heart defects are inherited, but the cause of most cases is unknown. , and gastrointestinal abnormalities. The relative risk of having a DS baby is approximately tin 1,250 at age 19, 1 in 350 at age 35, and 1 in 100 at age 40. In Down syndrome, MSAFP levels are 25 percent lower than in unaffected pregnancies; uE3 concentrations are also lower by about 25 percent; and hCG values are at least two times greater.
FIRST TRIMESTER TESTING
A combination of two relatively independent biochemical and biophysical approaches is being tried in first trimester testing. Measurement of biochemical markers, e.g., free beta hCG and serum pregnancy associated plasma protein A (PAPP-A PAPP-A Pregnancy-Associated Plasma Protein A ), in conjunction with evaluation of a sonographic marker (nuchal translucency), offers the hope of better risk assessment earlier in pregnancy. Nuchal translucency (NT) is an ultrasonographic measure of the fluid accumulation at the back of the fetal neck between 10 weeks to 13 weeks of gestation. NT is increased in fetuses with chromosomal abnormalities and has proven to be a strong predictor of Down syndrome and Trisomy 18. An individual certified as a sonographer Sonographers are medical professionals who operate ultrasonic imaging devices to produce diagnostic images and scans, videos, or 3D volumes of anatomy and diagnostic data. Sonography requires specialized education and skills to view, analyze and modify the scan to optimize the is required to obtain transvaginal sonographic NT measurements of the uniformity and accuracy necessary for use in risk assessment. (42) Reference to a "combined test" means NT performance along with measurements of free beta hCG and PAPP-A. First trimester screening with or without the ultrasound marker nuchal nuchal (nyōōˑ·kl),
adj pertaining to the posterior or nape of the neck. tr anslucency is reported to have a false positive rate less than that of the second trimester triple screen for Down syndrome. (42) Even if first trimester screening for Down syndrome becomes routine, a further screening for neural tube defects is still required in the second trimester.
Free beta hCG
Free beta hCG is the sole biochemical marker presently known to be useful in both first and second trimester screenings. Maternal serum levels of free beta hCG are elevated in DS pregnancies and dramatically reduced in cases of Trisomy 18. The median concentration for free beta hCG in DS is 1.9 MoM compared to a MoM of 1.0 in an unaffected pregnancy. Intact hCG does not discriminate as well since its median MoM is less than 1.3. (42)
At present, the most promising new first trimester serum marker is pregnancy-associated plasma protein A Pregnancy-associated plasma protein A is a protein used in screening tests for Down syndrome. References
1. ^ Breathnach FM, Malone FD (2007). (PAPP-A). PAPP-A is a glycoprotein synthesized in the placental trophoblast and released into the maternal circulation. The function of PAPP-A remains unclear. (43) During the first trimester, the concentration of PAPP-A in maternal serum increases rapidly with gestational age in unaffected pregnancies, but is noticeably reduced in DS and Trisomy 18 pregnancies. Because there is little difference in PAPP-A concentration between affected and unaffected pregnancies by the second trimester, this marker is not suitable for use in later screening. (44) Of interest is the report that the median PAPP-A level in maternal smokers is reduced, unrelated to DS risk. (45)
In DS, the median MoM for PAPP-A is 0.44 compared to the MoM of 1.0 for unaffected pregnancies. (46, 42) PAPP-A can be detected by enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses. (ELISA) or fluoroimmunoassay. If maternal serum levels of PAPP-A and free beta hCG are measured at 10 weeks to 13 weeks of gestation, the DS detection rate is 68 percent with an initial positive rate of 5 percent. PAPP-A levels are not useful in NTD detection. A three-year study (1995-1998) of more than 10,000 specimens collected at nine weeks to 13 weeks of gestation indicated that first trimester screening using PAPP-A, free beta-hCG, and NT measurement significantly improved detection of DS and Trisomy 18, with detection rates of 91 percent and 97 percent respectively. (47) For NTD screening, the patient must return during the second trimester. No significant gender-related differences in NT and PAPP-A concentrations have been reported. However, free beta hCG levels are significantly higher if the fetus is female rather than male. (48)
By taking advantage of the fact that different screening markers discriminate between the presence and absence of Down syndrome differently depending upon when in gestation they are measured, the integrated test offers a high detection rate and a very low false positive rate. Reduction in the false positive rate is especially great among women 35 years of age or older. To accomplish an integrated screening, a woman should be tested between 10 weeks and 13 weeks of gestation and return within five weeks for further testing. Performance for integrated screening for DS is impressive -- an 85 percent detection rate and less than 1.0 percent false positive. (2)
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. (2) 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.
Sharon M. Miller, PhC, CLS (Common Language Specification) The structure and syntax of .NET and CLI programming languages. See .NET. (NCA (Network Computing Architecture) An architecture from Oracle for developing applications within a networked computing environment. It provides a three-tier distributed environment based on CORBA that uses program components known as "cartridges. ), MT(ASCP ASCP American Society of Clinical Pathologists. ), is professor and associate dean. College of Health and Human Sciences, and Jeanne M. Isabel, MSEd., CLSpH(NCA). MT(ASCP), is associate professor, School of Allied Health Professions, both at Northern Illinois University , DeKalb, IL.
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An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus. of human chorionic gonadotropin, its free subunits, and metabolites Metabolites
Substances produced by metabolism or by a metabolic process.
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Any of various enzymes, including the proteinases and peptidases, that catalyze the hydrolytic breakdown of proteins. secreted by human fibroblasts Fibroblasts
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Table 1 AN EXAMPLE OF DATA REPORTING FOR MATERNAL SERUM AFP Reporting results as Multiples of the Median (MoMs) for a given week of gestation, applying the appropriate correction factors based upon patient information. (See calculations below.) Clinical information: Maternal race: African-American Maternal Type 1 diabetes mellitus: Yes Gestational age: 15 weeks 5 days Gestation: Singleton Clinical results: Maternal serum AFP (MSAFP) = 50 [micro]g/L Sample calculation: Median MSAFP at 15 weeks, 5 days gestation = 30 [micro]g/L Correction factor for maternal race = 1.10 Correction factor for maternal diabetic status = 0.80 MoM = Maternal serum AFP([micro]g/L)/ Median MSAFP([micro]g/L) for gestational age x applicable correction factors MoM = 50 [micro]g/L/ 30 [micro]g/L x 1.10 x 0.80 Patient's MOM = 1.89 Open NTD cutoff = 2.0 MoM Interpretation: Open spina bifida Negative (The risk of open neural tube defect is less than the screening cutoff.)