Harvard-MIT Division of Health Sciences and Technology HST.071: Human Reproductive Biology Course Director: Professor Henry Klapholz IN SUMMARY HST 071 PRENATAL DIAGNOSIS PRENATAL GENETIC DIAGNOSIS Indications for prenatal diagnosis • Advanced maternal age • Positive maternal serum alpha fetal protein • Balanced maternal or paternal translocation • Risk for detectable Mendelian disorder • Family history of neural tube defects • Abnormal fetal ultrasonography • History of fetal wastage • Parental concern Alpha Fetal Protein • Glycoprotein MW 70,000 Dalton • Produced by yolk sac and liver at 4-8 weeks • Liver later becomes dominant source • Most MSAFP gets to mother by diffusion • Transmembranous transport from AF is 6% • Any increase in production (twins) or increase in AF (NTD) leads to increase • Expressed as multiples of the median (MOM) for given GA • Maternal race, weight, multiple pregnancy, IDDM • Each – – – – lab must establish norms and risks Diabetics have overall increased risk for anomalies AA have higher AFP at any given GA FH impacts risk as well Concentrated in very thin, diluted in very obese • Elevated for α-fetal protein & acetylcholinesterase • MSAFP is also expressed as MoM for normal pregnancies of same gestational age • Using 2.5 MoM we can detect 93-96% of open spina-bifida and 100% of anencephalics • False positives are high (contamination of AF by fetal blood – especially crossed by needle) • AChE is so large that it is not in fetal urine. It will detect 99% of open spiOther causes of elevated AFP • Abdominal wall defects • Renal agenesis • Fetal demise or impending demise • Teratoma • Congenital nephrosis • Congenital diaphragmatic hernia • Some maternal tumors • IBD in mother • Feto-maternal hemorrhage • Oligohydramnios • Fetal growth restriction if placenta is na-bifidaIN SUMMARY HST 071 PRENATAL DIAGNOSIS Incidence of chromosomal abnormalities by age Figure removed due to copyright restrictions. Sonography • All women had been encouraged to have amniocentesis if at risk in past years • Modern sonography will detect virtually all lesions • Gestational age errors, multiple gestation, fetal demise are all detectable • Normal U/S allows 90% reduction in risk for NTD based on α-fetal protein • Early genetic sonography is highly sensitive and statistically superior to later ultrasonography for Down syndrome detection. • Early midtrimester sonography achieves a diagnostic accuracy similar to that currently reported for first-trimester nuchal translucency. Triple Screen • Α Fetal Protein (AFP) • Human chorionic Gonadotropin (hCG) • Unconjugated estriol (µE3) • Estimate risk of fetus with trisomy 18 and tr• Low AFP, hCG and µE3  trisomy 18 • Low AFP, µE3 and high hCG  trisomy 21 isomy 21 • Biologic basis for this unknown • Three specific adjustments • Maternal weight • Obese women have l• Diabetes Mellitus ower MASAFP – dilution is 2/3 that of non-diabetic• • Race • • Smok• IDDM have AFP that AA women have AFP 9-15% higher ing ???? Have lower incidence of trisomy 21 !!!!!IN SUMMARY HST 071 PRENATAL DIAGNOSIS First Trimester Screening • Now an option for pregnant women if certain criteria are met • Nuchal translucency (NT), have allowed for earlier, noninvasive screening for chromosomal abnormalities and, when combined with serum screening in the first trimester, have comparable detection rates as standard second-trimester screening • Low serum AFP (31% of trisomies) • Free beta-hCG reduced in aneupoidy • Schwangerschafts protein 1 (SP1) also known as pregnancy specific beta-1 glycoprotein -median for abnormal group (trisomy 18 and 21) is ½ that of normal group Quadruple Screen • AFP, estriol, Hcg, Inhibin Inhibin in combination with alpha fetal protein • The best three-analyte combination was maternal serum -fetoprotein, free -human chorionic gonadotropin, and dimeric inhibin A • 97% of Down syndrome cases were detected at a false-positive rate of 16%. • At a slightly higher false-positive rate (18%) maternal serum -fetoprotein, estriol, and intact human chorionic gonadotropin detected only 79% of cases. • 67% (37/55) detection was obtained with use of the 2-analyte combination of a- fetoprotein and dimeric inhibin A Nuchal Translucency • Higher rates of nuchal translucency screening were associated with lower rates of chorionic villus sampling and invasive testing. • The addition of first-trimester screening may lead to reduced rates of invasive testing and fewer losses of normal pregnancies. • The use of nuchal translucency adds to the sensitivity of detection but can add as much as $300,000 in cost for each detected Down’s syndrome baby. • Increased nuchal skin alone, in the absence of other ultrasonographic dysmorphologic features, does not generally help to identify fetuses with other abnormal karyotypes. • The nuchal thickness/humerus length ratio and maternal age had a 79.8% detection rate at a 22.1% false-positive rate, compared with maternal age plus humerus length (sensitivity, 55.1%) or maternal age plus nuchal thickness (sensitivity, 66.7%) at the same false-positive rate. For women >35 years old the values were 80% and 22.0%, respectively. • Nuchal thickness, humerus length, and maternal urine β-core fragment levels are another sensitive assay from Down’s syndrome • Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results • Midtrimester nuchal thickness measurement significantly detected postnatally confirmed CHD in chromosomally normal fetuses.IN SUMMARY HST 071 PRENATAL DIAGNOSIS PAPP • First-trimester free -human chorionic gonadotropin and pregnancy-associated plasma protein A screening for Down syndrome can achieve detection rates as high as those associated with –alpha-fetoprotein and human chorionic gonadotropin or alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol screening in the second trimester. • Liklihood ratios for detectiTEST No test NT alone PAPP-A, fbhCG NT, PAPP-A, fbhCG on of various abnormalities wiDOWN SYNDROME AFP, uE3, hCG (triple test) AFP, uE3, hCG, INH-A (quad test) All 7 tests • 1.0 4.9 10.6 36.1 8.4 14.0 260.9 th given tests UNAFFECTED 1.00 0.28 0.15 0.08 0.13 0.08