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Biochemical markers of prenatal diagnosis

This document discusses prenatal diagnosis and screening for fetal abnormalities. It defines prenatal diagnosis as detecting abnormalities in the fetus before birth through various screening and testing methods. The goals of prenatal diagnosis are to provide informed choices for couples at risk, provide reassurance, allow for confirmation of disorders, and enable prenatal management or treatment when possible. Several screening modalities are described that use biomarkers like alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and nuchal translucency measurements to detect disorders like Down syndrome, neural tube defects, and chromosomal abnormalities. Integrated screening combining tests is noted to have the lowest false positive rates.

Health & Medicine◦
BY Dr KHALED SALEH 30 April 2014
Definition: ‘Prenatal diagnosis is defined as the detection of abnormalities in the fetus, before birth’ Screening is the process of surveying a population, usinga specific marker or markers and defined screening cut-off levels, to identify the individuals in the population at higher risk for a particular disorder.
The purpose of prenatal diagnosis is not simply to detect abnormalities in fetal life and allow termination.It rather have following goals : Provide a range of informed choice to the couples at risk of having a child with abnormality. Provide reassurance & remove anxiety, especially among high risk groups. Allow couples at high risk to know that the presence or absence of the disorder can be confirmed by testing. Allow the couples the option of appropriate management ( psychological, pregnancy/delivery, postnatal) To enable prenatal treatment of the fetus.
Some Disorders for which PRENATAL DIAGNOSIS is available: 1. Congenital malformations 2. Chromosomal disorders 3. Non genetic Fetal disorders Fetal infections, Immune hydrops, DM,Fetal effects of maternal drugs e.g valproic acid 4. Single gene disorders -Multiple malformation synd *Holt oram, Craniosynostosis, Orofacial digital synd -Hematological disorders *Thalassemias, Hemoglobinopathies, Hemophilia -Metabolic Disorders *Tay sach, Wilson, -Neuromuscular disorders *Huntington chorea, Myotonic dystrophy, Fragile X
-Renal Disoders *kidney disease -Connective tissue dis / Skeletal dysplasia * Osteogenesis imperfecta, Ehlers Danlos, Achondroplasia, Marfan. -Skin disorders *Epidermolysis bullosa, Ectodermal dysplasia 5
Down’s Syndrome  – Down’s syndrome (DS) is a congenital disorder, caused by a trisomy of chromosome 21  – risk increases with the mother’s age
Incidence of Down’s Syndrome  Down syndrome is a chromosomal disorder caused by an error in cell division, the likelihood of such an error occuring increases with maternal age. This means that an older mother is more likely to give birth to a child with Down sydrome than her younger counterpart. The likelihood of a woman under 30 years of age giving birth to a child with Down syndrome is less than 1:1000, but increases the older the woman gets (see chart below), with an incidence of about 1:100 and 1:30 at 40 and 45 years of age respectively.
Risk of DS and Chromosomal Abnormalities at Term Maternal Age at Delivery (yr) Risk of DS Risk of Any Chromosomal Abnormality 20 1/1650 1/530 25 1/1250 1/480 30 1/950 1/390 35 1/385 1/180 40 1/100 1/65 45 1/30 1/19
Neural tube defects  NTD (Neural tube defects) can affect 1 in 500 infants  – Commonest forms of NTD known as anencephaly or spina bifida  – Neural tube beneath the backbone fails to develop definitive diagnosis relies on amniocentesis  – high levels of AFP (Alphafetoprotein) seen in NTD
BIOCHEMICAL MARKERS PRENATAL DIAGNOSIS 1- Alpha-fetoprotein (AFP) a protein synthesized by the fetus is detectable in maternal serum from week 6 of pregnancy,with a peak in week 34 of gestation (4 mg / ml), its value decreasing in 8-12 months after birth. Measurement of alpha-fetoprotein can be done from amniotic fluid or from maternal blood.
Elevated values of alpha-fetoprotein are found in:  Multiple pregnancies  Skin diseases;  Organ failure;  Congenital nephropathy;  Cystic higroma;  Hepatic necrosis;  Neural tube defects  Abdominal wall defects. 
Low values of alpha-fetoprotein are recorded in cases Chromosomal abnormalities Defects of the placenta Fetal hydrops Trophoblastic disease Diabetic mothers
BIOCHEMICAL MARKERS PRENATAL DIAGNOSIS 2-Human Chorionic Gonadotropin  The hormone human chorionic gonadotropin (better known as HCG) is produced during pregnancy. It is made by cells that form the placenta, which nourishes the egg after it has been fertilized and becomes attached to the uterine wall.  Levels can first be detected by a blood test about 11 days after conception and about 12 - 14 days after conception by a urine test.  In general the HCG levels will double every 72 hours. The level will reach its peak in the first 8 – 11 weeks of pregnancy and then will decline and level off for the remainder of the pregnancy.
 There are two common types of HCG tests. A qualitative HCG test detects if HCG is present in the blood. A quantitative HCG test (or beta HCG) measures the amount of HCG actually present in the blood.
What can a low HCG level mean?  A low HCG level can mean any number of things and should be rechecked within 48-72 hours to see how the level is changing. A low HCG level could indicate  1- Miscalculation of pregnancy dating  2-Possible miscarriage or blighted ovum A blighted ovum (also known as “anembryonic pregnancy”) happens when a fertilized egg attaches itself to the uterine wall, but the embryo does not develop. Cells develop to form the pregnancy sac, but not the embryo itself. A blighted ovum occurs within the first trimester, often before a woman knows she is pregnant. A high level of chromosome abnormalities usually causes a woman’s body to naturally miscarry.
 3- Ectopic pregnancy An ectopic pregnancy occurs when the fertilized egg attaches itself in a place other than inside the uterus. Almost all ectopic pregnancies occur in a fallopian tube, and are thus sometimes called tubal pregnancies. The fallopian tubes are not designed to hold a growing embryo; the fertilized egg in a tubal pregnancy cannot develop normally and must be treated. An ectopic pregnancy happens in 1 out of 50 pregnancies
What can a high HCG level mean?  A high level of HCG can also mean a number of things and should be rechecked within 48-72 hours to evaluate changes in the level.  Miscalculation of pregnancy dating  Molar pregnancy A molar pregnancy is an abnormality of the placenta, caused by a problem when the egg and sperm join together at fertilization. Molar pregnancies are rare, occurring in 1 out of every 1,000 pregnancies. Molar pregnancies are also called gestational trophoblastic
Can anything interfere with my HCG levels?  Nothing should interfere with an HCG level except medications that contain HCG. These medications are often used in fertility treatments.  All other medications such as antibiotics, pain relievers, contraception or other hormone medications should not have any effect on a test that measures HCG.
BIOCHEMICAL MARKERS PRENATAL DIAGNOSI 3-Beta-human chorionic gonadotropin(β- HCG) 3 weeks LMP: 5 – 50 mIU/ml 4 weeks LMP: 5 – 426 mIU/ml 5 weeks LMP: 18 – 7,340 mIU/ml 6 weeks LMP: 1,080 – 56,500 mIU/ml 7 – 8 weeks LMP: 7, 650 – 229,000 mIU/ml 9 – 12 weeks LMP: 25,700 – 288,000 mIU/ml 13 – 16 weeks LMP: 13,300 – 254,000 mIU/ml 17 – 24 weeks LMP: 4,060 – 165,400 mIU/ml 25 – 40 weeks LMP: 3,640 – 117,000 mIU/ml Non-pregnant females: <5.0 mIU/ml Guideline to HCG levels during pregnancy/ LMP Last menstrual period
BIOCHEMICAL MARKERS IN PRENATAL DIAGNOSIS 4-Unconjugated estriol  Estriol (E3) is one of the three major naturally occurring estrogens, the others being estradiol (E2) and estrone (E1).  In non-pregnant females, the major estrogen is estradiol produced by the ovaries.  During pregnancy, estriol is secreted by the placenta and fetus and becomes the dominant estrogen form.  The primary form of estriol measured during pregnancy is unconjugated estriol (also referred to as “free” estriol or uE3).  Maternal serum uE3 levels have been used as a functional marker of the fetal-placental unit and in the evaluation of pregnancy complications.
BIOCHEMICAL MARKERS OF PRENATAL DIAGNOSIS 5- Inhibin - A  Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B.  Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion.  Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation.  The precise biological function of inhibin A in pregnancy is could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life.  The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms.
BIOCHEMICAL MARKERS OF PRENATAL DIAGNOSIS 6- Pregnancy-associated plasma protein-A  It largest of the pregnancy associated proteins produced by both the embryo and the placenta during pregnancy  This protein is thought to have several different functions, including preventing recognition of the fetus by the maternal immune system, matrix mineralization and angiogenesis.  Detection of this protein is also suggested as a first and second trimester diagnostic test for aneuploidies, including Trisomies 21 or Down’s Syndrome
Prenatal Screening Modalities for DS and trisomy 18  Integrated Prenatal Screening (IPS)  Serum Integrated Prenatal Screening (Serum IPS)  First Trimester Screening (FTS)  Quadruple maternal serum screening (Quad)  Maternal serum screening (Triple) What is available in your community?
Integrated Prenatal Screening (IPS)  2 step screening combining:  T1 (11-13+ 6/7 weeks – ideally 11)  Nuchal translucency measurement  Maternal serum marker  PAPP-A (pregnancy-associated plasma protein)  T2 (15-20 weeks – ideally 15-17)  Maternal serum markers  AFP, uE3, HCG
Nuchal Translucency  Subcutaneous fluid-filled space located between back of fetal neck and skin. At minimum an NT scan will measure CRL to determine gestational age (GA) and the NT  Crown-rump length (CRL) is the measurement of the length of human embryos and fetus from the top of the head (crown) to the bottom of the buttocks (rump)  Measured on U/S between 11–13+ 6/7 weeks, measurement is not valid outside of this time period  NT increases with gestational age Age CRL 6.1Weeks 0.4 cm 7.Weeks: 1.0 cm 8.Weeks: 1.9 cm 9.Weeks: 2.5 cm 10.Weeks 4.0 cm 12.Weeks 5.5 cm 13.Weeks 6.90 cm 14.Weeks 8.0 cm
Nuchal Translucency Increased NT associated with:  Trisomies 21, 18, 13, triploidy and Turner syndrome  Spontaneous fetal loss  With normal chromosomes: cardiac defects, diaphragmatic hernia, pulmonary defects, skeletal dysplasias, congenital infection, metabolic/haem disorders, rare single gene disorders  Normal pregnancy – chance of a normal birth varies with size of NT measurement NT measurement Chance of normal birth ≤ 3.4mm 95% 3.5 – 4.4mm 70-86% 4.5 – 5.4mm 50-77% 5.5 – 6.4mm 67% ≥ 6.5mm 31%
Nuchal Translucency (NT)
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Serum Integrated Prenatal Screening (SIPS)  Serum only - 2 step approach  Combines first and second trimester serum markers to produce single risk assessment  T1  PAPP-A: 11-13+6/7 weeks  11 weeks is ideal  T2  AFP, uE3, hCG, Inhibin-A: 15–20 weeks  15-17 weeks is ideal  Consider when NT not available False positive rate lower with a dating ultrasound
First Trimester Screening (FTS)  NT measurement: 11 to 13+6/7 weeks  T1 serum markers  PAPP-A, free beta hCG: 11-13+6/7 weeks  11 weeks ideal  NTD screening with MS-AFP and/or ultrasound is still recommended in T2
Quadruple Screening – Quad test  Second trimester maternal serum screening  15-20 weeks – 15-17 weeks optimal  AFP, uE3, HCG, Inhibin-A Maternal Serum Screening (Triple)  Same as Quad screening but without Inhibin-A False positive rate lower with a dating ultrasound
Biochemical markers in the second trimester
Comparison of Prenatal Screening Tests in Detecting Down Syndrome Test Detection Rate (DR) False Positive Rate (FPR) IPS 85 - 90% 2 - 4% Serum IPS 80 - 90% 2 - 7% FTS 78 - 85% 3 - 9% Quad 75 - 85% 5 - 10% Triple 60 - 85% 5 - 12% NT alone 60 - 70% 5%
Biochemical markers of prenatal diagnosis