PRENATAL DIAGNOSIS

Prenatal diagnosis of a suspected genetic/hereditary disease or congenital malformation is an important component of genetic counseling, referral to suitable centers for delivery and further management, as well as to prepare the family for the expected or unexpected outcomes.

Indications for prenatal diagnosis usually include:

• Advanced maternal age (gt;35 years) at delivery

• Obstetric history of recurrent abortions/stillbirths or neonatal deaths

• History of a potentially genetic disease or malformation in previous child

• History of a genetic disease, carrier state or abnormal karyotype in parents

• Abnormal maternal serum markers during antenatal screening

• Antenatal history of exposure to potential teratogens, e.g. infections, drugs, irradiations, etc.

• Abnormal prenatal USG/anomaly scans.

Prerequisites: Prenatal diagnosis is a costly and time consuming procedure, with inherent risks of diagnostic interventions. Hence, it should be offered only in selected cases, when:

• Accurate diagnosis of index case is available and parents have been identified with abnormal carrier state or chromosomal abnormality,

• Estimated risk of recurrence is fairly high and expected fetal disorder is sufficiently severe, to justify the need and risk for prenatal diagnosis.

• Available prenatal diagnostic tests for suspected defect are fairly sensitive and specific.

• No satisfactory postnatal treatment is available for suspected defect or delayed diagnosis is likely to worsen the outcome.

• Option of pregnancy termination or fetal/gene therapy is acceptable to the couple in case of abnormal result.

• Family has made an informed decision to accept risks / benefits of such intervention and consented in writing.

Techniques: Prenatal diagnostic tests may be broadly divided into: (a) screening tests, and (b) specific diagnostic tests (Table 11.6).

Screening tests are simple and cost-effective inter­ventions to identify high-risk mothers in need of further investigations and should form the part of regular antenatal workup. Pre-conception carrier state for many recessive disorders may be identified by selected screening investigations in high-risk mothers, e.g. serum CPK levels for Duchenne muscular dystrophy, HbA₂

TABLE 11.14: Prenatal diagnostic tests

Maternal studies

• Prenatal USG studies

- Level 1 and 2 anomaly scans

- Early transvaginal scans

- Late malformation scans

• Biochemical

- Triple marker test

- Quadruple marker test

• Non-invasive prenatal screening

• Others: TORCH screen, Hb electrophoresis

Fetal studies

• Cytogenetic and molecular diagnostic tests

- Chorionic villous biopsy (~11-13 weeks)

- Amniocentesis (~17-23 weeks)

- Cordocentesis,(gt; 18 weeks)

• Biochemical enzyme assays

• Others: Fetoscopy, fetal echocardiography

levels for thalassemia, etc. Important prenatal screening tests (Table 11.14) are as follows:

• Prenatal ultrasonography is the most commonly used prenatal screening test to detect major/minor structural malformations in utero, as well as to assist in collection of samples for advanced cytogenetic studies. Routine transabdominal USG screening is recom­mended at 11-13 weeks (Level 1 anomaly scan) and again at 18-20 weeks (Level 2 anomaly scan) of gestation in all antenatal mothers. However, additional USGs are advised in high-risk pregnancies, as follows:

Early transvaginal scans to detect markers of chromosomal defects, e.g. first trimester markers, e.g. cystic hygroma, hydrops fetalis, nuchal translucency, growth retardation and fetal heart rate abnormalities; and second trimester markers, e.g. nuchal thickening, echogenic bowel, short extremities, pyelectasis, intracardiac echogenic foci, brain ventriculomegaly, clinodactyly, etc.

Late scans (20-24 week) to detect malformations, which may be missed on routine USG at 18-20 weeks, e.g. small bowel atresia, esophageal atresia, diaphragmatic hernia, renal tract anomalies and achondroplasia. Disorders, e.g. skeletal dysplasia may be identified, using intrauterine nomograms and growth curves on serial scans from second trimester onwards.

3-D USG scans are also available to detect minor fetal malformations, e.g. cleft palate, single vertebral defects.

Maternal biochemical markers: Conventional proto­cols for biochemical screening at 11-13 weeks gestation include Triple marker test at 11-13 weeks of gestation (#945;-fetoprotein, total or free #946;-human chorionic gondotropin and unconjugated estriol levels) and Quadruple marker test at 14-16 weeks (Triple markers + inhibin levels), to predict fetal chromosomal defect, e.g. Down syndrome (Ch 11.3.1).

• Non-invasive prenatal screening (NIPS) is a new screening test in high-risk cases to analyse free fetal DNA in maternal plasma at ~10^th week of gestation. It can detect aneuploidies of chromosome 21 with 99% sensitivity but false-positive results are possible and must be confirmed with cytogenetic studies.

Specific genetic studies in fetus are indicated only in a selected subset of high-risk mothers, as identified on routine screening tests or with known risk of genetic disease. While most of them are expensive and require invasive sample collections with inherent risk of procedure, information obtained is often precise enough to confirm or exclude a suspected defect. These tests include karyotyping, molecular diagnosis and enzyme studies in fetal samples to confirm or exclude suspected genetic defect.

Choice of the method to collect these samples depends on the gestational age at the time of proposed prenatal diagnosis and usually include chorionic villous biopsy at ~11-13 weeks, amniocentesis at ~17-23 weeks and cordocentesis, at gt;18 weeks. Fetoscopy is most traumatic and rarely used, except to obtain samples of fetal tissues, e.g. liver or skin for enzymatic studies.

All these techniques except fetoscopy, are fairly safe in expert hands with estimated risk of fetal loss as 0.1­0.2%. Fetoscopy is associated with gt;5% risk of abortion. However, some fetomaternal hemorrhage is inevitable with these procedures and hence, administration of Rh immunoglobulin is indicated in all Rh -ve mothers taken up for these studies.

11.6