Quadruple Marker Maternal Serum Screening with Dimeric Inhibin A
by Lorraine Suslak, MS, CGC, March 2000

Prenatal screening for Down syndrome is currently based on measuring the concentrations of alpha-fetoprotein, uncongugated estriol, and human chorionic gonadotropin in maternal serum between 15 and 22 weeks of pregnancy. These measurements, in conjunction with the age of the woman, provide tools to estimate the risk of having a baby with Down syndrome. By using these parameters, about 60-70% of Down syndrome pregnancies can be identified. In addition, it has been estimated that the detection rate can be increased by 5 to 10% if ultrasound is used as an adjunct to establish gestational age.

Efforts to improve biochemical screening have centered on the investigation of screening in the first trimester and on the search for better markers in both the first and the second trimesters of pregnancy. Several investigations have found elevated serum levels of inhibin A in women in the second trimester of pregnancy whose fetuses were affected by Down syndrome (Van Lith 1992, Spencer et al. 1993, Cuckle 1994 ). Inhibin A is a dimeric glycoprotein composed of one alpha subunit and one of two beta subunits (beta A or beta B). Inhibin A and B are synthesized by the ovaries and regulate the secretion by the pituitary of follicle-stimulation hormone. In pregnancy the main source of inhibin secretion switches from the corpus luteum of the ovary to the placenta, and the level of immunoreactive or bioactive inhibin is significantly higher than in nonpregnant women.(Tovanbutra 1993, Qu 1991).

Aitken in 1996 reported that in the second trimester, inhibin A in the maternal serum of women with Down syndrome fetuses was 2.06 times the median value of the amount found in women with normal pregnancies. Why the amount of inhibin increases in the serum of women who have fetuses with Down syndrome is not yet known. Aitken showed that measuring inhibin A in combination with measurements of alpha-fetoprotein and the beta subunit of human chorionic gonadotropin significantly improved the detection rate of Down syndrome. Their detection rate increased from 53% to 75%, both with a false positive rate set at 5%.

In 1999, Wenstrom et.al. published data in which the sera of 1256 patients were evaluated, including 23 aneuploidies (13 with Down syndrome and 10 others). They found that the use of dimeric inhibin A in addition to the standard multiple marker screening (alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin) detected 85% of Down syndrome cases, in contrast to 69% when the triple marker screening test alone was used.

It is estimated that 1/3 of Down syndrome cases undetected by standard triple marker screening could be identified with quadruple marker screening. Approximately 78-80% of Down syndrome in pregnancies of women less than 35 years and 85-95% of pregnancies of women more than 35 years would be detectable by quadruple marker screening with inhibin A. Preliminary evidence also indicates that inhibin A may be a useful marker for Turner syndrome. Lambert-Messerlian et. al. in 1999 investigated the distribution of inhibin A levels among 21 pregnancies with trisomy 18 and 22 with Turner syndrome, including 12 with hydrops and 10 without hydrops. In trisomy 18 the median level of inhibin A was 0.88 multiples of the median (MOMs) for unaffected pregnancies of the same gestation. Therefore the inclusion of inhibin A in the multimarker screening protocol was not useful in the detection of trisomy 18. In Turner syndrome the MOM for inhibin A was 3.91 for those with hydrops and 0.64 for those without hydrops. This study and several other published studies have also shown that inhibin A is a poor maternal serum marker for trisomy 18, but adds impressively to the detection of Turner syndrome in the second trimester of pregnancy.

At least one major commercial laboratory involved in second trimester maternal serum screening for aneuploidy has already added inhibin A to their triple marker screening. It is likely that in the near future other laboratories will begin doing the same.

REFERENCES

1. Van Lith JMM, Pratt JJ, Beekhuis JR, Mantingh A: " Second-trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome" Prenat Diagn 12: 801-806, 1992.

2. Spencer K, Wood PJ, Anthony FW: " Elevated levels of maternal serum inhibin immunoreactivity in second trimester pregnancies affected by Down's syndrome" Ann Clin Biochem 30: 219-220, 1993.

3. Cuckle HS, Holding S, Jones R: "Maternal serum inhibin levels in second trimester Down's syndrome pregnancies" Prenat Diagn 14: 387-390, 1994.

4. Tovanbutra S, Illingworth PJ, Ledger WL, Glasier AF, Baird DT: " The relationship between peripheral immunoreactive inhibin, human chorionic gonadotropin, oestradiol and progesterone during human pregnancy" Clin Endocrinol 38: 101-107, 1993.

5. Qu J, Vankrieken L, Burulet C, Thomas K: " Circulating bioactive inhibin levels during pregnancy" J Clin Endocrinol Metab 72: 862-866, 1991.

6. Aitken DA, Wallace MR, Crossley JA, Swanston IA, Van Pareren Y, Van Maarle M, Groome NP, Macri JN, Connor MJ: "Dimeric inhibin A as a marker for Down's syndrome in early pregnancy" New Engl J Med 334(19): 1231-1236, 1996.

7. Wenstrom KD, Owen J, Chu D, Boots L: "Prospective evaluation of free beta-subunit of human chorionic gonadotropin and dimeric inhibin A for aneuploidy detection" Am J Obstet Gynecol 181(4):887-892, 1999.

8. Lambert-Messerlian GM, Saller DN Jr., Tumber MB, French CA, Peterson CJ, Canick JA: "Second-trimester maternal serum progesterone levels in Turner syndrome with and without hydrops and in trisomy 18" Prenat Diagn 19(5):476-479, 1999.