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Letters to the Editor |
1 Departments of Pathology and Laboratory Medicine, and2
Obstetrics and Gynecology, Women and Infants Hospital and, Brown Medical School, Providence, RI
3 Westerly Hospital, Westerly, RI
aAddress correspondence to this author at: Geralyn Lambert-Messerlian, Division of Prenatal and Special Testing, Women and Infants Hospital, 70 Elm Street, 2nd floor, Providence, Rhode Island 02903. Fax 401-276-7882; gmesserl{at}wihri.org.
To the Editor:
Maternal serum screening for Down syndrome is commonly performed in the 2nd trimester using 
fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A. Concentrations of each marker are combined with maternal age to calculate a patient-specific risk of fetal Down syndrome. In cases of Down syndrome, inhibin A concentration is, on average, approximately twice as high as in unaffected singleton pregnancies (1). Second trimester maternal serum inhibin A is also increased in twin pregnancies [1.99 multiples of the median (MoM) (1)] and in Turner syndrome with hydrops (3.91 MoM; (2)). Markedly increased inhibin A has been observed in pregnancies with complete hydatidiform mole [4–7 MoM; (3)]. Increased inhibin A may also be seen in nonpregnant women with ovarian cancer (4).
We describe a woman having 2nd trimester serum inhibin A concentration 80 times that expected for gestational age. The patient was seen at 16 weeks of pregnancy for routine maternal serum screening. Her result indicated a low risk for Down syndrome (1 in 3300) and no further action was recommended. AFP, uE3, and hCG were 1.25, 1.00, and 0.74 MoM, respectively, but a markedly increased inhibin A was noted (13 214 ng/L). The pregnancy and delivery were otherwise unremarkable. Because of the patient’s increased inhibin, she was referred to oncology 9 months postpartum to explore the possibility of an ovarian tumor. At that time, her inhibin A was again markedly higher (61 362 ng/L) than expected during the normal menstrual cycle (10–160 ng/L). Ultrasound and computed tomographic scans of the abdomen and pelvis were normal.
Inhibin A was measured with the assay from Diagnostic Systems Laboratories. Intra- and interassay imprecision (CV) was <15%, and the lower limit of detection was 10 ng/L. The presence of heterophilic antibody interference was assessed using blocking tubes from Scantibodies Laboratory, Inc. A variation in result >30% (2 SD, 95% confidence) after blocking treatment was considered a significant change.
To examine possible heterophilic interference in other prenatal screening samples with a high inhibin A concentration, we searched laboratory records compiled during a 2-year time period (n = 9079). An inhibin A value >5 MoM was considered unusually high (higher than the median level in twins or pregnancies affected by Down or Turner syndrome). This study was approved by the Institutional Review Board for Human Studies at Women and Infant’s Hospital.
In the case in question, inhibin A was <10 ng/L (at 1:100 dilution) after heterophilic antibody blocking, indicating that the very high result was attributable to interference. In a review of more than 9000 previous screens, 26 samples had an apparent inhibin A >5 MoM (0.3%), and 2 of 23 tested (3 had insufficient volume) showed a significant decrease in results after heterophilic antibody blocking treatment (Table 1
).
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Maternal serum concentrations of the placental secretory products inhibin A and hCG are moderately correlated (r = 0.2–0.4) (5) in the 2nd trimester. In this dataset, serum hCG MoM values were 
1.8 among those samples having an inhibin A MoM 5.0, with the exception of 2 patients (1.25 and 0.71 MoM hCG) that had falsely increased inhibin A. Furthermore, concentrations of AFP and uE3 were also unremarkable in these samples.
Heterophilic antibody interference, which has been well documented in various immunoassays, most often results in artificially increased concentrations, and when unrecognized can lead to unnecessary medical intervention. Immunoassays can incorporate passive blocking solutions to prevent interference, but particular antibody affinities may lead to persistence of some heterophilic, interfering antibodies. The impact of an artificially increased inhibin A on Down syndrome screening results is likely to be minimal, however, because multiple markers are used in risk calculation, never inhibin A alone, and truncation limits of the MoM are routinely implemented. Nevertheless, prenatal screening laboratories may want to consider using heterophilic antibody blocking reagents as a routine protocol for isolated very high inhibin A results, before results are reported, to avoid unnecessary concern.
References
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