Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia Significantly Reduce False Positive Rates: Ten Years` Experience in Israel

נעמי פודה-שקד ^1,2,3 Ayala Blau ⁴ Ben Pode-Shakked ^2,3,5 Dov Tiosano ^6,7 Naomi Weintrob ^3,8 Ori Eyal ^3,9 Amnon Zung ¹⁰ Floris Levy-Khademi ¹¹ Yardena Tenenbaum-Rakover ^7,12 David Zangen ^13,14 David Gilis ^13,14 Orit Pinhas-Hamiel ^3,15 Neta Loewenthal ^16,17 Liat de Vries ^3,18 Zohar Landau ^3,19 Eliana Arbel ^14,20 Mariana Rachmiel ^3,21 Abdulsalam Abu-Libdeh ²² Alon Eliakim ^3,23 David Strich ^24,25 Ilana Koren ^7,26 Alina German ²⁷ Joël Zlotogora ¹⁴ Joseph Sack ³ Shlomo Almashanu ^3,4

¹Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
²The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
³Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
⁴The National Newborn Screening Program, Ministry of Health, Tel-Hashomer, Ramat Gan, Israel
⁵The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
⁶Division of Pediatric Endocrinology, Mayer Children's Hospital, Rambam Medical Center, Haifa, Israel
⁷The Rappaport Faculty of Medicine, The Technion – Israel Institute of Technology, Haifa, Israel
⁸Dana-Dwek Children's Hospital, Tel-Aviv Souraski Medical Center, Tel-Aviv, Israel
⁹Tel-Aviv Medical Center, Pediatric Endocrinology Unit, Dana-Dwek Children's Hospital, Tel-Aviv, Israel
¹⁰Pediatrics Department, Kaplan Medical Center, Rehovot, Israel
¹¹Division of Pediatric Endocrinology, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel
¹²Pediatric Endocrine Institute, Ha'Emek Medical Center, Afula, Israel
¹³Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
¹⁴Faculty of Medicine, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israel
¹⁵Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel
¹⁶Pediatric Endocrinology Diabetes Unit, Soroka Medical Center, Beer Sheva, Israel
¹⁷Faculty of Medicine, Ben Gurion University of the Negev, Beer Sheva, Israel
¹⁸The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
¹⁹Pediatric Endocrine and Diabetes Unit, E. Wolfson Medical Center, Holon, Israel
²⁰Department of Neonatology, Kaplan Medical Center, Rehovot, Israel
²¹Pediatric Endocrinology Clinic, Assaf Harofeh Medical Center, Zerifin, Israel
²²Pediatric Department, Division of Pediatric Endocrinology, Makassed Islamic Hospital, Mount of Olives, Jerusalem, Israel
²³Child Health and Sport Center, Pediatric Department, Meir Medical Center, Kfar Sava, Israel
²⁴Jerusalem District, Clalit Health Services, Jerusalem, Israel
²⁵Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel
²⁶Department of Pediatrics, Carmel Medical Center, Haifa, Israel
²⁷Department of Pediatrics, Bnai Zion Medical Center, Haifa, Israel

Background: Congenital Adrenal Hyperplasia (CAH was therefore among the first genetic disorders to be included in newborn screening (NBS) programs worldwide, most commonly based on the measurement of 17a-hydroxyprogesterone (17-OHP) in dried blood spots. However, the success of NBS for CAH has always been hampered by high false positive (FP) rates.

Objective: We sought to establish a set of cutoff values using a novel strategy adjusting for both gestational-age and birth-weight, with the aim of reducing FP result rates.

Methods: 17-OHP cutoff level was set as the 99.00^th centile for premature low birth-weight infants and as the 99.99^th centile for full term newborns. A follow-up survey was sent to the pediatric endocrinologist few weeks following positive NBS results. False negative (FN) cases were reported to the National NBS Program by the endocrinologists nationwide.

Results: A total of 1,378,132 newborns were included in the National NBS Program between 01.01.2008-31.12.2017. Of these, 88 were ultimately diagnosed with CAH, 84 of whom detected upon NBS, constituting 94% of all referred newborns (87) for immediate attention. The four FN CAH infants (sensitivity, 95.4%) were ultimately diagnosed with the simple-virilizing type. 425 positive cases (0.03%) were within normal limits on the recall sample, therefore designated as FP results.

Conclusions: The use of cutoff values adjusted both for gestational-age and birth-weight significantly reduces the FP rate (0.03%), and increases the overall PPV (16.5%). Based on our ten years` experience we recommend using this novel two-parameter adjusted approach in NBS for classical CAH.