ARTICLE A new algorithm DEtectS critical Congenital Heart Disease at different altitudes: ANDES-CHD study Katia Bravo-Jaimes 1 ✉ , Tania Vasquez-Loarte 2 , Jose Rojas-Camayo 3 , Monica Medina 4 , Christian R. Mejia 5 , Henry Zapata-Galarza 6 , Marilia Berrocal 7 , Jeanette Orozco 7 , Daniel Lozano 8 , Maryuri Santivañez 8 , Carlos Sangay 9 , William Rosales 10 , Leddy Mamani 11 , Nelly Macedo 11 , Joel Coronado 12 , Gian Huaman 13 , Rafael Marquez 13 , Zhuo Li 1 , Kiran M. Masood 14 , Juan Alejos 15 , Leigh Reardon 15,16 and Jeannette Lin 16 © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024 BACKGROUND: Neonatal pulse oximetry screening (POS) algorithms for critical congenital heart disease (CCHD) have contributed towards decreasing neonatal mortality but cannot be applied at high altitudes. New POS algorithms at high altitudes are needed. METHODS: This observational, prospective study included newborns born at different altitudes from 0 to 4380 meters above the sea level in Peru. Healthy newborns underwent neonatal preductal and postductal oximetry, echocardiography and telephonic follow-up up to 12 months of age. Newborns with CCHD underwent preductal and postductal oximetry at the time of telemedicine evaluation while located at the high-altitude hospital where they were born, and their diagnoses were confirmed with echocardiography locally or after arriving to the referral center. Two new algorithms were designed using clinically accepted neonatal oximetry cutoffs or the 5th and 10th percentiles for preductal and postductal oximetry values. RESULTS: A total of 502 healthy newborns and 15 newborns with CCHD were enrolled. Echocardiography and telephonic follow-up were completed in 227 (45%) and 330 healthy newborns (65%), respectively. The algorithm based on clinically accepted cutoffs had a sensitivity of 92%, specificity of 73% and false positive rate of 27% The algorithm based on the 5th and 10th percentiles had a sensitivity of 80%, specificity of 88% and false positive rate of 12%. CONCLUSIONS: Two algorithms that detect CCHD at different altitudes had adequate performance but high false positive rates. Journal of Perinatology; https://doi.org/10.1038/s41372-024-01888-5 INTRODUCTION Neonatal mortality is a public health problem that disproportio- nately affects low and middle-income countries (LMIC) [1]. Relevant causes of neonatal death in LMIC include perinatal asphyxia, sepsis, and congenital birth defects [2]. Congenital heart disease (CHD), the most common congenital birth defect, affects 1 in every 100 newborns and its mortality is disproportionally higher in LMIC (108.1 vs 41.5 infant deaths per 100,000 children younger than 1 year in Andean America compared to the United States) [3]. Critical CHD (CCHD) is present in one quarter of CHD cases and requires surgery or catheterization in the first year of life (but limited to 12 core CHD conditions) [4]. Without appropriate newborn CCHD screening, mortality rates can be as high as 50% [5], therefore neonatal pulse-oximetry screening (POS) was developed and implemented in developed countries [6]. POS achieved not only early CCHD detection but reduced infant cardiac deaths [7] and also identified sepsis, pneumonia, and other causes of neonatal death prior to hospital discharge [7, 8]. Despite POS moderate sensitivity of 76.3%, an excellent cost- effectiveness profile and specificity of 100% [9], current POS algorithms cannot be applied at moderate (>1500 meters above the sea level -masl-) or high (>2500 masl) altitudes because of their high false positive rates [10, 11]. This represents an important unmet need for neonatal populations living at moderate or high- altitude, such as those living in the Andes [12]. CCHD screening in this setting has to overcome significant physiological challenges including the lower partial pressure of atmospheric oxygen seen with increasing altitudes leading to lower pulse oximetry values across all ages (without affecting oxygen consumption) [13, 14], a blunted hypoxic ventilatory response [15], higher hemoglobin levels [16], larger lung volumes, narrower alveolar to arterial oxygen gradients [17], slightly less hypoxic pulmonary vasocon- strictor response, higher standard deviation in oxygen saturation [18], slower remodeling of the pulmonary vasculature [19], and higher pulmonary artery pressures seen with very high altitude [20]. To address this gap, the ANDES-CHD study aimed to develop Received: 19 October 2023 Revised: 12 January 2024 Accepted: 18 January 2024 1 Department of Cardiovascular Medicine. Mayo Clinic, Jacksonville, FL, USA. 2 Wyckoff Heights Medical Center, New York, NY, USA. 3 Florida Center for Allergy and Asthma Care, Florida, FL, USA. 4 Instituto Nacional de Salud del Niño de San Borja, Lima, Peru. 5 Universidad de Huanuco, Huanuco, Peru. 6 University of Florida at Jacksonville, Florida, FL, USA. 7 Hospital Nacional Alberto Sabogal Sologuren, Callao, Peru. 8 Universidad Continental, Junin, Peru. 9 Hospital Regional de Cajamarca, Cajamarca, Peru. 10 Hospital EsSalud II Pasco, Cerro de Pasco, Peru. 11 Hospital EsSalud III Juliaca, Puno, Peru. 12 Universidad Nacional Mayor de San Marcos, Lima, Peru. 13 Instituto Nacional Cardiovascular, Lima, Peru. 14 Department of Pediatrics, University of California, Los Angeles, CA, USA. 15 Department of Pediatrics, Mattel Children´s Hospital, California, CA, USA. 16 Ahmanson/UCLA Adult Congenital Heart Disease Center, University of California, Los Angeles, CA, USA. ✉ email: bravo.katia@mayo.edu www.nature.com/jp Journal of Perinatology 1234567890();,: