{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:40:18Z","timestamp":1782888018113,"version":"3.54.5"},"reference-count":33,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chiang Mai University Research Fund","award":["CMU-2568"],"award-info":[{"award-number":["CMU-2568"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>A total of 30 hydropic fetuses, including 25 cases from published reports and 5 from our own series, were reviewed, validated, and analyzed. This review yielded the following key findings: (1) Unlike most cases of nonimmune hydrops fetalis (NIHF), hydrops caused by syphilis is not only preventable but also treatable, with complete resolution possible when appropriately managed. (2) Syphilis-associated hydrops carries a poor prognosis if timely and appropriate treatment is not administered. (3) Based on limited data, intravenous penicillin G is probably more effective than intramuscular benzathine penicillin in treating hydropic fetuses. (4) Middle cerebral artery peak systolic velocity (MCA-PSV) measurements are increasingly used as a reliable and noninvasive tool for assessing fetal anemia, determining the need for intrauterine transfusion (IUT), and monitoring treatment response. (5) A significant number of cases did not receive prenatal treatment due to false-negative serologic results caused by the prozone effect, as well as the omission of syphilis from the differential diagnosis of NIHF, leading to missed prenatal diagnoses. (6) IUT may help mitigate cellular damage in developing vital organs caused by anemic hypoxia, particularly while awaiting the effects of medical treatment. In conclusion, the modern approach to managing this ancient disease includes: (1) prioritizing intensive intravenous penicillin G therapy over conventional intramuscular benzathine penicillin G; (2) utilizing MCA-PSV in conjunction with other indicators of anemia to monitor its severity; and (3) implementing IUT to prevent anemic hypoxic injury in cases where the hematocrit falls below 30%.<\/jats:p>","DOI":"10.3390\/jcm14113671","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:58:09Z","timestamp":1747994289000},"page":"3671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hydrops Fetalis Caused by Congenital Syphilis: Case Series and a Comprehensive Review"],"prefix":"10.3390","volume":"14","author":[{"given":"Yuri","family":"Yanase","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Nakornping Hospital, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirinart","family":"Sirilert","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phudit","family":"Jatavan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7203-5067","authenticated-orcid":false,"given":"Mallika","family":"Pomrop","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krittaya","family":"Phirom","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Sirindhorn Hospital, Bangkok 10250, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3389-6478","authenticated-orcid":false,"given":"Theera","family":"Tongsong","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"426.e1","DOI":"10.1016\/j.ajog.2014.05.049","article-title":"Progression of ultrasound findings of fetal syphilis after maternal treatment","volume":"211","author":"Rac","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ajog.2016.11.1052","article-title":"Syphilis during pregnancy: A preventable threat to maternal-fetal health","volume":"216","author":"Rac","year":"2017","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/OLQ.0000000000002093","article-title":"A Narrative Review of Congenital Syphilis in the United States: Innovative Perspectives on a Complex Public Health and Medical Disease","volume":"52","author":"Lehman","year":"2025","journal-title":"Sex. Transm. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1017\/S0950268819000281","article-title":"The resurgence of syphilis in high-income countries in the 2000s: A focus on Europe","volume":"147","author":"Spiteri","year":"2019","journal-title":"Epidemiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1177\/0956462417733866","article-title":"Congenital syphilis in England and amendments to the BASHH guideline for management of affected infants","volume":"28","author":"Kingston","year":"2017","journal-title":"Int. J. STD AIDS"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.2807\/1560-7917.ES.2017.22.49.17-00750","article-title":"Factors associated with four atypical cases of congenital syphilis in England, 2016 to 2017: An ecological analysis","volume":"22","author":"Furegato","year":"2017","journal-title":"Euro Surveill."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1097\/AOG.0000000000005700","article-title":"Rising Stillbirth Rates Related to Congenital Syphilis in the United States From 2016 to 2022","volume":"144","author":"Machefsky","year":"2024","journal-title":"Obstet. Gynecol."},{"key":"ref_8","first-page":"CD001143","article-title":"Antibiotics for syphilis diagnosed during pregnancy","volume":"2010","author":"Walker","year":"2001","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_9","first-page":"338","article-title":"Penicillin levels following the administration of benzathine penicillin G in pregnancy","volume":"82","author":"Nathan","year":"1993","journal-title":"Obstet. Gynecol."},{"key":"ref_10","first-page":"947","article-title":"Fetal syphilis: Clinical and laboratory characteristics","volume":"97","author":"Hollier","year":"2001","journal-title":"Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.rr7004a1","article-title":"Sexually Transmitted Infections Treatment Guidelines, 2021","volume":"70","author":"Workowski","year":"2021","journal-title":"MMWR Recomm. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ajog.2014.12.018","article-title":"Society for maternal-fetal medicine (SMFM) clinical guideline #7: Nonimmune hydrops fetalis","volume":"212","author":"Norton","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/0002-9378(90)91107-N","article-title":"False-negative syphilis screening: The prozone phenomenon, nonimmune hydrops, and diagnosis of syphilis during pregnancy","volume":"163","author":"Berkowitz","year":"1990","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0002-9378(11)91625-1","article-title":"Nonimmune hydrops fetalis associated with maternal infection with syphilis","volume":"167","author":"Barton","year":"1992","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","first-page":"173","article-title":"Nonimmune hydrops fetalis and fetal congenital syphilis. A case report","volume":"37","author":"Hallak","year":"1992","journal-title":"J. Reprod. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1155\/S1064744993000031","article-title":"Intravenous penicillin for antenatal syphilotherapy","volume":"1","author":"Galan","year":"1993","journal-title":"Infect. Dis. Obstet. Gynecol."},{"key":"ref_17","first-page":"412","article-title":"Primary syphilis and nonimmune fetal hydrops in a penicillin-allergic woman. A case report","volume":"39","author":"ElTabbakh","year":"1994","journal-title":"J. Reprod. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1055\/s-2007-993933","article-title":"Nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum maternal serology screening","volume":"15","author":"Levine","year":"1998","journal-title":"Am. J. Perinatol."},{"key":"ref_19","first-page":"318","article-title":"Congenital Syphilis as a Cause of Hydrops Fetalis in a Woman with Spyhilis Incognito","volume":"5","author":"TANER","year":"2004","journal-title":"J. Turkish German Gynecol. Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1701-2163(16)34658-8","article-title":"Successful outcome with intrauterine transfusion in non-immune hydrops fetalis secondary to congenital syphilis","volume":"32","author":"Chen","year":"2010","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_21","first-page":"478436","article-title":"Prenatal diagnosis of congenital syphilis using two- and three-dimensional ultrasonography: Case report","volume":"2012","author":"Rolo","year":"2012","journal-title":"Case Rep. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.3109\/14767058.2013.853288","article-title":"Fetal anemia as a signal of congenital syphilis","volume":"27","author":"Castaigne","year":"2014","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1159\/000364804","article-title":"Syphilis Infection: An Uncommon Etiology of Infectious Nonimmune Fetal Hydrops with Anemia","volume":"39","author":"Fuchs","year":"2016","journal-title":"Fetal Diagn. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Duby, J., Bitnun, A., Shah, V., Shannon, P., Shinar, S., and Whyte, H. (2019). Non-immune Hydrops Fetalis and Hepatic Dysfunction in a Preterm Infant with Congenital Syphilis. Front. Pediatr., 7.","DOI":"10.3389\/fped.2019.00508"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1177\/0956462419876487","article-title":"Hydrops fetalis caused by congenital syphilis: An ancient disease?","volume":"30","year":"2019","journal-title":"Int. J. STD AIDS"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"149","DOI":"10.18597\/rcog.3591","article-title":"Congenital syphilis with hydrops fetalis: Report of four cases in a general referral hospital in Bogota, Colombia between 2016\u20132020","volume":"72","year":"2021","journal-title":"Rev. Colomb. Obstet. Ginecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111","DOI":"10.14745\/ccdr.v48i23a09","article-title":"Exploring management of antenatally diagnosed fetal syphilis infection","volume":"48","author":"Rosenthal","year":"2022","journal-title":"Can. Commun. Dis. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.1055\/a-2028-7727","article-title":"Complete Resolution of Nonimmune Hydrops Fetalis Secondary to Maternal Syphilis Infection","volume":"13","author":"Dinicu","year":"2023","journal-title":"AJP Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3109\/08880010903091897","article-title":"Hemophagocytosis: The cause of anemia and thrombocytopenia in congenital syphilis","volume":"26","author":"Yarali","year":"2009","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1097\/AOG.0b013e3181656a11","article-title":"Prenatal diagnosis of anoxic cerebral lesions caused by profound fetal anemia secondary to maternal red blood cell alloimmunization","volume":"112","author":"Carbonne","year":"2008","journal-title":"Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Luewan, S., Apaijai, N., Chattipakorn, N., Chattipakorn, S.C., and Tongsong, T. (2024). Fetal hemodynamic changes and mitochondrial dysfunction in myocardium and brain tissues in response to anemia: A lesson from hemoglobin Bart\u2019s disease. BMC Pregnancy Childbirth, 24.","DOI":"10.1186\/s12884-023-06232-x"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.ajog.2015.01.059","article-title":"Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: The fetus at risk for anemia--diagnosis and management","volume":"212","author":"Mari","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (ACOG) (2018). Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy. Obstet. Gynecol., 131, e82\u2013e90.","DOI":"10.1097\/AOG.0000000000002528"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3671\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:39:19Z","timestamp":1760031559000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":33,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["jcm14113671"],"URL":"https:\/\/doi.org\/10.3390\/jcm14113671","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,23]]}}}