{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T23:06:36Z","timestamp":1768604796101,"version":"3.49.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background\/Objectives: It is well established in the modern literature that newborns delivered from multiple gestations are more predisposed to low birthweight in comparison to their singleton equivalents. In this study, we sought to explore the potential of first-trimester biochemical (PAPP-A and free \u03b2-hCG) and biophysical indices (uterine artery Doppler) to predict low birthweight in one or both twins. Methods: This is a retrospective cohort analysis of 400 twin viable pregnancies presenting for routine first-trimester assessment in four fetal medicine centers between 2014 and 2025. The examination included the recording of maternal demographic characteristics and medical history, the assessment of markers of aneuploidy and the fetal anatomy, the measurement of mean arterial pressure, the assessment of uterine arteries and the measurement of serum concentration of PAPP-A and free \u03b2-hCG. The evaluated outcomes included BW \u2264 3rd centile and BW \u2264 10th centile in one or both twins based on local population birthweight reference charts. Results: The study cohort consisted of 400 twin pregnancies. BW \u2264 3rd centile in one or both twins was reported in 1.5 and 3.8% of cases, respectively, and there was no association of BW \u2264 3rd centile with any of the studied parameters. BW \u2264 10th centile in one or both twins was reported in 14.8 and 9.8% of the cases, respectively. PAPP-A MoM values were significantly lower in cases complicated by BW \u2264 10th centile in one and in both twins, remaining statistically significant even after the appropriate multiple logistic regression. PAPP-A MoM demonstrated statistically significant but low prognostic value for BW \u2264 10th centile in either one or both twins. Conclusions: Low PAPP-A levels were associated with BW \u2264 10th centile in one and both twins and its significant value as a risk marker was demonstrated. Higher PAPP-A MoM halves the risk of having at least one twin with low BW. Other maternal biophysical and biochemical indices did not seem to be predictive of low birthweight.<\/jats:p>","DOI":"10.3390\/life16010149","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:39:37Z","timestamp":1768563577000},"page":"149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Low PAPP-A Levels and Growth in Twin Pregnancies"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7760-0608","authenticated-orcid":false,"given":"Ioakeim","family":"Sapantzoglou","sequence":"first","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-7755","authenticated-orcid":false,"given":"Dimitrios","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Athens Naval and Veterans Hospital, 11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afroditi Maria","family":"Kontopoulou","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8992-8793","authenticated-orcid":false,"given":"Christina","family":"Karasmani","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angeliki","family":"Rouvali","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afroditi","family":"Pegkou","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Simou","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Pafilis","sequence":"additional","affiliation":[{"name":"Iatriki Embryou-Ioannis Pafilis, 10676 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athina","family":"Souka","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8280-7796","authenticated-orcid":false,"given":"Marianna","family":"Theodora","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-5922","authenticated-orcid":false,"given":"Panagiotis","family":"Antsaklis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-211X","authenticated-orcid":false,"given":"Georgios","family":"Daskalakis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.ajog.2010.04.031","article-title":"Twins: Prevalence, problems, and preterm births","volume":"203","author":"Chauhan","year":"2010","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.bpobgyn.2013.12.002","article-title":"Diagnosis of twin-to-twin transfusion syndrome, selective fetal growth restriction, twin anaemia-polycythaemia sequence, and twin reversed arterial perfusion sequence","volume":"28","author":"Sueters","year":"2014","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_3","unstructured":"Committee on Practice Bulletins\u2014Obstetrics, and Society for Maternal\u2013Fetal Medicine (2016). Practice Bulletin No. 169: Multifetal Gestations: Twin, Triplet, and Higher-Order Multifetal Pregnancies. Obstet. Gynecol., 128, e131\u2013e146."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bpobgyn.2022.08.003","article-title":"Assessment of fetal growth in twins: Which method to use?","volume":"84","author":"Kalafat","year":"2022","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1515\/jpm-2016-0089","article-title":"Birth weight discordance and adverse perinatal outcomes","volume":"45","author":"Jahanfar","year":"2017","journal-title":"J. Perinat. Med."},{"key":"ref_6","unstructured":"(2025, November 03). America\u2019s Health Rankings analysis of U.S. Department of Health and Human Services; Centers for Disease Control and Prevention; National Center for Health Statistics; National Vital Statistics System; Natality Public Use Files via CDC WONDER Online Database, United Health Foundation. Available online: https:\/\/AmericasHealthRankings.org."},{"key":"ref_7","unstructured":"(2025). National Vital Statistics Reports."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/uog.23531","article-title":"Prediction of pre-eclampsia in twin pregnancy by maternal factors and biomarkers at 11\u201313 weeks\u2019 gestation: Data from EVENTS trial","volume":"57","author":"Wright","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/uog.17531","article-title":"Competing-risks model in screening for pre-eclampsia in twin pregnancy according to maternal factors and biomarkers at 11\u201313 weeks\u2019 gestation","volume":"50","author":"Francisco","year":"2017","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/ijgo.15706","article-title":"First-trimester uterine artery Doppler and hypertensive disorders in twin pregnancies: Use of twin versus singleton references","volume":"167","author":"Domingues","year":"2024","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00404-024-07547-6","article-title":"First-trimester serum biomarkers in twin pregnancies and adverse obstetric outcomes-a single center cohort study","volume":"310","author":"Gomes","year":"2024","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_12","first-page":"43","article-title":"First-trimester screening and small for gestational age in twin pregnancies: A single center cohort study","volume":"311","author":"Bernardo","year":"2025","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/uog.15821","article-title":"ISUOG Practice Guidelines: Role of ultrasound in twin pregnancy","volume":"47","author":"Khalil","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/uog.29166","article-title":"ISUOG Practice Guidelines (updated): Role of ultrasound in twin pregnancy","volume":"65","author":"Khalil","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/uog.22134","article-title":"ISUOG Practice Guidelines: Diagnosis and management of small-for-gestational-age fetus and fetal growth restriction","volume":"56","author":"Lees","year":"2020","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/uog.8956","article-title":"First-trimester ultrasound determination of chorionicity in twin pregnancy","volume":"38","author":"Dias","year":"2011","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1002\/pd.5069","article-title":"Association of maternal serum PAPP-A levels, nuchal translucency and crown-rump length in first trimester with adverse pregnancy outcomes: Retrospective cohort study","volume":"37","author":"Bilagi","year":"2017","journal-title":"Prenat. Diagn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1002\/uog.23118","article-title":"Competing-risks model for prediction of small-for-gestational-age neonate from maternal characteristics, serum pregnancy-associated plasma protein-A and placental growth factor at 11\u201313 weeks\u2019 gestation","volume":"57","author":"Papastefanou","year":"2020","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1111\/1471-0528.17814","article-title":"Investigation and Care of a Small-for-Gestational-Age Fetus and a Growth Restricted Fetus (Green-top Guideline No. 31)","volume":"131","author":"Morris","year":"2024","journal-title":"BJOG"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/uog.22129","article-title":"Competing-risks model for prediction of small-for-gestational-age neonate from maternal characteristics and medical history","volume":"56","author":"Papastefanou","year":"2020","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2021). Indications for Outpatient Antenatal Fetal Surveillance: ACOG Committee Opinion, Number 828. Obstet. Gynecol., 137, e177\u2013e197.","DOI":"10.1097\/AOG.0000000000004407"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1159\/000321694","article-title":"Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11\u201313 weeks","volume":"29","author":"Karagiannis","year":"2011","journal-title":"Fetal Diagn. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sapantzoglou, I., Giourga, M., Kontopoulou, A.M., Pergialiotis, V., Daskalaki, M.A., Antsaklis, P., Theodora, M., Thomakos, N., and Daskalakis, G. (2024). Low PAPPA and Its Association with Adverse Pregnancy Outcomes in Twin Pregnancies: A Systematic Review of the Literature and Meta-Analysis. J. Clin. Med., 13.","DOI":"10.3390\/jcm13226637"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16206","DOI":"10.1038\/s41598-024-67300-6","article-title":"Evaluating the predictive efficacy of first trimester biochemical markers (PAPP-A, f\u03b2-hCG) in forecasting preterm delivery incidences","volume":"14","author":"Swiercz","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Saletra-Bieli\u0144ska, A., Kosi\u0144ska-Kaczy\u0144ska, K., Szymusik, I., Kaczy\u0144ski, B., Brawura-Biskupski-Samaha, R., Koz\u0142owski, S., Jarmu\u017cek, P., Walasik, I., and Wielgo\u015b, M. (2020). Both Low and High PAPP-A Concentrations in the First Trimester of Pregnancy Are Associated with Increased Risk of Delivery before 32 Weeks in Twin Gestation. J. Clin. Med., 9.","DOI":"10.3390\/jcm9072099"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1080\/01443615.2022.2039904","article-title":"The association of maternal serum biomarkers and birth weight in twin pregnancy: A retrospective cohort study","volume":"42","author":"Kim","year":"2022","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101760","DOI":"10.1016\/j.ajogmf.2025.101760","article-title":"First-trimester combined screening for preeclampsia in twin pregnancies-results of the first 100 twin pregnancies included in the IPSISS (Implementing Preeclampsia Screening in Switzerland) cohort","volume":"7","author":"Monod","year":"2025","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"86.e1","DOI":"10.1016\/j.ajog.2020.06.050","article-title":"Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: A randomized, double-blind trial","volume":"224","author":"Rehal","year":"2021","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1159\/000533201","article-title":"Implementing Preeclampsia Screening in Switzerland (IPSISS): First Results from a Multicentre Registry","volume":"50","author":"Trottmann","year":"2023","journal-title":"Fetal Diagn. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/uog.13340","article-title":"Uterine artery Doppler evaluation in twin pregnancies at 11 + 0 to 13 + 6 weeks of gestation","volume":"44","author":"Rizzo","year":"2014","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/aogs.13890","article-title":"Screening for preeclampsia in low-risk twin pregnancies at early gestation","volume":"99","author":"Chen","year":"2020","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1002\/pd.4402","article-title":"First trimester markers of preeclampsia in twins: Maternal mean arterial pressure and uterine artery Doppler pulsatility index","volume":"34","author":"Svirsky","year":"2014","journal-title":"Prenat. Diagn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.3109\/00016349.2010.505639","article-title":"Biology of pregnancy-associated plasma protein-A in relation to prenatal diagnostics: An overview","volume":"89","author":"Kirkegaard","year":"2010","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ajog.2010.08.009","article-title":"The \u201cGreat Obstetrical Syndromes\u201d are associated with disorders of deep placentation","volume":"204","author":"Brosens","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Swiercz, G., Zmelonek-Znamirowska, A., Szwabowicz, K., Armanska, J., Detka, K., Mlodawska, M., and Mlodawski, J. (2024). Navigating Uncertain Waters: First-Trimester Screening\u2019s Role in Identifying Neonatal Complications. J. Clin. Med., 13.","DOI":"10.3390\/jcm13071982"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1111\/1471-0528.17096","article-title":"Serum PlGF compared with PAPP-A in first trimester screening for preterm pre-eclampsia: Adjusting for the effect of aspirin treatment","volume":"129","author":"Wright","year":"2022","journal-title":"BJOG"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1002\/uog.70095","article-title":"Role of aspirin therapy in modulating uterine artery resistance and placental growth between first and second trimesters of pregnancy","volume":"66","author":"Trilla","year":"2025","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kiserud, T., Piaggio, G., Carroli, G., Widmer, M., Carvalho, J., Neerup Jensen, L., Giordano, D., Cecatti, J.G., Abdel Aleem, H., and Talegawkar, S.A. (2017). The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002284"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/1\/149\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:05:31Z","timestamp":1768565131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/1\/149"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,16]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["life16010149"],"URL":"https:\/\/doi.org\/10.3390\/life16010149","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,16]]}}}