Prenatal Tobacco Exposure and Newborn Outcomes: A Maternal Urinary Cotinine Study

Official title

Association of Prenatal Tobacco Exposure Verified by Maternal Urinary Cotinine With Umbilical Cord Blood Lactate, Fetal Carboxyhemoglobin, and Early Neonatal Outcomes: A Prospective Single-Center Observational Study

Overview

Prenatal exposure to tobacco smoke, through either active maternal smoking or secondhand exposure, has been associated with impaired fetal oxygenation, metabolic stress, and adverse early neonatal outcomes. This prospective, single-center observational cohort study will objectively assess maternal tobacco exposure using cotinine measured in maternal urine and examine its association with early neonatal biochemical, metabolic, and clinical outcomes. Consecutive eligible mother-newborn dyads will be recruited at a tertiary academic hospital after written informed consent is obtained. A clean-catch midstream maternal urine sample will be collected within 24 hours before delivery, preferably at admission to the delivery unit and before intravenous fluid administration, for quantitative cotinine and creatinine measurement. Maternal tobacco exposure will be assessed using the urinary cotinine concentration, the cotinine-to-creatinine ratio, and maternal self-reported smoking and secondhand smoke exposure. Based on prespecified biomarker thresholds and exposure history, participants will be classified as having active exposure, passive exposure, or no exposure. No experimental intervention will be administered. Neonatal data will include umbilical cord blood gas parameters, including pH, pCO2, pO2, base excess, bicarbonate, lactate, and fetal carboxyhemoglobin (FCOHb). Birthweight, length, head circumference, Apgar scores, oxygen saturation, heart rate, and blood pressure will also be recorded. Routine laboratory measurements obtained during the early postnatal period will include complete blood count parameters, hematologic and inflammatory indices such as NLR and PLR, albumin, the albumin-to-lactate ratio, HDL, LDL, and other routinely available biochemical markers. Thyroid-stimulating hormone results from the national newborn screening program and newborn hearing screening results will be recorded. Postnatal weight loss and bilirubin measurements from routine follow-up visits will also be collected when available. The primary objective is to determine whether increasing maternal urinary cotinine exposure is associated with higher umbilical cord blood lactate and FCOHb levels, indicating greater metabolic stress and impaired fetal oxygenation. Secondary objectives include evaluating associations with cord blood gas parameters, birthweight, early hematologic and biochemical indices, albumin and the albumin-to-lactate ratio, blood pressure, bilirubin levels, thyroid screening results, and hearing screening outcomes. Maternal, obstetric, and perinatal variables, including maternal age, parity, gestational age, mode of delivery, smoking history, intrapartum factors, and relevant maternal comorbidities, will be recorded for adjusted analyses. Statistical analyses will include comparisons among the three exposure groups and multivariable regression models evaluating urinary cotinine both as a continuous measure and as a categorical exposure variable. This study is designed to provide prospectively collected, biomarker-verified evidence regarding the relationship between maternal tobacco exposure and immediate neonatal metabolic, hematologic, and physiologic outcomes using measurements that are feasible within routine clinical care.

Interventions

• Other Maternal Urinary Cotinine Assessment
  A clean-catch midstream maternal urine sample will be collected within 24 hours before delivery, preferably at admission to the delivery unit and before intravenous fluid administration. Urinary cotinine and creatinine concentrations will be measured, and the cotinine-to-creatinine ratio will be used to objectively classify prenatal tobacco exposure. No treatment or behavioral intervention will be assigned.

Primary outcome measures

• Umbilical Cord Blood Lactate [Time frame: At birth (sample obtained within 10 minutes of delivery; analyzed within routine lab turnaround)]

Secondary outcome measures (3)

• Umbilical Cord Blood pH [Time frame: At birth (within 10 minutes)]
• Umbilical Cord Blood Base Excess (BE) [Time frame: At birth (within 10 minutes)]
• Fetal Carboxyhemoglobin (FCOHb) [Time frame: At birth (same cord sample, routine CO-oximetry if available)]

Eligibility criteria

Inclusion criteria

• Pregnant individual expected to deliver a liveborn infant at the study hospital and providing written informed consent before delivery.
• Singleton pregnancy with an anticipated gestational age of ≥35 completed weeks at delivery.
• Maternal clean-catch urine sample obtainable within 24 hours before delivery, preferably at admission and before intravenous fluid administration, for urinary cotinine and creatinine measurement.
• Availability of routine umbilical cord blood gas analysis at birth, including at minimum lactate, pH, and base excess, with fetal carboxyhemoglobin recorded when available.
• Availability of routine neonatal clinical data, including birthweight, anthropometric measurements, Apgar scores, vital signs, and early postnatal assessments according to unit practice.

Exclusion criteria

• Multiple gestation.
• Major congenital anomaly, known chromosomal or genetic disorder, or major metabolic disease likely to affect neonatal adaptation or the study outcomes.
• Emergency clinical circumstances in which obtaining informed consent or the maternal urine sample could delay or interfere with urgent maternal or neonatal care.
• Inability to obtain an adequate maternal urine sample before delivery for cotinine and creatinine measurement.
• Severe perinatal condition preventing acquisition or reliable interpretation of the primary outcome data, including major birth trauma or prolonged intensive care requirement.
• Missing umbilical cord blood lactate measurement or other critical primary outcome data.
• Previous enrollment of the same mother-newborn dyad.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Abraham M, Alramadhan S, Iniguez C, Duijts L, Jaddoe VW, Den Dekker HT, Crozier S, Godfrey KM, Hindmarsh P, Vik T, Jacobsen GW, Hanke W, Sobala W, Devereux G, Turner S. A systematic review of maternal smoking during pregnancy and fetal measurements with meta-analysis. PLoS One. 2017 Feb 23;12(2):e0170946. doi: 10.1371/journal.pone.0170946. eCollection 2017. PMID 28231292
• Filis P, Hombach-Klonisch S, Ayotte P, Nagrath N, Soffientini U, Klonisch T, O'Shaughnessy P, Fowler PA. Maternal smoking and high BMI disrupt thyroid gland development. BMC Med. 2018 Oct 23;16(1):194. doi: 10.1186/s12916-018-1183-7. PMID 30348172
• Di HK, Gan Y, Lu K, Wang C, Zhu Y, Meng X, Xia WQ, Xu MZ, Feng J, Tian QF, He Y, Nie ZQ, Liu JA, Song FJ, Lu ZX. Maternal smoking status during pregnancy and low birth weight in offspring: systematic review and meta-analysis of 55 cohort studies published from 1986 to 2020. World J Pediatr. 2022 Mar;18(3):176-185. doi: 10.1007/s12519-021-00501-5. Epub 2022 Jan 28. PMID 35089538
• Berlin I, Heilbronner C, Georgieu S, Meier C, Spreux-Varoquaux O. Newborns' cord blood plasma cotinine concentrations are similar to that of their delivering smoking mothers. Drug Alcohol Depend. 2010 Mar 1;107(2-3):250-2. doi: 10.1016/j.drugalcdep.2009.10.008. Epub 2009 Nov 24. PMID 19939584
• Hayde M, Bernaschek G, Stevenson DK, Knight GJ, Haddow JE, Widness JA. Antepartum fetal and maternal carboxyhemoglobin and cotinine levels among cigarette smokers. Acta Paediatr. 1999 Mar;88(3):327-31. doi: 10.1080/08035259950170123. PMID 10229047
• Wang X, Tager IB, Van Vunakis H, Speizer FE, Hanrahan JP. Maternal smoking during pregnancy, urine cotinine concentrations, and birth outcomes. A prospective cohort study. Int J Epidemiol. 1997 Oct;26(5):978-88. doi: 10.1093/ije/26.5.978. PMID 9363518

Identifiers

NCT: NCT07201181 · 141-2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗