(19) Maternal and Fetal Effects Associated With Perinatal Xylazine Exposure: A Systematic Review

Background & Introduction: Opioid use disorder (OUD) is a significant contributor to maternal morbidity, partially driven by increased pregnancy-associated overdoses. [1,2] Inpatient mortality is staggering as pregnant women who use opioids are nearly four times more likely to die before pregnancy-related discharge. [2] Moreover, opioid use in pregnancy is associated with worsening fetal outcomes, including higher rates of fetal growth restriction, preterm labor, and demise.

Xylazine, a veterinary sedative and potent ⍺2-adrenergic receptor agonist, is increasingly used as an adulterant in illicit fentanyl as it is relatively inexpensive and prolongs sedation. [3] Because of xylazine’s significant sedative effects, soft tissue complications, and complex withdrawal symptoms, the White House Office of National Drug Control Policy designated xylazine-adulterated fentanyl as an emerging drug threat in 2023. [4]

While the adverse effects of xylazine exposure in humans are well-documented in recent literature, the understanding of its effects in human pregnancy is less established. Clinicians have thus extrapolated findings from animal studies on xylazine exposure, which have demonstrated reduced uterine blood flow, impaired fetal oxygenation, and other harmful physiologic effects. To characterize current literature on xylazine exposure in human pregnancy, we conducted a systematic review to identify reported maternal and neonatal outcomes and areas for further exploration. Please note that our manuscript titled "Adverse Maternal and Neonatal Effects Associated with Perinatal Xylazine Exposure: A Systematic Review," is currently under preparation.

Methods: Inclusion criteria for the studies included: (1) manuscripts available in English; (2) case studies or reports of pregnant patients and/or newborns with xylazine exposure; and (3) peer-reviewed journals or academic projects found in our grey literature search. Exclusion criteria included (1) non-English language literature; (2) non-peer-reviewed journals; (3) literature that was not research; (4) animal studies of xylazine exposure in pregnant or fetal populations; (5) nonpregnant human studies of xylazine exposure; and (6) studies that did not include effects on the birthing parent and/or infant.

We searched five databases: CINAHL (EBSCO), EMBASE (Elsevier), APA PsycINFO (EBSCO), PubMed (NLM), and Web of Science (Clarivate). The first 100 results of a grey literature search using Google Advanced Search and Google Scholar were also evaluated for inclusion.

This review utilized Covidence systematic review software for study screening and data extraction. Two reviewers independently screened titles and abstracts generated by the search, followed by the full text review. Discrepancies were resolved by a third team member. The grey literature was reviewed by all three team members, which led to the addition of three grey literature results to the eight included studies (from databases) to be included in the review.

Results: 11 studies met our defined criteria. Seven out of the 11 studies detailed a total of 19 patient cases for which clinical outcomes were available. Out of these 19 cases, two noted maternal outcomes and 16 reported singleton neonate outcomes. One case reported both maternal and neonatal outcomes. Four of the 11 studies reported only toxicology results based on patient matrix samples, and one yielded both toxicology data and patient clinical outcome data.

The toxicology matrix studies reported xylazine testing results from blood, urine, umbilical cord and liver tissue, totaling 58 samples from 55 unique patients. Sample sizes from these studies varied, and three out of the five studies utilized umbilical cord tissue as the testing matrix. Due to the small number of identified studies, descriptive statistics were employed. The prevalence of xylazine in opioid samples ranged from 2.3 to 47.2% and the most frequently reported substance co-occurring in the samples was fentanyl or its derivatives (53/58, 91%), followed by morphine and its derivatives (4/58, 7%), cocaine or benzoylecgonine (4/58, 7%), and amphetamines (4/58, 7%).

In the subset of studies reporting clinical case data, co-occurring substances were detected in 12 of those cases, with fentanyl identified in 11/12 (92%). The second most identified substance co-occurring with xylazine was cocaine and benzoylecgonine (7/12, 58%), followed by methamphetamine (6/12, 50%).

Of the 11 studies identified in this systematic review, only two reported directly on the clinical condition of individual birthing parents. The data, though limited, noted sedation and respiratory depression in one case, and erythematous papules, as well as encephalopathy and spontaneous abortion in the other.

Neonatal clinical symptoms of preterm birth, respiratory distress, difficulty feeding and morphine for withdrawal symptoms were reported. Maternal placental abruption and fetal demise was noted in one case as well.

Conclusion & Discussion: Matrix testing indicated xylazine most frequently occurred in samples with fentanyl or its metabolites, supporting our understanding of xylazine as a fentanyl adulterant. Xylazine is not typically sought out and exposure is considered incidental. Thus, consideration of its risk profile and effects on pregnancy may not be prioritized in discussions between patients and their clinicians, to the extent that fentanyl would be. Therefore, increased awareness about the co-presentation and risks of both substances is needed. Greater understanding of xylazine’s adverse effects in humans may help clinicians identify exposures, anticipate complications, and provide counseling for pregnant individuals.

Respiratory depression or acidosis was noted in all maternal cases. These patients also required prolonged hospitalizations and presented with several other medical complications. Exposed neonates experienced respiratory distress and feeding difficulties. It is important to note that other veterinary adulterants have potential for harmful use in humans, which may enhance potency and extend duration of effect of illicit drugs. These substances introduce profound unpredictability in clinical toxicity and management.

This study is limited by the small number of articles identified by our inclusion criteria, limiting the generalizability of these findings. Additionally, the frequent co-occurrence of xylazine with other substances complicates attribution of observed effects.

References: 1. Auty SG, Frakt AB, Shafer PR, Stein MD, Gordon SH. Severe Maternal Morbidity Among Pregnant People With Opioid Use Disorder Enrolled in Medicaid. JAMA Netw Open. 2025;8(1):e2453303. doi:10.1001/jamanetworkopen.2024.53303

2. Whiteman VE, Salemi JL, Mogos MF, Cain MA, Aliyu MH, Salihu HM. Maternal Opioid Drug Use during Pregnancy and Its Impact on Perinatal Morbidity, Mortality, and the Costs of Medical Care in the United States. J Pregnancy. 2014;2014:906723. doi:10.1155/2014/906723

3. Montero F, Bourgois P, Friedman J. Potency-Enhancing Synthetics in the Drug Overdose Epidemic: Xylazine (“Tranq”), Fentanyl, Methamphetamine, and the Displacement of Heroin in Philadelphia and Tijuana. J Illicit Econ Dev. 2022;4(2). doi:10.31389/jied.122

4. Office of National Drug Control Policy. Fentanyl Adulterated or Associated with Xylazine (FAAX) Implementation Report. Executive Office of the President; 2024. Accessed July 31, 2025. https://www.whitehouse.gov/wp-content/uploads/2025/03/ONDCP-2024-FAAX-Implementation-Report.pdf

5. Patrick SW, Richards MR, Dupont WD, et al. Association of Pregnancy and Insurance Status With Treatment Access for Opioid Use Disorder. JAMA Netw Open. 2020;3(8):e2013456. doi:10.1001/jamanetworkopen.2020.13456