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12 December 2025

In Utero Treatment of Lymphatic Malformations: A Narrative Review of the Literature, Considerations, and Future Directions

,
,
and
1
Department of Surgery, University of California, Davis, Sacramento, CA 95817, USA
2
Department of Surgery, Oregon Health and Science University, Portland, OR 97239, USA
*
Author to whom correspondence should be addressed.
Lymphatics2025, 3(4), 46;https://doi.org/10.3390/lymphatics3040046
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Abstract

Lymphatic malformations are rare congenital anomalies that range from small, self-limited lesions to large, rapidly expanding masses capable of causing serious perinatal complications, including hydrops fetalis, polyhydramnios, airway obstruction, and fetal demise. Although most lesions are managed expectantly or postnatally, in utero interventions have been attempted in highly select cases where lesions threaten pregnancy viability or safety of delivery. Reported approaches include the perinatal option of ex utero intrapartum therapy, intrauterine ultrasound-guided cyst aspiration for decompression, intrauterine intralesional sclerotherapy with agents such as OK-432, and more recently, maternal pharmacologic therapy targeting the mTOR pathways. This review summarizes the available literature describing prenatal management of these lesions, including procedural techniques, maternal and fetal outcomes, and emerging strategies. Together, these findings highlight the potential promise and the caution necessary in translating postnatal therapeutic advances for lymphatic malformations to the prenatal setting.

1. Introduction

Lymphatic malformations (LMs) are rare congenital anomalies, occurring in approximately 1 in every 2000–16,000 live births [1]. These lesions encompass a wide range of phenotypes including disorders of lymph central circulation, lymphatic drainage, or localized mass-like lesions that are characterized as macrocystic, microcystic, or mixed. LMs are thought to arise from disorganized and dilated lymphatic channels that develop separately from the normal lymphatic vasculature [2].
The natural history of these lesions is generally uncomplicated, and they may regress after a period of observation [3]. However, in more severe cases, large lesions and their associated complications can be lethal. For example, prenatally diagnosed cervicofacial lesions that are large or rapidly growing may cause airway obstruction, necessitating emergent procedures at birth to secure the airway [4]. Severe cases may also contribute to polyhydramnios, right heart failure, non-immune hydrops fetalis, and preterm labor and delivery [5].
Prenatal ultrasound and MRI are efficacious in detecting and surveilling these lesions during pregnancy [6,7,8]. Importantly, many studies describe prenatal imaging findings and their role in guiding patient counseling, planning for delivery, and postnatal management. Historically, management focused on postnatal surgical excision. In some cases, however, factors such as anatomy, size, or septal nature of these lesions may make complete excision difficult and thus result in a high likelihood of recurrence [9]. Therefore, alternative and adjunct therapies, including sclerotherapy, ablative or laser techniques, and new emerging pharmacologic options, are vital in the management of LMs.
Developmentally, the human lymphatic vasculature emerges from venous endothelium under PROX1 and VEGF-C/VEGFR3 signaling, followed by sprouting, valve formation, and remodeling throughout gestation [2]. Advances in understanding lymphatic malformation developmental biology have identified recurrent somatic alterations converging on the PI3K–AKT–mTOR pathway, motivating targeted approaches such as postnatal sirolimus (rapamycin) used both topically and orally [10,11,12,13,14,15,16]. Given that earlier intervention appears more effective after birth, the clinical question of whether carefully selected, high-risk fetal cases might benefit from in utero therapy follows.
In utero treatment is rare and has only been reported for select cases with an otherwise very poor prognosis. While the observation that some LMs regress prenatally may challenge the rationale for in utero intervention, this also suggests an intrinsic capacity for in utero remodeling. This finding suggests a potential rationale for targeted prenatal intervention in the small subset of rapidly progressive, life-threatening fetal LMs.
To our knowledge, a comprehensive synthesis of these prenatal therapeutic approaches for lymphatic malformations has not been reported. This narrative review therefore aims to summarize reported in utero interventions for lymphatic malformations, specifically cervicofacial LMs, evaluate translational limitations, and discuss opportunities for future directions.

2. Identification of Relevant Literature

We performed a literature search in Pubmed, Scopus, and Embase from inception to 1 October 2025 using search terms such as “lymphatic malformation,” “cystic hygroma,” “fetal,” or “intrauterine,” or “prenatal,” “treatment,” “mTOR,” “rapamycin,” “sirolimus,” “sclerotherapy.” Though this is a narrative review, we did apply inclusion criteria for studies outlined in Table 1 and Table 2, including (1) description of prenatally diagnosed LM, (2) intrauterine therapy was used to treat the lesion, and (3) follow-up information was provided (of any duration). Studies were evaluated for inclusion by two independent reviewers (ER and DR). Studies were excluded if they discussed only postnatal management, were not available in English, or if a full text was not available.

3. Ex Utero Intrapartum Therapy and Placenta Support

In the case of large craniofacial LMs (also referred to as cystic hygroma, nuchal lucencies, or cervicofacial LMs) with concern for airway compromise on prenatal imaging, Ex Utero Intrapartum Treatment (EXIT) has been described as a bridge to definitive airway in select fetuses. This approach utilizes maternal cesarean section with the establishment of an endotracheal or surgical airway while the fetus is still dependent on maternal–fetal circulation (EXIT-to-airway) [17,18,19]. In one retrospective series, prenatal anatomic findings that were associated with the performance of EXIT included anterior midline mass, tracheal deviation, mass greater than 5 cm, fetal neck extension, and compression of neck vessels, to name a few [20].
EXIT-to-airway limits neonatal hypoxia, but is not without significant complications [4,17,19]. Maternal complications include blood loss and increased risk of uterine rupture in subsequent pregnancies. Risks to neonates include possible tracheostomy and gastrostomy due to persistent postnatal respiratory support and feeding difficulties, as well as sequelae of prematurity in fetuses requiring early EXIT (e.g., necrotizing enterocolitis, pulmonary hypoplasia) [4,17,18,19].
Current evidence is limited to small case series and case reports, and procedures must be performed in specialized centers with multidisciplinary teams after extensive prenatal work-up and counseling [18,20]. While EXIT may be life-saving in carefully selected fetuses who have craniofacial LMs with airway obstruction, the technique has not been routinely described in other presentations of LMs. In an effort to limit the need for this high-risk procedure, or prolong pregnancy to reach this opportunity, other strategies have been described.

4. Decompressive Therapy

Large LMs of the head and neck that may depend on EXIT-to-airway for survival at birth may cause a mass effect resulting in tracheal compression and decreased fetal swallowing, resulting in polyhydramnios, with severe cases progressing to non-immune hydrops fetalis [21]. These fetuses may not survive long enough for the opportunity for an EXIT procedure. As early as the 1990s, several case reports and small case series have described ultrasound-guided aspiration of cystic hygromas to help address this obstructive process [22]. Case reports of this procedure are generally successful in temporizing the physiologic impact of these malformations; however, the cystic structures reaccumulate and most neonates still require intervention at birth to secure an airway. In other cases, cyst aspiration is reported just prior to vaginal delivery to prevent complications such as shoulder dystocia [23]. Later, aspiration is described in combination with intrauterine sclerotherapy of LMs.

5. Sclerotherapy

Sclerosing agents are commonly utilized adjuncts for treatment of lymphatic malformations in children. Sclerosants include OK-432 (Picibanil), doxycycline, ethanol, bleomycin, among others [24]. These agents work by inducing local inflammation and endothelial injury within the malformation, leading to fibrosis and involution of cystic structures. OK-432 is a lyophilized mixture of a low-virulence strain of group A Streptococcus pyogenes incubated with benzylpenicillin. OK-432 is among the most cited, most effective, and is generally considered safe.
Reported cases of success with its use in lymphatic malformations prompted a prospective and randomized trial to formally establish its efficacy in significantly reducing or resolving lymphatic malformations in children [16]. Numerous subsequent studies corroborate its safety and efficacy either as an independent therapy or as an adjunct to surgery. A 2024 systematic review and meta-analysis of head and neck lymphatic malformations found that surgical excision generally achieved higher complete-resolution rates than sclerotherapy for mixed lesions, while outcomes were comparable for macrocystic disease, and combination therapy appeared most beneficial for microcystic lesions [24].
Because large lymphatic malformations have the potential to be morbid perinatally, prenatal intervention with aspiration in conjunction with sclerotherapy has been reported in select, high-risk cases, in which the fetus is affected by non-immune hydrops fetalis, there is concern for airway obstruction at delivery, or the lesion is rapidly enlarging on interval imaging. Descriptions of prenatal sclerotherapy consists of few case reports and series from 1996 onward to treat cervical lesions, all with either associated hydrops or airway obstruction (Table 1) [25,26,27,28,29,30,31,32,33,34]. Despite several reports prior to 2000, there was no preclinical safety data until 2006. A study in rabbits established 1 KE/1 kg to be a safe dose for intrauterine treatment [29]. In the reported cases, the volume of sclerosant used, timing of intervention, and number of treatments varies in the literature.
Fetal outcomes were variable. Across cases, all treated lesions were cervicofacial lesions and most decreased or stabilized in size on interval imaging and facilitated an uncomplicated delivery. Of the studies represented in Table 1, two demises were reported: preterm premature rupture of membranes (PPROM) and preterm delivery associated with neonatal respiratory failure and death, and another secondary to hydrops fetalis despite sclerotherapy one day prior [33].
While sclerotherapy is perhaps a more definitive option compared to intrauterine aspiration alone, some lesions required multiple treatments, each exposing the mother and fetus to additional risk, specifically of PPROM and preterm delivery. Less invasive treatments are preferred, and may be possible via transplacental drug delivery, leveraging new understanding of pathophysiologic mechanisms.
Table 1. Representative studies utilizing intrauterine sclerotherapy as a treatment for lymphatic malformations.
Table 1. Representative studies utilizing intrauterine sclerotherapy as a treatment for lymphatic malformations.
First Author and Year,
n of Patients		IndicationDescription of LesionGA(s) at TreatmentOK-432 DoseNo. TreatmentsOutcomesComplications
Watari et al. 1996 (n = 1) [25]Hydrops, rapid enlargementMultiloculated cervical, 5.2 × 2.2 × 1.5 cm22, 280.01 mg/mL in 1 mL saline; 0.02 mg in 2 mL saline2Decreased size, resolved hydrops, uncomplicated vaginal deliveryNone reported
Ogita et al. 2001 (n = 2) [33]Hydrops,
progressive
enlargement		4 Cervical lesions 3 cm; 4 cervical lesions largest 5 × 8 cm27, 291 KE per lesion; 4 KE 1–2Decreased size;
demise		PPROM and preterm
delivery at 32 weeks,
neonatal demise,
respiratory
failure at birth (n = 1)
Intrauterine demise POD 1 (n = 1)
Sasaki et al. 2003 (n = 1) [31]Not specifiedMultiloculated, cervical, 4 × 2.5 × 4 cm27 + 5; 30 + 50.1 KE 2Decreased size,
uncomplicated
delivery		None reported
Kuwabara et al. 2004 (n = 1) [30]Rapid enlargementCervical, cystic, 4 cm262 KE1Decreased size,
uncomplicated
cesarean delivery		None reported
Mikovic et al. 2009 (n = 2) [28]Rapid
enlargement,
polyhydramnios; airway obstruction		Cervical, 49 mL (volume); cervical 67 mL (volume)28; 28Concentration not specified, 30 mL volume; 40 mL2Decreased size,
uncomplicated vaginal delivery; decreased size,
uncomplicated
cesarean delivery		None reported

6. Maternal Pharmacologic Therapy

Across the literature, approximately 75–90% of lymphatic malformations not associated with another syndrome are associated with a somatic mutation in the mTOR-AKT-PI3K pathway (higher estimates occur in cohorts that include PIK3CA-related overgrowth phenotypes) [35,36,37]. Since this discovery, many studies support the safety and efficacy of mTOR inhibition for treatment of pediatric lymphatic malformations [38,39]. Oral sirolimus is generally well tolerated, but reported side effects may include oral mucositis, mild respiratory infections, and transient laboratory derangements such as elevated liver enzymes [39]. A recent systematic review and meta-analysis reported decreased size of cervicofacial lesions as well as associated tracheostomy decannulation with childhood treatment of lymphatic malformations [38].
Because lymphangiogenesis and related metabolic signaling are highly active during gestation, the dysregulated PI3K–AKT–mTOR activity that underlies many LMs may be more responsive before structural maturation of the lymphatic vasculature. Human lymphatic malformation specimens and patient-derived lymphatic endothelial cells demonstrate AKT hyperphosphorylation and activation of downstream mTOR targets, observations that are reversible with rapamycin treatment [8,9]. These findings suggest that targeted drugs, such as sirolimus (rapamycin) or upstream inhibitors, could take advantage of the plasticity of the fetal endothelium to stabilize lesion growth and perhaps improve perinatal outcomes. Although the mechanism of action of mTOR inhibitors specifically in fetal patients has not been definitively characterized, maternal drug therapy using sirolimus has been reported in few cases.
Transplacental pharmacotherapy has precedent in multiple fetal conditions and offers important lessons for applying molecularly targeted agents in utero. Maternal administration of glucocorticoids such as dexamethasone and betamethasone efficiently cross the placenta and are routinely used to promote lung maturity, establishing clear pharmacokinetic models for small molecules in pregnancy [40]. Likewise, antiarrhythmics such as digoxin and flecainide demonstrate reliable maternal–fetal drug transfer for treatment of supraventricular tachycardia, while maternal propranolol has been successfully used to stabilize fetal cervicofacial lymphatic malformations (Table 2) [41,42]. Similarly, maternal immunosuppressants including tacrolimus and azathioprine have well-characterized safety profiles for maternal immunosuppression [43,44]. Maternal immunosuppression for fetal indications, i.e., treatment of severe lymphatic malformations, has been reported only a few times.
These reports, like those of intrauterine sclerotherapy, were reserved for fetuses with polyhydramnios, hydrops, or concern for airway obstruction. The first case of rapamycin utilized for a large cervicofacial lymphatic malformation was reported by Livingston et al. [45]. This lesion was inhibiting fetal swallowing and thus contributing to polyhydramnios. The regimen included a 15 mg loading dose followed by 5 mg daily, titrated to a therapeutic range in maternal blood, which was followed throughout pregnancy. Weekly ultrasound monitoring demonstrated stabilization of the lesion size and no fetal or maternal complications were reported.
Additional examples of maternal sirolimus to treat fetal LMs included a cervicofacial lymphatic malformation in which the mother developed transient mucositis, as well as a series of two fetuses by Klosowska et al., one with an LM spanning the abdomen, pelvis, and lower extremity, and the other with a malformation of the chest and abdominal wall [46,47,48]. In each of these cases, the lesion decreased in size on follow up ultrasound. No maternal or fetal complications were reported.
While optimal dosing is unknown, studies report careful monitoring of drug levels during pregnancy. Drug monitoring strategies differed among studies. While all included serial maternal level assessment for dose titration, only a subset obtained cord blood measurements, demonstrating fetal sirolimus concentrations averaging 20–30% of maternal levels. For example, Seront et al. found that only 30% of the drug crossed the placenta by cord blood sampling [47]. In this case report, the child had regression of a large cervicofacial lesion after in utero treatment starting at 22 weeks gestation and a safe delivery after maternal cessation of the medication as planned two weeks prior to deliver. After birth, there was recurrence of the lesion with associated tracheal compression, prompting neonatal sirolimus therapy 0.1 mg twice daily, followed by formal resection with adjunctive sclerotherapy. The child continued sirolimus therapy with antibiotic prophylaxis for three months post-operatively and had no recurrence at six years of age. While definitive management was still required postnatally, in utero treatment of the lesion possibly facilitated a safe delivery without need for EXIT procedure or emergent airway at birth. Of course, in each of these examples, the natural history of the lesions in the absence of sirolimus treatment is unknown.
Table 2. Representative reports of maternal pharmacologic therapy for fetal lymphatic malformations.
Table 2. Representative reports of maternal pharmacologic therapy for fetal lymphatic malformations.
First Author and Year, n of
Patients		IndicationLesion Size and TypeGA(s) at TreatmentMedication and DoseDrug MonitoringOutcomesComplications
Wu et al. 2016 (n = 1) [42] Airway
compromise		Cervical, size not specified35→39Propranolol 10 mg TIDNone reportedLesion stabilized, term delivery without complicationsNone reported
Livingston et al. 2021 (n = 1) [45]Rapid
enlargement
Polyhydramnios		Cervical, 7.1 × 7.5 × 7.8 cm30 + 4→37Rapamycin 15 mg loading dose, then titratedMaternal plasma (target 5–15 ng/mL); cord blood at delivery (6.0 ng/mL)Lesion stabilized, polyhydramnios improved, EXIT-to-airway deliveryNone reported
Seront et al. 2023 (n = 1) [47]Rapid enlargementCervical22→2 weeks prior to deliverySirolimus 6 mg loading dose then titratedMaternal plasma (target 10–15 ng/mL); fetal cord sampling Decreased size,
uncomplicated
delivery, resumed therapy at birth		Maternal mucositis (grade 2)
Klosowska et al. 2025 (n = 2) [46]Bleeding with
anemia; rapid
enlargement with polyhydramnios		Abdominal/pelvic; thoracic32 wks for 11 days; 33 wks for 31 daysSirolimus 2–6 mg/dayMaternal plasma (target 7–12 ng/mL); fetal cord samplingBleeding resolved; decreased size;
uncomplicated
cesarean deliveries		None reported
Megier et al. 2025 (n = 1) [48]Rapid enlargementAxillary 4 × 2.3 × 4 cm24→35Rapamycin 6 mg/day then
titrated		Maternal plasmaDecreased size;
uncomplicated
vaginal delivery		None reported
TID: three times daily; arrow depicts duration of treatment
While conclusions are limited by sample size across a few case reports, these early experiences demonstrate that maternal administration of mTOR inhibitors can achieve therapeutic fetal levels and are associated with clinical stabilization without apparent short-term toxicity for mother or fetus. Some preclinical findings related to the developmental biology of the lymphatic system support the potential receptivity of lymphatic endothelial cells to treatment, an opportunity to intervene during a phase of rapid growth and remodeling [48]. For example, Prox1 is necessary to promote lymphatic endothelial cell fate, perhaps suggesting that pharmacologic agents along the mTOR signaling pathway may be more effective or definitive before birth. Future studies must address pharmacokinetics, placental transport mechanisms, and developmental safety with continued long-term follow up to determine whether this targeted therapy could offer a viable prenatal option for severe, life-threatening LMs.

7. Translational Limitations and Future Directions

The most notable limitation in the utilization of in utero treatments for large or life-threatening LMs is the small number of case reports and series. These interventions have been typically applied when lesions threatened pregnancy viability or fetal survival through hydrops fetalis, airway compression, or cardiac compromise. While many lesions may spontaneously regress, intervention may be warranted in rapidly expanding cases, those complicated by hydrops, or when airway obstruction at delivery is anticipated. The decision of when and whether to intervene is challenging as any uterine instrumentation may increase the risk of preterm labor, membrane rupture, preterm delivery, or fetal demise. As with all prenatal therapies, timing of intervention requires careful consideration of maternal and fetal risks and benefits.
Despite these encouraging initial cases, no randomized trials or prospective cohort studies have validated the safety or efficacy of prenatal pharmacologic therapy for lymphatic malformations. Not surprisingly, given the rare nature of severe LMs detected prenatally, as well as the relatively recent discovery of mTOR inhibitor treatment success, robust preclinical data defining drug pharmacokinetics, placental transfer, and fetal dose–response relationships remain lacking. Much of the current understanding is extrapolated from experience with transplacental sirolimus for fetal cardiac rhabdomyoma [46]. Translating mTOR inhibitors and other PI3K–AKT–mTOR pathway modulators into the prenatal setting will require rigorous assessment of fetal biodistribution, developmental toxicity, and maternal safety. Although maternal sirolimus has been generally well tolerated in reported cases, the immunosuppressive nature of these agents necessitates careful consideration of infection risk and long-term effects.
Progress in this field is also limited by the relative absence of suitable animal models for lymphatic malformations. Current preclinical studies rely largely on murine and zebrafish models expressing somatic activating mutations in PIK3CA, each of which reproduces dilated, dysplastic lymphatic channels and progressive malformations resembling human disease [13,49,50]. These models have been essential in confirming the role of mTOR pathway activation and in demonstrating that targeted inhibition with rapamycin or PI3K-selective inhibitors reverses lymphatic overgrowth and normalizes vessel morphology. Zebrafish models have further enabled high-throughput screening of PI3K/mTOR pathway modulators during early lymphangiogenesis and provide some insight into safety at embryonic stages [51,52,53]. Unlike a fetal condition like myelomeningocele in which preclinical safety data was acquired through rigorous large-animal studies, no large-animal models currently exist that reproduce congenital lymphatic malformations. Without these models, it is difficult to understand pharmacokinetic properties and dosing strategies necessary for translating therapy to human fetal LMs.
Emerging work in drug engineering may offer new opportunities to reach lymphatic targets more selectively. Nanoparticle and lipid-based drugs could enhance lymphatic uptake after maternal or local administration, prolong availability within lymphatic endothelium, and perhaps reduce systemic toxicity. Targeted engineering strategies using polyethylene-glycolylated liposomes, albumin-binding prodrugs, and ligand-modified carriers have demonstrated preferential transport through intestinal chylomicron pathways and nodal retention in animal models [54]. While innovative, these targeting mechanisms may prove challenging for LMs as they are discontinuous from the normal lymphatic system. However, with optimization, these advances in lymphatic-targeted biodistribution studies may ultimately enable precise delivery of pathway inhibitors for LMs.
Collectively, these efforts reflect a growing intersection between developmental biology, pharmacologic innovation, and fetal therapy, perhaps laying the groundwork for translating molecularly targeted strategies from postnatal management to safe, mechanism-based intervention before birth.

Author Contributions

Conceptualization, E.R. and D.L.F.; methodology, E.R.; formal analysis, E.R., D.R. and E.B.; investigation, E.R., D.R. and E.B.; writing—original draft preparation, E.R. and D.R.; writing—review and editing, E.R., D.R., E.B. and D.L.F.; visualization, E.R. and D.L.F.; supervision, D.L.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data was obtained as part of this study.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
EXITEx utero Intrapartum Therapy
KEKlinische Einheit (Ok-432 dose units)
No. Number
GAGestational age
PI3K–AKT–mTORPhosphoinositide 3-kinase/Protein Kinase B (Akt)/Mammalian Target of Rapamycin

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