Successful live birth via in vitro fertilization in a patient with lymphangioleiomyomatosis: a case report

Abstract

Background

Lymphangioleiomyomatosis is a rare, estrogen-sensitive multisystem disorder that predominantly affects women of reproductive age. Pregnancy and fertility interventions present a unique challenge in patients with lymphangioleiomyomatosis, as an elevated estrogen level during controlled ovarian hyperstimulation and pregnancy may exacerbate the disease.

Case presentation

We describe a 43-year-old Han Chinese female patient diagnosed with sporadic lymphangioleiomyomatosis because of recurrent pneumothorax and diminished ovarian reserve who had a strong desire for pregnancy. In vitro fertilization was considered the most effective treatment to improve pregnancy rate, with low-estrogen protocols recommended following a comprehensive multidisciplinary evaluation. In the first controlled ovarian hyperstimulation cycle, the patient was treated with a microstimulation protocol, resulting in a peak estradiol level of 621 pg/ml. Two fresh embryos were transferred but did not achieve pregnancy. In the second controlled ovarian hyperstimulation cycle, a combination of letrozole and antagonist protocol was used, with a peak estradiol level of 248 pg/ml. Endometrial preparation for the frozen embryo transfer was conducted using a natural cycle, leading to a successful pregnancy. Throughout the pregnancy, multidisciplinary collaboration ensured continuous monitoring of both lung function and fetal development. Eventually, she achieved a full-term live birth via elective cesarean section, and pulmonary parameters remained stable after pregnancy.

Conclusion

This is the first case report presenting a female diagnosed with sporadic lymphangioleiomyomatosis and diminished ovarian reserve who successfully achieved a live birth via in vitro fertilization with no lymphangioleiomyomatosis-related complication. The use of low-estrogen protocols and multidisciplinary collaboration are essential to ensure maternal–fetal safety and to minimize the risk of lymphangioleiomyomatosis progression during controlled ovarian hyperstimulation and pregnancy.

Introduction

Lymphangioleiomyomatosis (LAM) is a rare, progressive, multisystemic disease characterized by diffuse cystic lung lesions. It predominantly affects women of reproductive age, with an estimated incidence of 20.9–26.04 cases per million adult female individuals [1]. LAM is categorized into two subtypes: sporadic LAM (S-LAM) and tuberous sclerosis complex-associated LAM (TSC-LAM). Patients typically manifest with progressive dyspnea, recurrent pneumothorax, chylous effusions, and renal angiomyolipomas. Before diagnosis, they need some examination, such as thoracic computed tomography (CT), lung biopsy, serum vascular endothelial growth factor-D (VEGF-D) levels, tuberous sclerosis complex (TSC) gene testing, and pulmonary function tests. The mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus) are the most important drug for patients with LAM, while oxygen therapy and lung transplantation may be considered in severe cases.

Estrogen plays a pivotal role in LAM pathogenesis, as underscored by its predilection for premenopausal women. Disease progression is often exacerbated during pregnancy or following exogenous estrogen administration, whereas the condition is usually stable after menopause. LAM tumor cells express both estrogen and progesterone receptors [2]. Experimental models, both animal studies and in vitro LAM models, demonstrate estrogen sensitivity. As a result, estrogen may promote disease progression by stimulating LAM cell proliferation and migration while simultaneously inhibiting apoptosis [3]. Furthermore, estrogen induces the upregulation of protease expression and enhances glucose uptake in TSC-deficient cells, thereby bolstering their tolerance to oxidative stress [3]. Taken together, these findings demonstrate that LAM is an estrogen-responsive neoplasm.

The widespread adoption of chest CT screening has facilitated earlier diagnosis and intervention in patients with LAM, thereby creating an opportunity to address and evaluate reproductive issues in this population. A study of 328 patients with LAM reported that 69% had desires to bear children [4]. However, pregnancy in this population remains contentious. While some clinicians regard pregnancy as contraindicated, others advocate for personalized decision-making [5, 6]. However, elevated estrogen levels during pregnancy present potential risks for patients with LAM, often deterring patients from attempting conception. Furthermore, women with LAM exhibit diminished fertility and fewer parities compared with the general population [7]. Moreover, therapeutic drugs may contribute to ovarian cysts and menstrual irregularities [8], thereby impairing fertility in this population and highlighting the need for assisted reproductive technologies (ART). However, there was no report about successful ART outcomes in patients with LAM. Here, we present the first documented case of a live birth through in vitro fertilization (IVF) in a 43-year-old Han Chinese female patient with LAM, providing an in-depth account of the treatment regimen and associated perinatal outcomes.

Case description

Patient history of lymphangioleiomyomatosis

A Han Chinese female patient came to our institution in September 2007, and presented with pneumothorax when she was 33 years old. Chest CT demonstrated diffuse bilateral cystic changes, with cysts measuring up to 9 mm in diameter, raising suspicion for LAM. Following chest drainage, complete pulmonary re-expansion was achieved. After 2 months, the pulmonary function testing revealed normal ventilatory and diffusing capacities. Subsequent follow-up assessments of lung function at 6 and 30 months showed no abnormalities. At the 30-month follow-up, serum vascular endothelial growth factor-D (VEGF-D) concentration was measured at 620 pg/ml, consistent with mild disease activity.

In February 2012, the patient experienced a recurrent pneumothorax and subsequently underwent a thoracoscopic lung biopsy with pleurodesis. Pathological examination revealed spindle-shaped smooth muscle cell proliferation with cuff-like nodules in the walls of the pulmonary bullae. Immunohistochemical analysis was positive for desmin (+), smooth muscle actin (+), actin (+), estrogen receptor (+), progesterone receptor (+), and human melanoma black 45 (±); confirming the diagnosis of pulmonary LAM. Serial pulmonary function testing in October 2014 demonstrated normal ventilatory parameters (forced expiratory volume in 1 second (FEV1) 86% predicted; forced vital capacity (FVC) 96% predicted; FEV1/FVC ratio 77.1%) with a mild reduction in diffusion capacity (diffusing capacity of the lung for carbon monoxide (DLCO) 74% predicted).

In vitro fertilization treatment process

The patient had a full-term cesarean delivery in 2000, prior to LAM diagnosis. In 2014, following confirmation of stable pulmonary function, she expressed a desire to conceive again. However, despite discontinuing contraception, she did not achieve pregnancy. In 2017, at the age of 43 years, she sought fertility evaluation at the Department of Reproductive Medicine. Her serum anti-Müllerian hormone level was 0.01 ng/ml, and an ultrasound scan revealed only two antral follicles bilaterally. Basal sex hormones and semen analysis were within normal limits. She was diagnosed with infertility, diminished ovarian reserve, LAM, and a scarred uterus. On the basis of this clinical profile, in vitro fertilization (IVF) was recommended.

The patient reported no respiratory symptoms, including dyspnea or chest pain, and was able to climb six flights of stairs without rest. A multidisciplinary consultation involving reproductive endocrinology, pulmonology, and maternal–fetal medicine teams concluded that the patient was eligible for ART on the basis of the following conditions: (1) stable LAM, with no recent pneumothorax over a 5-year period; (2) normal cardiopulmonary function, with no need for oxygen therapy or sirolimus; and (3) willingness to take potential risks and sign informed consent from patients. The patient was diagnosed with S-LAM but not TSC-LAM; therefore, there was no need for preimplantation genetic testing. To minimize estrogen exposure, the low-estrogen protocols for ovarian stimulation and endometrial preparation were recommended. Considering the patient’s age and ovarian function, a microstimulation protocol was employed for ovulation stimulation, using 100 mg of clomiphene for 5 days and 150 IU of gonadotropin for 6 days. The peak estradiol level was 621 pg/ml, yielding two oocytes, which developed into two high-quality embryos (scores: 811 and 812). These embryos were freshly transferred but did not result in pregnancy. In the second cycle, an antagonist protocol incorporating letrozole was used to reduce estrogen levels. Letrozole 2.5 mg was combined with gonadotropins for ovulation stimulation, resulting in a peak estradiol level of 248 pg/ml and the retrieval of two oocytes. One of them developed into a blastocyst (score: 4BB). Considering only one blastocyst and risk of blastocyst biopsy, preimplantation genetic testing (PGT-A) was not performed. Endometrial preparation for the frozen embryo transfer (FET) was conducted using a natural cycle, leading to a successful pregnancy (Fig. 1).

Fig. 1.

Patient’s pregnancy management. This figure was created by the authors

The patient was on time for maternity check-ups. Given the patient’s advanced maternal age, invasive prenatal diagnostic testing was recommended, but she opted for noninvasive prenatal testing owing to concerns over the potential risk of abortion. Cell-free DNA analysis demonstrated no chromosomal abnormalities. In the second trimester, she was diagnosed with gestational diabetes mellitus, which was well managed through medical nutrition therapy. She had no shortness of breath or other respiratory symptoms. On the basis of clinical assessment, a 6-min walk test was selected for functional evaluation instead of pulmonary function testing owing to the risk of pneumothorax. In the third trimester, a multidisciplinary team, including doctors in obstetrics, respiratory medicine, anesthesiology, and neonatology, conducted a thorough evaluation of her condition. The multidisciplinary team’s conclusions are discussed in continuation.

The patient was a parturient of advanced maternal age with a prior cesarean delivery and multiple spontaneous pneumothoraxes. During the second stage of labor, the expulsive efforts could have led to marked elevation of intra-abdominal pressure, which may have induced pneumothorax. In addition, the uterine scar in this patient, who was of advanced maternal age, demonstrated diminished tolerance to the mechanical stress of labor. As a result, the elective cesarean section was performed at 39 gestational weeks. In April 2018, a healthy male infant was delivered via lower segment cesarean section, weighing 3300 g with Apgar scores of 10.

Postnatal period

The patient reported no discomfort after delivery, and her pulmonary function remained stable. She successfully breastfed her infant for 18 months.

In May 2021, she experienced a third episode of pneumothorax, precipitated by physical exertion. She was treated with salperin administered into the thoracic cavity to promote pleural adhesion. Meanwhile, sirolimus was initiated at a dosage of 2 mg/day and gradually decreased to 1 mg/day as the patient showed good performance on the 6-minute walk test.

The pulmonary function testing in September 2021 revealed a mild obstructive pattern (FEV1 73.2% predicted; FEV1/FVC 70.44%), accompanied by persistent diffusion impairment (DLCO 66% predicted). Serum VEGF-D levels remained stable at 610 pg/mL.

In November 2021, the patient experienced a fourth episode of pneumothorax, which was again treated with salperin administered into the thoracic cavity for pleural adhesion. However, recurrence occurred 1 month later and was managed conservatively.

Discussion

This report presents the multidisciplinary management of the case of S-LAM in a 43-year-old woman who successfully achieved a live birth through assisted reproductive technology. The patient underwent two cycles of controlled ovarian stimulation, with an initial failure following fresh embryo transfer, subsequently attaining clinical pregnancy after frozen embryo transfer. She delivered a healthy baby by elective cesarean section at 39 weeks’ gestation. Notably, her pulmonary function remained stable throughout the pregnancy (FEV1/FVC ratio > 70%; DLCO > 65% predicted), with no LAM-related complications observed. This case highlights the critical role of comprehensive, multidisciplinary care throughout both the prenatal and postnatal periods in optimizing pregnancy outcomes for patients with LAM.

Evaluation before pregnancy in patients with lymphangioleiomyomatosis

Pregnancy induces hormonal alterations and uterine expansion, driving adaptive lung function changes: elevated tidal volume, decreased functional residual capacity, and elevated oxygen consumption. LAM is an estrogen-responsive neoplasm, raising theoretical concerns that pregnancy may induce the disease progression. However, in this case, the trajectory of pulmonary function remained comparable before and after pregnancy, indicating that gestation did not significantly influence her pulmonary function (Fig. 2). However, all three patients in the report by Wilson et al. exhibited declines in lung function after pregnancy [9]. Taveira-DaSilva et al. proposed that pregnancy was more likely to impact pulmonary function in patients with preexisting impairments [10], while Fluticason et al. concluded that pregnancy did not exacerbate pulmonary decline [11]. These findings underscore that pregnancy does not invariably compromise lung function in individuals with LAM, highlighting the importance of personalized, clinical decision-making in the management of pregnancy in this population.

Fig. 2.

Change of patient’s pulmonary function. The patient’s pulmonary function was assessed using forced expiratory volume in 1 second, forced vital capacity, forced expiratory volume in 1 second/forced vital capacity ratio, and diffusing capacity of the lung for carbon monoxide values. Across two consecutive 7-year intervals, one of which encompassed pregnancy, the rate of lung function decline demonstrated a comparable trajectory, indicating no significant deviation attributable to the gestational period. This figure was created by the authors

Therefore, a comprehensive preconception evaluation is crucial for patients with LAM, including chest CT, pulmonary function testing, serum VEGF-D levels, and screening for extrapulmonary manifestations. A previous study indicated that 20% of patients with LAM develop pulmonary symptoms during pregnancy [4]. Patients with preexisting abnormal lung function were at greater risk of decline in lung function and episodes of pneumothorax during pregnancy [2, 9, 12]. A study of 328 patients with LAM recommended that patients planning a pregnancy should have an FEV1/FVC ratio greater than 68%, while patients diagnosed during pregnancy should maintain a ratio above 50% [4]. In this case, the patient’s FEV1/FVC% was above 70%, reflecting stable pulmonary function. VEGF-D is also a critical biomarker of LAM severity; elevated levels are associated with a greater likelihood of pregnancy complications [13]. LAM can be diagnosed when VEGF-D exceeds 800 pg/ml in conjunction with characteristic cystic changes on high-resolution CT [14]. In contrast, a previously reported case described a patient with a VEGF-D level of 1200 pg/ml who developed pneumothorax during pregnancy, though ultimately achieving a successful delivery [15].

A history of successful pregnancy and delivery without major complications suggests better gestational tolerance, supporting consideration of subsequent pregnancies. However, patients diagnosed with LAM during pregnancy are at an elevated risk for serious complications [4]. Evidence indicates that a prior history of pneumothorax significantly increases the risk of recurrence during pregnancy [2]. In this case, the patient experienced a pneumothorax 5 years prior to conception, with no recurrence during pregnancy. Similarly, another patient who experienced five pneumothoraxes at an age of 30 years had a successful pregnancy at the age of 35 years with no episodes [16]. Thus, the absence of recent pneumothorax episodes is a favorable prognostic factor. Sirolimus is the main pharmacologic treatment for LAM. However, animal studies have shown embryo-fetal toxicity, and comprehensive safety data in humans remain limited. Therefore, sirolimus is recommended to discontinue at least 12 weeks before conception owing to potential teratogenicity. Nevertheless, disease progression often resumes following discontinuation [17]. Limited clinical cases suggested that low-dose sirolimus may be safe for fetuses [12, 18]. Thus, the use of sirolimus in patients who are pregnant requires a careful, individualized risk–benefit assessment, balancing maternal disease control against potential risks to fetal development.

Optimization of in vitro fertilization treatment protocols for patients with lymphangioleiomyomatosis

Clinicians should implement personalized treatment protocols for patients with LAM undergoing IVF. Given that both LAM and breast cancer are estrogen-sensitive conditions, clinical insights from the management of the latter can be invaluable. It is advisable to adopt strategies that minimize estrogen exposure, such as antagonist protocols, mild stimulation regimens, and natural cycles while concurrently reducing gonadotropin dosages to prevent ovarian hyperstimulation syndrome.

Letrozole, a third-generation, highly selective aromatase inhibitor, reduces circulating estrogen levels by inhibiting the conversion of testosterone to estrogen. This alleviates the negative feedback on the hypothalamic–pituitary axis, thereby stimulating the pituitary gland to secrete follicle-stimulating hormone, which promotes follicular development [19]. The use of letrozole in ovarian stimulation has become a well-established approach for fertility preservation in patients with breast cancer [20]. Notably, studies have demonstrated that letrozole administration may benefit patients with LAM, as it improves FEV1 in postmenopausal individuals with LAM [21]. In this case, letrozole was employed to lower estradiol levels and reduce gonadotropin doses (75–150 IU). The estradiol peak was 248 pg/ml on the trigger day.

For FET, three endometrial preparation protocols are commonly used: ovulation induction, hormone replacement therapy, and natural cycles. The hormone replacement therapy protocol necessitates extended exogenous estrogen administration coupled with intensive luteal phase support for a duration of at least 2 months. In this case, pregnancy was successfully achieved using a natural cycle for endometrial preparation, thereby avoiding exogenous estrogen exposure. The letrozole-based ovulation induction protocol is also recommended for endometrial preparation in patients with LAM. Furthermore, since TSC-LAM is a monogenic disease, preimplantation genetic testing can be employed to select mutation-free embryos for transfer in patients with TSC-LAM [22].

Gestational monitor and perinatal management

A recent study recommends a staged, trimester-specific approach to managing pregnancy in patients with LAM [2]. In the first trimester, clinicians should assess baseline pulmonary function, address comorbidities, and discuss fetal genetic risks, especially if there is a maternal diagnosis of TSC. Early ultrasonography should be performed to confirm gestational age. In the second trimester, management should include reassessment of pulmonary function, evaluation of obstetric anesthesia risks, and planning for labor and delivery. Prenatal genetic diagnosis is strongly recommended for women with TSC-LAM. In the third trimester, the timing and mode of delivery should be guided by standard obstetric indications. Collaboration between obstetricians, gynecologists, and pulmonologists is advised to determine the delivery method, considering the risk of pneumothorax during delivery [23]. McLoughlin et al. recommend epidural analgesia during labor to mitigate hyperventilation and abrupt intrathoracic pressure fluctuations associated with uterine contractions, thereby minimizing pulmonary complications. To prevent overexertion during the second stage of labor, the criteria for instrumental delivery should be lowered, especially for women with a history of nonsurgical pneumothorax treatment, as they are at a high recurrence rate [24]. However, the high percentage of cesarean deliveries reported in previous studies warrants consideration. For instance, in this case, the patient opted for cesarean delivery owing to concerns about pneumothorax, suggesting a potential overestimation of the risk in clinical decision-making.

For patients with LAM who are pregnant, the onset of pulmonary symptoms requires immediate monitoring of oxygen saturation, vital signs, and chest imaging. If symptoms worsen, an urgent consultation with a pulmonologist should be prioritized, alongside fetal assessment with an obstetrician. In severe cases, termination of pregnancy may be necessary. However, the proportion of spontaneous versus medically induced preterm labor remains unclear [2]. In addition, given the heightened risk of preterm delivery, when gestational age is less than 34 weeks, antenatal corticosteroids should be indicated. This intervention aids in promoting fetal lung maturation and preventing respiratory distress in preterm infants. Postpartum, pulmonary function should be reassessed. Given the excretion of sirolimus in breast milk, formula feeding is recommended for patients undergoing sirolimus therapy. Furthermore, nonhormonal contraception is recommended postpartum, and estrogen-containing medications are contraindicated owing to their potential effects on LAM.

Global studies show patients with LAM seek more information about the effects of the disease on fertility, pregnancy, offspring, and parenting. However, many patients are dissatisfied with the insufficiency of the information provided [25], which can exacerbate psychological distress. In this case, the patient experienced significant anxiety, fear, and guilt owing to insufficient clinical guidance. Despite these emotional challenges, she successfully achieved a live birth through IVF, aided by coordinated, multidisciplinary care. This case provides valuable clinical insights into IVF-assisted treatment from preconception to postpartum and may serve as a potential guide for reproductive management and pregnancy care in patients with LAM.

Conclusion

We describe a female patient diagnosed with S-LAM and diminished ovarian reserve who successfully achieved a live birth via IVF with no LAM-related complication. The use of low-estrogen protocols and multidisciplinary collaboration are essential to ensure maternal–fetal safety and to minimize the risk of LAM progression during COH and pregnancy.

Abbreviations

LAM

Lymphangioleiomyomatosis

TSC

Tuberous sclerosis complex

S-LAM

Sporadic LAM

TSC-LAM

Tuberous sclerosis complex-associated LAM

ART

Assisted reproductive technologies

COH

Controlled ovarian hyperstimulation

IVF

In vitro fertilization

FET

Frozen-thawed embryo transfer

CT

Computed tomography

VEGF-D

Vascular endothelial growth factor D

FET

Frozen embryo transfer

FEV1

Forced expiratory volume in 1 second

FVC

Forced vital capacity

DLCO

Diffusing capacity of the lung for carbon monoxide

Author contributions

Conception and design: HW and YL. Writing—original draft: YO, WW, and YX. Editing: YL, YZ, and YX. Literature search: YC and XZ. Manuscript review and approval: All authors.

Funding

This work was supported by Innovation Team Project of Guangdong Universities, China (Natural, No. 2024KCXTD019), and China Health Promotion Foundation (No. 2024–16).

Data availability

To safeguard the privacy of study participant, we cannot openly share the data. However, the datasets used or analyzed in this study can be obtained from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study was conducted at the Guangdong Provincial People’s Hospital and was approved by the Ethics Review Committee of Guangdong Provincial People’s Hospital (No. KY2025-280–01).

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.