Complications of lymphangioleiomyomatosis in pregnancy: a case report and review of the literature.

A 37-year-old primigravid patient at 29 weeks 5 days gestational age initially presented with 2 days of right-sided chest pain. Her only significant past medical history was mild chronic hypertension. She denied dyspnea, cough, edema, fevers, and rashes. A computed tomography (CT) angiography of the chest to rule out a pulmonary embolism demonstrated a right-sided pneumothorax measuring 2.2 cm and at least 20 thin-walled cysts (blebs) ranging from 0.5 to 1 cm in diameter ( Figure 1 ). There were also 3 sub-centimeter exophytic left renal hyperattenuating lesions, concerning for hemorrhagic cysts. A right chest tube was placed to relieve the pneumothorax, suspected to be secondary to ruptured blebs. The patient received betamethasone for fetal lung maturity and magnesium for fetal neuroprotection and was then transferred to our facility for a higher level of care for these findings and also because of new severe-range blood pressures concerning for superimposed preeclampsia. Figure 1 Computed tomography scan of chest Blue arrow indicates a pneumothorax; green arrows indicate cystic lesions. Figure 1 Wang-Koehler. Lymphangioleiomyomatosis in pregnancy. Am J Obstet Gynecol Glob Rep 2024. Computed tomography scan of chest Blue arrow indicates a pneumothorax; green arrows indicate cystic lesions. Upon arrival at our hospital, the patient was in significant pain at the chest tube site and required a hydromorphone patient-controlled analgesia (PCA) pump. The patient had several severe-range blood pressure measurements necessitating multiple doses of intravenous labetalol, as well as proteinuria (urine protein/creatinine ratio of 0.4) but without preeclampsia symptoms or abnormalities in the platelet counts or creatinine or transaminase levels. The interventional pulmonology division was consulted with a working diagnosis of a primary spontaneous pneumothorax. The chest tube was removed after the patient passed a clamp trial, and a subsequent chest x-ray the next day showed no evidence of recurrence. On the second day of hospitalization, the patient complained of severe abdominal pain and constipation, although she was passing gas and denied nausea or vomiting. Significant abdominal distention was noted without rebound or guarding. Over the course of the day, she developed nausea, nonbloody and nonbilious emesis, and an increase in fetal heart rate from the 130s to 160s observed during electronic fetal monitoring. Maternal vital signs were notable for ongoing hypertension and worsening tachycardia with a low-grade fever. Laboratory studies demonstrated normal white blood cell counts, hemoglobin, amylase, lipase, hepatic function tests, creatinine, lactate, fibrinogen, and other coagulation markers. Magnetic resonance imaging of the abdomen and pelvis revealed dilated segments of large bowel without obstructing lesions and left-sided renal lesions suggestive of lipid-poor angiomyolipomas ( Figure 2 ). Given the combination of spontaneous pneumothorax, cystic lung lesions, and renal angiomyolipomas, a diagnosis of lymphangioleiomyomatosis (LAM) was made in consultation with radiology and pulmonology. The patient did not have any family history or other symptoms to suggest tuberous sclerosis. Figure 2 MRI of abdomen demonstrating renal lesions MRI , magnetic resonance imaging. Figure 2 Wang-Koehler. Lymphangioleiomyomatosis in pregnancy. Am J Obstet Gynecol Glob Rep 2024. MRI of abdomen demonstrating renal lesions MRI , magnetic resonance imaging. After remaining clinically stable with improved vital signs and reassuring fetal well-being over the subsequent day, the patient experienced worsening abdominal pain and distention on the fourth day of hospitalization with progressive bilious emesis. The fetus, now at 30 weeks and 2 days gestation, was noted concurrently to have numerous late and prolonged decelerations during routine monitoring. Because of clinical concern for concealed placental abruption in the setting of preeclampsia with severe features, the decision was made to proceed with delivery, which was accomplished via cesarean delivery because of fetal malpresentation. Before proceeding to the operating room, a nasogastric tube was placed, which produced 1 L of bilious output immediately upon connection to low continuous wall suction. The primary cesarean delivery itself was uncomplicated with no evident signs of placental abruption. The bowel was examined and noted to be dilated throughout, although pink and seemingly healthy. Milky ascites, possibly consistent with chyle, were noted at the time of peritoneal entry, but could not be appropriately sampled given the urgency of delivery and subsequent intermixing with blood and amniotic fluid. The male neonate, weighing 1836 grams, was transferred to the neonatal intensive care unit (NICU) for further management of prematurity with Apgar scores of 4 and 8 at 1 and 5 minutes of life, respectively. On the first postoperative day, the patient's abdominal distension and pain persisted. A CT scan of the abdomen and pelvis with oral contrast demonstrated small bowel dilation concerning for possible small bowel obstruction or ileus. The patient also had acute kidney injury (creatinine level, 1.53 mg/dL), tachycardia (120–140 beats per minute), a fever (to 104℉), and leukopenia (nadir 3.4 × 10 9 /L) concerning for sepsis and was started on empiric broad spectrum antibiotics with vancomycin and cefepime. The patient then developed atrial fibrillation with rapid ventricular response and was started on amiodarone with transfer to the surgical intensive care unit (ICU) for further management. After the arrhythmia was controlled, the patient remained in the ICU for several days with continued severe abdominal pain and distension and copious output from the nasogastric tube. On postoperative day 4, a repeat CT scan noted a small bowel obstruction with free air under the diaphragm concerning for bowel perforation. She was taken urgently to the operating room where a cecal perforation was found. The general surgery division performed an ileocecectomy, and the bowel was left in temporary discontinuity with open fascia and a plan to return to the operating room in several days for re-evaluation. The patient ultimately required a right hemicolectomy with end ileostomy. It was hypothesized that the precipitant of her bowel disease was peritonitis secondary to chylous ascites, which triggered refractory bowel dilation distal to the cecum and ultimately a spontaneous perforation. The patient's postoperative course was also complicated by a peri-splenic abscess that required drainage, a pulmonary embolism, and a recurrent right pneumothorax that necessitated repeated chest tube replacement. The patient was followed closely by the surgery, pulmonology, interventional radiology, and maternal-fetal medicine divisions throughout the extended hospital course, during which time the patient spent 10 days in the ICU. After a prolonged hospitalization, the patient was stable for discharge to acute rehabilitation on hospital day 37. The neonate did well in the NICU and was discharged home on hospital day 66.

Eileen Wang-Koehler: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. Adina R. Kern-Goldberger: Conceptualization, Supervision, Writing – review & editing. Sindhu K. Srinivas: Conceptualization, Supervision, Writing – review & editing.

Of the 29 studies reviewed, the majority (24) were case reports that described LAM during pregnancy. Of the remaining studies, 1 was a descriptive chart review, 2 were survey questionnaires, 1 was a combined chart review and survey, and 1 was a national observational cohort study. Of the case reports, most cases presented with symptoms during pregnancy and were diagnosed with LAM either during or shortly after pregnancy (see Table 1 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ). Six women had diagnoses preceding the pregnancy, 2 of whom did not report any symptoms during the pregnancy. 10 , 11 Two were also diagnosed with tuberous sclerosis. The median age of presentation with symptoms was 29.5 years, and the median gestational age at presentation was 20.5 weeks with case presentations evenly distributed across all trimesters. A total of 12 cases were primiparous and 5 were multiparous, although the parity for 7 cases was not reported. Dyspnea (12), cough (6), chest or shoulder pain (2), hemoptysis (2), flank pain (2), and hypoxia (2) were the most commonly reported presenting signs or symptoms. A total of 11 of 24 cases reported pneumothoraces during pregnancy, 4 of which recurrent episodes. Only 1 case had chylothorax or chylous ascites during pregnancy. Nine cases had renal angiomyolipomas that were present during pregnancy. Six cases reported concomitant obstetrical complications, including preeclampsia, fetal growth restriction, placenta previa, and preterm labor, whereas 7 cases had other medical complications related to LAM (including re-intubation, pulmonary hypertension, acute respiratory distress syndrome, and pulmonary infection). In total, 75% of patients received some invasive intervention, including a chest tube, pleurodesis, thoracostomy or thoracotomy, extracorporeal membrane oxygenation, nephrectomy, or embolization of AMLs. Table 1 Case reports of LAM and pregnancy Table 1 Authors Maternal age Parity Diagnosis preceding pregnancy? GA at presentation or worsening symptoms Presenting symptoms during pregnancy Complications of LAM during pregnancy Other pregnancy complications Treatment and/or interventions Delivery mode Indication for CD GA at delivery (wk) Term or preterm Neonatal outcome Agrawal et al, 3 2020 29 Unknown No 28 Dyspnea, hypoxia Pneumothorax, bronchopleural fistula Preeclampsia, fetal growth restriction Chest tube and Heimlich flutter valve, postdelivery sirolimus Cesarean Unplanned, worsening preeclampsia Unknown Unknown Unknown Alkemade et al, 2 2021 36 Primiparous No 39 Dyspnea, shoulder or chest pain, cough Pneumothorax None None, spontaneous resolution of pneumothorax Cesarean Planned, elective 39 Term Healthy Brunelli et al, 4 1996 26 Unknown No 35 Dyspnea Chylothorax None Bilateral closed tube thoracostomy, TPN, ligation of lymphatic channels Cesarean Unplanned, severe dyspnea secondary to chylothorax 35 Preterm Unknown Cho et al, 5 2009 33 Multiparous No 39 Hypoxia Renal angiomyolipoma, tuberous sclerosis Placenta previa Intubation, ICU transfer because of hypoxia Cesarean Placenta previa 39 Term Healthy Cleary-Goldman et al, 6 2004 23 Primiparous Yes 26 Dyspnea, cough Renal angiomyolipoma Pulmonary infection Bilateral renal stents, levofloxacin, supplemental oxygen, and albuterol Cesarean Planned, elective, concern for renal rupture with hemorrhage 34 Preterm Healthy Crawford et al, 7 2015 37 Primiparous No 21 Dyspnea, cough, fever None ARDS, influenza, preeclampsia, and HELLP syndrome Bronchoscopy, antibiotics and oseltamivir, V-V ECMO, steroid therapy, recombinant activated factor VII; sirolimus Cesarean Unplanned, worsening preeclampsia 24 Preterm Healthy Creagh-Brown et al, 8 2006 37 Multiparous No 14 Dyspnea Recurrent pneumothorax None Pneumothorax aspiration, VATs and pleurodesis Cesarean Unknown Term Term Healthy Faehling et al, 9 2011 29 Primiparous Yes 21 Dyspnea, cough Pneumothorax None Chest tube, sirolimus, chest tube, pleurectomy and resection Cesarean Unplanned, secondary to pneumothorax 32 Preterm Healthy Faehling et al, 10 2015 34 Multiparous Yes N/A N/A stable lung function on sirolimus None None Sirolimus Cesarean Unknown 32 Preterm Healthy Fujimoto et al, 11 2005 30 Primiparous Yes N/A N/A None None N/A Cesarean Planned, concern for spontaneous pneumothorax 38 Term Healthy Gargari et al, 12 2009 35 Multiparous No 8 Dyspnea None None None Cesarean Planned, elective 37 Term Healthy Iruloh et al, 13 2013 23 Primiparous No 31 Dizziness, blurry vision, dyspnea, fatigue, itching Renal angiomyolipoma None Coil and particle embolization of angiomyolipoma after cesarean delivery Cesarean Planned, elective 38 Term Unknown John et al, 14 2022 29 Unknown No 37 Constipation, abdominal pain Renal angiomyolipoma None Left nephrectomy Cesarean Unplanned, likely in setting of renal mass 37 Term Unknown Johnston et al, 15 2011 18 Primiparous No 20 Dyspnea, fatigue None Fetal growth restriction Bilateral chest tubes, thoracoscopy with lung stapling, eventual lung transplant Cesarean Fetal growth restriction 29 Preterm Unknown McCartney et al, 16 2009 30 Multiparous No 19 Dyspnea Recurrent pneumothorax None Aspiration of pneumothorax, chest drain placement, VATs, left-sided pleurodesis Cesarean Unplanned, history of cesarean delivery, worsening clinical status 34 Preterm Healthy McLoughlin et al, 17 2003 29 Primiparous Yes 4 Flank pain Renal angiomyolipoma None Enucleation of angiomyolipoma without nephrectomy after delivery Vacuum-assisted vaginal delivery Planned, elective 39 Term Unknown Mitra et al, 18 2004 30 Unknown No 8 Dyspnea, cough None Right ventricular failure with pulmonary hypertension Pulmonary HTN treated with oxygen, antibiotics and diuretics; medroxyprogesterone Vaginal N/A 36 Preterm Fetal demise at 9 mo Pais et al, 19 2017 26 Unknown No Unknown Cough, hemoptysis Renal angiomyolipoma None Hypoxia requiring supplemental oxygen Cesarean Planned, concern for neonatal or maternal adverse outcomes 30 Preterm Unknown Peces et al, 20 2011 25 Primiparous No 12 Flank pain Renal angiomyolipoma, tuberous sclerosis None Embolization of renal AMLs and radical left nephrectomy, sirolimus Cesarean Planned, elective 38 Term Healthy Toyoda et al, 21 2006 26 Primiparous No 27 Hemoptysis, chest pain Recurrent pneumothorax, renal angiomyolipoma Idiopathic thrombocytopenia ITP requiring IVIG. Recurrent pneumothorax leading to chest tube and VATs postpartum; home oxygen, leuprolide Cesarean Unknown 35 Preterm Healthy Weinans and van Loon, 22 1999 30 Primiparous No 10 Abdominal pain, fatigue, general malaise, weight loss Renal angiomyolipoma None Exploratory laparotomy of retroperitoneal mass, oxygen therapy, medroxyprogesterone Cesarean Failure to progress in first stage of labor 39 Term Healthy Wilson et al, 23 2001 24 Unknown No 6 Unknown, spontaneous pneumothorax Recurrent pneumothorax Preterm labor Abrasion pleurodesis of pneumothorax, kaolin insufflation; vaginal progesterone, medroxyprogesterone Unknown N/A 25 Preterm Neonatal death Yamashita et al, 24 2011 30 Primiparous Yes 36 Unknown, pneumothorax Pneumothorax None Chest tube, delivery; GnRH analogue after delivery Cesarean Planned, concern for progression of pneumothorax in labor 37 Term Healthy Yockey et al, 25 1986 33 Unknown No 18 Dyspnea Pneumothorax Preterm labor; obstructive hydronephrosis, acute respiratory failure requiring intubation, mesangial proliferative glomerulonephritis Left thoracotomy during pregnancy; chest tube, Tamoxifen and Provera. Ultimately required pleurectomy and pleurodesis TAH/BSO Obstructed labor secondary to massive fibroid––inability to evacuate uterus and thought that placental or ovarian estrogen production was stimulating disease 20 Preterm Abortion AML , angiomyolipoma; ARDS , acute respiratory distress syndrome; BSO , bilateral salpingo-oophorectomy; CD , cesarean delivery; GA , gestational age; GnRH , gonadotropin-releasing hormone; HELLP , hemolysis, elevated liver enzymes, low platelet count; HTN , hypertension; ICU , intensive care unit; ITP , immune thrombocytopenic purpura; IVIG , intravenous immune globulin; LAM , lymphangioleiomyomatosis; N/A , not applicable; TAH , total abdominal hysterectomy; TPN , total parenteral nutrition; VATs , video-assisted thoracic surgery; V-V ECMO , venovenous extracorporeal membrane oxygenation. Wang-Koehler. Lymphangioleiomyomatosis in pregnancy. Am J Obstet Gynecol Glob Rep 2024. Case reports of LAM and pregnancy AML , angiomyolipoma; ARDS , acute respiratory distress syndrome; BSO , bilateral salpingo-oophorectomy; CD , cesarean delivery; GA , gestational age; GnRH , gonadotropin-releasing hormone; HELLP , hemolysis, elevated liver enzymes, low platelet count; HTN , hypertension; ICU , intensive care unit; ITP , immune thrombocytopenic purpura; IVIG , intravenous immune globulin; LAM , lymphangioleiomyomatosis; N/A , not applicable; TAH , total abdominal hysterectomy; TPN , total parenteral nutrition; VATs , video-assisted thoracic surgery; V-V ECMO , venovenous extracorporeal membrane oxygenation. In terms of delivery, nearly 83% (20/24) of patients delivered by cesarean delivery. Among those whose cesarean delivery indication was reported, 8 were planned or elective cesarean deliveries in anticipation of poor outcomes related to LAM, 5 were for an obstetrical indication (preeclampsia, FGR, placenta previa, failure to progress in labor), and 4 were unplanned in response to a LAM complication, such as pneumothorax or worsening dyspnea. Of the 2 reported vaginal deliveries, neither developed a pneumothorax during labor. The median gestational age at delivery was 35.5 weeks and half delivered in the preterm period. Fetal outcomes were not reported in many cases, but the majority of those reported were healthy; 1 was a fetal demise at 9 months, 1 was an abortion because of worsening maternal clinical status at 20 weeks’ gestation, and 1 was a neonatal death because of prematurity at 25 weeks’ gestation. A total of 5 studies were included in the literature review with results mirroring the case reports ( Table 2 26 , 27 , 28 , 29 , 30 ). Two survey studies 26 , 28 demonstrated that more women diagnosed with LAM before or during pregnancy either avoided pregnancy or had an abortion because of concern for LAM complications. Per patient report, these same 2 studies demonstrated higher rates of miscarriages, including those on sirolimus, 26 , 29 although 1 additional study of patients with tuberous sclerosis did not demonstrate this. 28 Studies demonstrated that those diagnosed with LAM during pregnancy were at higher risk for maternal respiratory or renal complications 26 , 29 and that the incidence of complications was also higher during pregnancy than at other times. 27 , 30 Of those who reported delivery outcomes, the majority were cesarean deliveries with an increased incidence of premature births, although it was unclear if these were iatrogenic. Table 2 Summary of studies on LAM and pregnancy Table 2 Authors Type of study Population Outcomes Main results Cohen et al, 26 2009 Survey questionnaire 328 women with LAM Pregnancy outcomes, pulmonary function, subjective and psychological functioning, quality of life, dyspnea and fatigue Pregnancy outcomes 37.3% of women had never been pregnant; 55% of women without children avoided pregnancy because of concern about impact of pregnancy on LAM; 3% worried about TSC and passing it onto child; 8.2% were unable to have children despite trying. 178/346 (51%) of women were diagnosed with LAM more than a year after completing their pregnancies, 15 women (4.5%) were diagnosed with LAM during a pregnancy, and 12 (3.6%) women had 15 pregnancies after they were diagnosed with LAM. Patients diagnosed with LAM during pregnancy had significantly more premature births and miscarriages (53%) than those diagnosed before pregnancy (20%) or after (15%). More women with an existing or emerging diagnosis of LAM during pregnancy had their pregnancies terminated (17%) than women diagnosed after pregnancy (7%). LAM complications 66.7% of those diagnosed during pregnancy experienced a pneumothorax vs 26% of those diagnosed before or 5.2% of those diagnosed after pregnancy. This was similar for breathlessness (66.7% vs 6.7% vs 7.2%, respectively). There was no difference in subjective and psychological functioning, quality of life, fatigue, or dyspnea among women diagnosed before, during, or after pregnancy. Johnson and Tattersfield, 27 2000 Chart review 50 women with LAM without TSC within a 5-y period Disease duration, incidence of complications (pneumothoraces, chylous effusions, related thoracic surgical procedures), type of treatment, lung function 28/50 (56%) patients had been pregnant; 7 (25%) were diagnosed with LAM before or during pregnancy or the postpartum period. Pregnancy outcomes 4/7 (57%) pregnancies were delivered by cesarean delivery, 1 of which was preterm. LAM complications Of these, 5 (71%) had complications; 2 developed chylous pleural effusions and 3 had 1 or more pneumothoraces. Three required lung surgery during pregnancy. Incidence of complications was 11 times higher during pregnancy than at other times (CI, 5.3–25.0; P <.001). Mitchell et al, 28 2003 Survey questionnaire 145 women with tuberous sclerosis complex Renal involvement (cysts, AML on imaging) and complications (hypertension, hemorrhage, pain, rupture, renal failure, treatments). Pulmonary involvement (cysts or LAM on imaging) and complications (pneumothorax). Pregnancy outcomes Pregnancy outcomes 81% of pregnancies were live births, 13.5% were miscarriages, 3% were abortions, 0.4% were ectopic pregnancy, 1.5% were stillbirths (1 secondary to uterine rupture in a woman with renal involvement, 1 secondary to AML rupture and severe blood loss, 1 related to malnutrition secondary to celiac disease, 1 with unknown causes). There were no maternal deaths. 89% of those who experienced pregnancy-related AML hemorrhages delivered live born infants. Renal involvement 67 women with renal involvement had at least 1 pregnancy. 57% had renal complications, majority after pregnancy. Of renal complications during pregnancy, 8 had hemorrhage 2/2 RAML. There was no significant difference in the rate of renal complications (57% vs 67%; P =.62) for pregnant and never-pregnant groups. Pulmonary involvement 22% of women with pregnancies had pulmonary involvement. 40% women experienced a pneumothorax, the majority after pregnancy. There was no significant difference in pneumothorax (40% vs 38%; P =1.00) for the pregnant and never-pregnant groups. Shen et al, 29 2021 Chart review and survey questionnaires 30 women with total of 34 pregnancies after LAM diagnosis Complications of LAM (pneumothorax, chlyothorax, AML bleeding), sirolimus usage, pregnancy outcomes Pregnancy outcomes 29% were live births, 18% were miscarriages, 53% were abortions (reasons included pneumothorax, sirolimus history, worries about LAM complications). LAM complications Complications occurred in 29.4% of patients. 20% reported worsening dyspnea, 9% pneumothorax, 6% bleeding AMLs, 0% chylothorax. Sirolimus treatment Sirolimus treatment was common (50%). 6/34 patients had livebirths after taking sirolimus; 3 discontinued prior to pregnancy and 3 were taking sirolimus at time of discovery of pregnancy, with subsequent discontinuation. Taveira-DaSilva et al, 30 2020 National observational cohort study 16 women with LAM and pre- and postpregnancy data Lung function and CT scans before and after pregnancy Pregnancy outcomes 25% were vaginal and 75% were cesarean deliveries. 12.5% complicated by preeclampsia. All gave birth to healthy babies. LAM complications 31% developed pneumothorax during pregnancy. Pregnancy was associated with a decrease in lung function, and cyst severity scores on imaging increased for all cases after pregnancy. This was two-fold greater than non-pregnant women with LAM. AML , angiomyolipoma; CI , confidence interval; CT , computed tomography; LAM , lymphangioleiomyomatosis; RAML , renal angiomyolipoma; TSC , tuberous sclerosis. Wang-Koehler. Lymphangioleiomyomatosis in pregnancy. Am J Obstet Gynecol Glob Rep 2024. Summary of studies on LAM and pregnancy AML , angiomyolipoma; CI , confidence interval; CT , computed tomography; LAM , lymphangioleiomyomatosis; RAML , renal angiomyolipoma; TSC , tuberous sclerosis.

LAM primarily affects younger adult women with an average age at onset of around 35 years, and it is known that estrogen plays a key role in driving LAM cell proliferation. Pregnancy itself can exacerbate LAM symptoms as evidenced by this literature review. Patients with LAM diagnosed before and during pregnancy have a greater risk of LAM-associated complications during pregnancy, including a pneumothorax, chylous effusion, exacerbation of dyspnea, and spontaneous bleeding of renal angiomyolipomas. As with the patient in this case report, these complications can contribute to severe maternal morbidity, prolonged hospitalizations, and multiple interventions with long-term consequences on health. Our patient's LAM was completely asymptomatic and unknown before pregnancy but rapidly became clinically significant and contributed to the complications that occurred during pregnancy and the postpartum period. Although her recurrent pneumothoraces were directly related to LAM, the reason behind her bowel perforation remains unclear. Bowel perforation is an extremely rare event during pregnancy of which there are only a few case reports. Mechanisms of injury that have been described include endometriosis, bowel obstruction, peritonitis, stercoral perforation, and inflammatory bowel disease. 31 Although several case reports have demonstrated an association between chylous ascites and intestinal obstruction or perforation, this is the first case report of bowel perforation in the context of LAM and specifically during pregnancy. 32 , 33 It is unclear whether LAM diagnosed during pregnancy inherently presents as a more aggressive disease or why pregnancy triggers a LAM flare up in some but not others. AMLs may also be at greater risk for rupture during pregnancy and should be serially monitored with imaging. In nonpregnant patients, the current guidelines recommend embolization if the AML size exceeds 4 to 8 cm. 34 However, the optimal threshold for intervention during pregnancy remains uncertain. This review also demonstrates the impact of a LAM diagnosis on obstetrical outcomes, with specific emphasis on the high cesarean delivery and preterm birth rate. Although many of these cesarean deliveries were in response to an obstetrical indication or worsening maternal clinical status, a sizable proportion were also elective given the risk of LAM-associated complications. Overall, the fetal outcomes were favorable despite an increased incidence of prematurity. Still, this highlights the combined medical and obstetrical morbidity rate associated with LAM during pregnancy. The diagnosis of LAM has several implications for patient counseling and treatment related to pregnancy. Female patients with LAM are often advised to avoid pregnancy given the risks for worsening symptoms, pneumothorax, and preterm birth. Successful pregnancy management requires multidisciplinary collaboration among specialists in maternal-fetal medicine, pulmonology, anesthesia, and possibly nephrology, neurology, and cardiology, depending on the associated symptoms. Pregnant patients with LAM are typically recommended to obtain pulmonary function tests every 3 months. In addition, if there are signs of hereditary tuberous sclerosis, such as personal or family history of characteristic skin lesions, seizures, or intellectual disability, additional counseling about genetic testing for the patient and the fetus should be provided. There is no consensus about the optimal mode of delivery in patients with LAM. However, given an increased risk for pneumothorax with increased intrathoracic pressure during labor, epidural analgesia with a low threshold to perform an operative vaginal delivery may be advisable, even if the patient has already undergone pleurodesis for a previous pneumothorax because of the risk for recurrence. 35 An elective cesarean delivery is also an option, and, from this review, it seems that many opt for this route, possibly because of the extent of the risk that patients or physicians are willing to undertake with labor. In terms of long-term treatment, sirolimus, an mTOR inhibitor that is typically used to prevent kidney transplant rejection, has been found to be a beneficial therapy to stabilize lung function and improve quality of life in LAM patients. However, safety data on sirolimus in pregnancy and lactation are limited. Current recommendations from the drug manufacturer are to discontinue sirolimus 12 weeks before pregnancy; however, 1 study found no congenital anomalies after brief exposure during pregnancy, 29 and there is 1 known case report of sirolimus that was continued throughout pregnancy without complication. 10 Given its immunosuppressant effects and impact on wound healing, sirolimus is usually withheld in the setting of severe infection and before surgeries, such as cesarean delivery. Currently, outside of pregnancy, it is only recommended for patients with LAM who have more advanced or rapidly declining lung disease or those with active chylous effusions. Its potential for benefit in the setting of prevention and/or treatment of LAM flare ups in pregnancy is unknown. Patients should also be counseled to avoid estrogen-containing contraceptives. In the past, medroxyprogesterone was administered to reduce circulating estrogen levels; however, there are no studies supporting that progesterone improves pulmonary function or the natural history of LAM disease progression. 36 Postmenopausal women should avoid hormone replacement therapy. In summary, our patient initially presented in the third trimester of pregnancy with acute chest pain, which was found to be secondary to a pneumothorax, and the ultimate cause was determined to be LAM. A spontaneous pneumothorax itself in pregnant women is rare and should be investigated with a broad differential diagnosis, including LAM. 37 This patient's overall clinical course was impacted by multiple complicating factors, including recurrent pneumothorax, severe preeclampsia, atrial fibrillation, pulmonary embolism, and bowel dilation and perforation. Although all these complications may not be directly related to LAM, it is clear that the acute diagnosis of LAM played a significant causative role in this previously healthy patient's severe maternal morbidity and preterm birth. From the literature review it is clear that this case outcome is not uncommon; many women diagnosed with LAM during pregnancy will experience some sort of prolonged hospitalization and morbidity. Of course, this review is limited by case report selection bias, which may skew toward more morbid clinical courses. Still, these outcomes align with registry and survey studies on pregnancy and LAM. Thus, for patients with a clinical suspicion of a new diagnosis of LAM in pregnancy, prompt recognition, diagnosis, and referral to appropriate multidisciplinary subspecialists is critical to mitigate complications and optimize outcomes, both during and after pregnancy.

A systematic literature review was conducted using OVID, Scopus, Embase, and PubMed databases with the aid of Covidence software. Studies and case reports were identified using the Medical Subject Headings search terms “pregnancy” or “pregnan*” and “lymphangioleiomyomatosis” from the inception of the database through October 2022. The search was limited to English language articles only. Studies were included if they described a diagnosis of pulmonary lymphangioleiomyomatosis and its relationship with clinical or obstetrical outcomes within the context of pregnancy or the immediate postpartum period. A total of 217 studies were imported for screening, and 102 duplicates were removed. A total of 57 full-text studies were then assessed for eligibility of which 28 were excluded ( Figure 3 ). Ultimately, 29 studies were included in this review and the relevant data were abstracted with a particular focus on obstetrical outcomes and medical complications during pregnancy. Figure 3 PRISMA flow diagram LAM , lymphangeioleiomyomatosis; PRISMA , Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Figure 3 Wang-Koehler. Lymphangioleiomyomatosis in pregnancy. Am J Obstet Gynecol Glob Rep 2024. PRISMA flow diagram LAM , lymphangeioleiomyomatosis; PRISMA , Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease characterized by the proliferation of smooth muscle cells in the lungs. It is associated with a mutation in the tuberous sclerosis gene (TSC2) and inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth. LAM can be isolated and sporadic or associated with tuberous sclerosis, which is an autosomal dominant genetic disorder involving seizures, cognitive impairment, and tumors, especially in the brain. LAM is characterized by proliferation of smooth muscle cells in the lungs, leading to characteristic thin-walled cysts, or blebs, and causing an obstructive pattern of lung disease. It can also affect other organ systems, including the kidneys and lymphatics. 1 Renal angiomyolipomas (AMLs), which are benign tumors containing smooth muscle, blood vessels, and adipose tissue, are found in up to 30% of patients with sporadic LAM and may cause acute bleeding. Other manifestations include chylous effusions and lymphadenopathy. Diagnosis of LAM is primarily based on radiology findings, although lung biopsy is the gold standard. Elevated vascular endothelial growth factor D (VEGF-D) levels, secreted by LAM cells in the lung, can also support the diagnosis. 2 LAM primarily affects premenopausal females, and estrogen plays a significant role in its pathogenesis. 1 Pregnancy and the use of estrogen-containing contraceptives can exacerbate the symptoms of patients with LAM. We report a case of LAM that presented as an acute, spontaneous pneumothorax in the third trimester of pregnancy and that was followed by significant peri-delivery maternal morbidity. Informed consent for publication of this case report was obtained from the patient. We also conducted a systematic literature review on LAM during pregnancy with specific focus on maternal morbidity, clinical course, and obstetrical outcomes that ultimately encompassed 24 case reports and 5 observational studies.