Effective Sirolimus Use in Prenatal and Postnatal Management of Symptomatic Extensive Congenital Capillary-Lymphatic-Venous Malformations (CLVMs): A Report of Two Cases

Abstract

Introduction

Congenital capillary-lymphatic-venous malformations (CLVMs) often result in life-threatening complications, which may begin in utero. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been successfully used in children and adults with CLVMs due to its antiproliferative and antiangiogenic properties. However, only two cases of prenatal sirolimus treatment of fetal CLVMs have been published to date, with very limited data on optimal therapeutic scheme and drug dosing.

Case Reports

Here we report two cases of effective prenatal and postnatal sirolimus treatment of extensive, complicated fetal CLVMs. The CLVMs were diagnosed prenatally by ultrasound and confirmed by magnetic resonance. The pregnancies were complicated with intralesional bleeding in both cases and polyhydramnios in one. The pregnant women received oral sirolimus from the 32nd and 33rd weeks of gestation to delivery (for 11 and 31 days, respectively). The dose of oral sirolimus for the pregnant women ranged from 2 to 6 mg/day, with a target trough whole-blood level of 7–12 ng/mL, which resulted in the umbilical cord arterial blood levels of 3.8 and 6.4 ng/mL, respectively. Therapeutic effects of prenatal sirolimus were observed in both fetuses: one experienced reduced intralesional bleeding, while the other had a significant decrease in CLVM size. The sirolimus treatment has been continued postnatally in both children, currently aged 20 and 9 months. The mothers and children experienced no adverse events from the treatment.

Conclusions

Administration of sirolimus during pregnancy with maternal blood drug-level monitoring seems to be an efficient and safe treatment option that should be considered in high-risk fetal CLVMs.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40272-025-00708-3.

Key Points

These two case reports confirm that sirolimus administered orally to the pregnant woman transfers from the maternal to the fetal circulation and may be used in the treatment of extensive, complicated fetal CLVMs in utero.

Prenatal sirolimus treatment may improve the prognosis for fetuses with complicated CLVMs causing fetal distress, such as bleeding and anemia, and seems to be safe both for the pregnant woman and the fetus.

On the basis of our findings, we consider that maternal trough sirolimus levels from 7 to 12 ng/mL may be sufficient to achieve therapeutic sirolimus levels in the fetal circulation.

Introduction

Capillary-lymphatic-venous malformations (CLVMs) are complex vascular anomalies that may develop in isolation or within the PIK3CA-related overgrowth spectrum (PROS) [1–6]. The majority of cases that have been sequenced are found to harbor a somatic PIK3CA-activating pathogenic variant, associated with hyperactivation of PI3K signaling pathway. Multiple downstream effectors, including AKT and mammalian target of rapamycin (mTOR), result in overgrowth of various tissues and disorganized vasculogenesis, leading to the development of vascular malformations [7]. The phenotype of CLVMs depends on their anatomical location, the proportions of involved vessel types, and the timing of developmental arrest. The CLVMs almost never undergo spontaneous involution, and their clinical course in utero may be dynamic and unpredictable [8]. If the fast growth of the lesion causes compression or dislocation of the crucial structures or organs, the CLVMs may be life-threatening both in utero, during delivery, and after the child’s birth [9]. Detected postnatally, the CLVMs often require individualized multidisciplinary management, including repeated procedures of aspirations, injections of sclerotherapy agents, surgical excisions, and off-label systemic treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (sirolimus), or PIK3CA inhibitors. Nevertheless, patients with CLVMs often experience a reduced quality of life due to chronic pain, physical disfigurement, and functional, emotional, and social limitations [10].

Management of CLVMs diagnosed prenatally is even more complex, especially because no treatment algorithms and recommendations exist [11]. In lesions that are not life- or function-threatening, active surveillance is usually pursued until delivery. If necessary, the pregnant woman is prepared for an elective caesarean section (CS) with or without an ex utero intrapartum treatment (EXIT) [12, 13]. However, extensive, fast growing, or unfavorably located CLVMs may compromise fetal vital functions and/or lead to delivery complications due to mass effect, polyhydramnios, or intralesional bleeding, causing fetus’ anemia, which, in severe cases, may result in intrauterine fetal demise. When parents wish to continue pregnancy, the prenatal management may include local treatments (e.g., thoraco-amniotic shunt or thoracentesis in case of chylothorax). However, these invasive procedures carry potential risks for both the mother and the fetus, including premature delivery, traumatic hemothorax, and procedure-associated fetal death. Another treatment option is pharmacological therapies, such as mTOR inhibition, which may decrease the volume of fetal CLVM through a noninvasive approach, potentially minimizing the need for intrauterine interventions and postnatal surgeries [14–18].

Sirolimus (rapamycin) is an mTOR inhibitor, registered as an immunosuppressant to prevent organ transplant rejection. Owing to its antiproliferative and antiangiogenic properties, it has been successfully used as an off-label systemic therapy of extensive vascular anomalies, including CLVMs [10, 19, 20]. It has been hypothesized that earlier sirolimus administration more effectively reduces the vascular anomaly’s size and its complications [16, 21]. However, sirolimus has a “C” category in a US Food and Drug Administration (FDA) classification of drugs used during pregnancy. In rat studies, increased mortality and decreased fetal body weight were stated (with concomitant delay of skeleton ossification) [22]. In literature, there are several reports on pregnant women treated with sirolimus to avoid solid organ transplant rejection due to maternal vascular malformation. Despite potential antiproliferative and antiangiogenic actions of sirolimus, no significant adverse effects were observed in fetuses and newborns of treated women, apart from modest hypotrophy and increased risk of premature birth [23, 24].

Only two literature reports on fetal vascular malformations treated with sirolimus in utero have been published worldwide. Both involved cranio-cervical area and posed significant risk to the babies; thus, prenatal introduction of sirolimus was decided to decrease the fetal CLVM’s volume and extent and reduce fetal distress and delivery complications [15, 16].

Here we report the first two Polish cases of effective prenatal sirolimus treatment of fetal CLVMs. In both, the consent of the Independent Bioethics Committee of the Medical University of Gdansk and informed written consent from the mothers were obtained before starting the off-label sirolimus therapy. The total sirolimus whole-blood levels in pregnant mothers, umbilical blood (arterial), and the neonates have been monitored using chemiluminescent microparticle immunoassay (CMIA). On the basis of literature data, the maternal target sirolimus whole-blood level was 7–12 ng/mL, to achieve fetal sirolimus blood level of 4–7 ng/mL. Adverse effects for both pregnant women and fetuses have been regularly checked and investigated during the treatment, including maternal oral mucositis and hyperlipidemia, infections, and any other conditions that could have been related to the drug exposure.

Case Descriptions

Case 1

A 42-year-old female in her first pregnancy was referred to the University Clinical Center in Gdansk, Poland, at the 32nd week of gestation (WOG) due to giant fetal CLVM. The CLVM was detected on prenatal ultrasound at the 20th WOG and confirmed at the 30th WOG on a fetal magnetic resonance imaging (MRI), which involved the abdominal cavity, pelvis, both buttocks, and entire left lower limb (Fig. 1). During the pregnancy, an increasing polyhydramnios and cervical shortening were observed, being a significant risk factor for preterm delivery. Therefore, a course of prenatal steroids and indomethacin was administered. In the 32nd WOG, an ultrasound examination detected an intense bleeding to the CLVM cysts causing the fetus’s hemodynamic compromise, manifested by increased peak systolic flow (up to 77 cm/s, 1.7 times the median) in the middle cerebral artery (MCA). These findings suggested moderate fetal anemia and prompted the decision to treat the fetal CLVM with sirolimus administered orally to the pregnant woman. No significant drug–drug interactions were expected—at that time, the pregnant woman was treated only with levothyroxine (225 µg/day) due to hypothyroidism in the course of Hashimoto’s thyroiditis.

Fig. 1.

Patient 1. a A true fast imaging with steady-state free precession (TRUFI) image in the sagittal plane showing fetal left lower limb (from thigh to foot) with a large vascular malformation causing limb enlargement with no bone destruction. Lesion is cystic, with numerous septa and inhomogeneous signal intensity due to the presence of blood metabolites; b a half-Fourier acquisition single-shot turbo spin-echo (HASTE) image in the transverse plane through fetal abdomen and partially lower limb demonstrating the vascular malformation compressing and shifting abdominal and pelvic organs (here urinary bladder) and vascular structures (aorta). Malformation crosses body spaces—from abdomen through pelvis, groin, and buttocks (not shown) to the left lower limb

Sirolimus was started at a dose of 1 mg twice daily, given orally in tablets during fat-containing meals (Supplementary Table 1). After 6 days, the maternal trough whole-blood level of 3.8 ng/mL was achieved, which prompted to increase the dose of sirolimus to 2 mg twice daily since the 33rd WOG. Owing to the high-risk pregnancy, the pregnant mother was hospitalized until delivery. The sirolimus level in the mother’s blood at delivery was 6.4 ng/mL, in the umbilical cord arterial blood it was 3.8 ng/mL (59% of maternal level), and in the newborn’s blood it was 4.2 ng/mL. MCA peak systolic flow significantly decreased after 2 days of sirolimus treatment, suggesting immediately reduced bleeding to the CLVM. The neonate was born via CS at the 35th WOG due to spontaneous premature delivery, in good general condition (APGAR 8→9; weight 3390 g). The hemoglobin level was 16.2 g/dL. Postnatally, a clinical suspicion of a PIK3CA-related overgrowth spectrum (PROS; Klippel–Trenaunay Syndrome) was raised. However, the molecular examination to confirm the presence of PIK3CA pathogenic variant in affected tissues of the left thigh was performed twice and was negative. Extended molecular analyses toward pathogenic variants in other overgrowth-associated variants are planned. Sirolimus has been continued in the child postnatally, which started with an oral dose of 0.25 mg/m² (0.025 mg) twice daily, according to the pharmacokinetics data for newborns [25] (Supplementary Table 2). In the 3rd day of life, the trough whole-blood level of sirolimus was as high as 19 ng/mL, so the dosage was decreased to 0.2 mg/m² twice daily. Within the 1st month of life, the dosage of sirolimus was decreased multiple times to finally achieve desirable trough blood levels of sirolimus of 4–7 ng/mL, with a dose of 0.1 mg/m² once daily in the 2nd month of life. After the 8th week of life, the drug was resumed at a dosing interval of every 12 h.

During the postnatal treatment with sirolimus, further significant reduction of the CLVM’s size within the abdomen, the pelvis, and the left lower limb was confirmed clinically and by MRI. However, ulceration and bleeding from the areas of the skin capillary malformation located on the lateral thigh surface recurred, with no improvement after conservative local treatment, including compression and specialized dressings. Therefore, a partial resection of the CLVM, embryonic lateral vein, and hypertrophic soft tissues of the left lower limb was performed at the age of 6 months. The surgery was complicated by necrosis of the wound edges and their separation, requiring a negative pressure dressing and secondary suturing of the wound.

The patient is currently 20 months old and continues sirolimus therapy with positive therapeutic effect (Fig. 2). No significant adverse events occurred in the mother and the child during sirolimus therapy.

Fig. 2.

Patient 1. Clinical improvement in the asymmetry of the lower limbs and skin capillary malformations at the age of 1 month (left) and 15 months (right). The patient continuously received sirolimus treatment. Owing to the repeated ulceration and bleeding from the area of capillary malformation on the lateral thigh, a partial resection of the CLVM, embryonic lateral vein, and hypertrophic soft tissues of the left lower limb was performed at the age of 6 months

Case 2

A 35-year-old female in her third pregnancy was referred to the University Clinical Center in Gdansk, Poland, at the 33rd WOG due to the giant fetal CLVM, located within the soft tissues of the chest and abdominal wall. It was first detected during prenatal screening ultrasound performed in the 13th WOG and initially was suspected to be a lipoma. In the 25th WOG, a rapid growth of the lesion was observed. The mass was echogenically heterogenous, with fluid spaces containing elements corresponding to thrombi (Fig. 3). The flow spectrum of the MCA was normal, and no signs of fetal anemia were observed. The growth profile of the fetus and amniotic fluid volume were normal. At the 27th WOG, a fetal MRI was performed, in which the lesion was described as CLVM, measuring 105 mm × 46 mm × 87 mm and involving mainly the chest and abdominal wall on the left side, with a smaller fraction penetrating inside the chest (Fig. 4). An extensive thrombus in one of the malformation cysts was described, indicating past bleeding to the lesion (partially visible in Fig. 4 as hypointense structures within the fluid). Subsequent ultrasound examinations performed in the 30th and 31st WOG showed significant growth of the CLMV. Owing to the huge size of the lesion and the risk of chest structure compression and of further bleeding, oral sirolimus was offered to the pregnant mother to treat the fetus. No significant drug–drug interactions were expected—at that time, the pregnant woman was treated only with acetylsalicylic acid (150 mg/day) owing to previous miscarriage and with levothyroxine (25 µg/day) owing to hypothyroidism.

Fig. 3.

Patient 2. a An ultrasound image of the CLMV at the 25th week of gestation showing the lesion measuring 94 mm × 53 mm in the long axis. Visible heterogeneous echogenicity of the lesion, with masses corresponding to clots; b an ultrasound image of the CLMV at the 35th week of gestation (2 weeks after the start of sirolimus treatment) showing the lesion measuring 110 mm × 48 mm in the long axis. A significant change in the echogenicity of the lesion can be seen compared with the study at the 25th week of pregnancy

Fig. 4.

Patient 2. a A TRUFI image in the transverse plane showing fetal chest with an extensive vascular malformation with no bone destruction. The mass is multiloculated and inhomogeneous, containing septa and blood clots. Malformation crosses body spaces and is visible in the body wall bilaterally (here shown only on the left) and in the pleural space; b a HASTE image in the coronal plane through fetal abdomen and chest in the longest dimension of the vascular malformation showing its intrathoracic extension next to the heart apex

On the basis of the experience gained from Case 1, sirolimus was administered orally in tablets at a dose of 2 mg twice daily (Supplementary Table 3). This dose resulted in a maternal trough whole-blood sirolimus level of 5.4 ng/mL after 3 days, so the dose was increased to 3 mg twice daily, aiming at a target maternal sirolimus blood level of 7–12 ng/mL. The treatment was started in the hospital, and due to the good tolerance and stable condition of the pregnant woman, it was continued in the ambulatory setting. Repeated fetal ultrasounds showed an evident reduction of the CLMV’s size to 87 mm × 25 mm × 30 mm at the 37th WOG (images not available, images from 35th WOG are shown in Fig. 3). The child was born via CS at the 38th WOG, as spontaneous delivery occurred, in good general condition (APGAR 9→10; weight 3440 g; Fig. 5). The sirolimus level in the mother’s whole-blood at delivery was 27.3 ng/mL (the blood was sampled 4 h after a dose), and in umbilical cord arterial blood it was 6.4 ng/mL (23.4% of the maternal level). The sirolimus level in the newborn’s blood was not measured. Postnatally, a clinical suspicion of PROS was raised. The molecular tests to confirm the presence of the PIK3CA pathogenic variant in the affected tissues are planned. Sirolimus has been continued in the child postnatally at an initial oral dose of 0.05 mg once daily, which corresponded to 0.45 mg/m² once daily and produced the blood sirolimus level of 5–8 ng/mL (Supplementary Table 4). The patient is currently 9 months old and continues sirolimus therapy with a good therapeutic effect visible clinically and radiologically. However, on the MRI performed in the 2nd month of life, a fraction of the malformation in the abdominal cavity was visualized, which was not visible in the prenatal MRI (assessed retrospectively).

Fig. 5.

Patient 2. Extensive capillary-lymphatic-venous malformation (CLVM) involving the left upper torso and flank at birth. Prenatal sirolimus treatment was initiated at 33 weeks of gestation and continued postnatally

During the follow-up, the child experienced one episode of bleeding to the malformation cyst, requiring surgical intervention (percutaneous drainage with doxycycline sclerotherapy). No other significant adverse events occurred in the mother and the child during sirolimus therapy.

Discussion

Here we report two cases of successful prenatal treatment with sirolimus of huge fetal CLMVs, being not only the first of such cases in Poland but also two of the very few described in literature worldwide. Sirolimus was administered orally to the pregnant women and then continued in the newborns postnatally.

Prenatal diagnosis of extensive vascular malformation is rare and poses a challenge for perinatologists owing to the lack of guidelines for optimal management. The decision to introduce the off-label sirolimus therapy during pregnancy is difficult, since published data on its efficacy in utero and safety for the pregnant mother and the fetus are scarce. To date, only two cases of prenatal use of sirolimus aimed at treating fetal head and neck vascular malformations have been reported. Oral sirolimus was administered to the mothers at the 30th + 4 WOG and 22nd WOG and produced the decrease of the growth rate of malformations and the normalization of polyhydramnios in both cases. No significant adverse effects were noted in fetuses and pregnant women [15, 16]. There are also literature reports on prenatal use of mTOR inhibitors (sirolimus and everolimus) for prenatally diagnosed rhabdomyoma of the heart in nine patients with tuberous sclerosis. In these cases, the sirolimus was started between the 23rd and the 36th WOGs and, despite various treatment schemes and different trough levels in maternal blood, all resulted in the desirable reduction of the tumors’ sizes. No severe adverse effects were reported [26]. On the basis of these literature data, it might be suggested that prenatal use of sirolimus (especially in the second half of pregnancy) for the treatment of fetal CLVM can be considered beneficial to the fetus and seems to be safe for the pregnant woman and the child. However, the number of reported cases is limited, and potential side effects could become apparent in a larger cohort of patients.

In our two cases, starting oral sirolimus in pregnant mothers was decided to stop intense intralesional bleeding, leading to fetal anemia in the first fetus, and to break the rapid increase of the extensive fetal CLMVs’ volume in the second. Although the localization of the CLMVs did not indicate the direct life-threatening compression of vital organs or structures, the multidisciplinary team concluded that delayed introduction of sirolimus after the children’s birth could result in increased risk of severe fetal distress, need for intrauterine blood transfusions, and complicated delivery. In addition, waiting to implement the systemic treatment of large and growing CLVMs until delivery might result in worse response to sirolimus. It is not possible to compare the results of prenatal and postnatal sirolimus treatment owing to the small number of cases, but it has been hypothesized that the earlier the therapy is introduced, the more favorable the effect achieved [16]. Both mothers have been informed explicitly and fully aware about the experimental nature of the therapy proposed to them and their babies, its anticipated benefits, and potential risks. They were also given alternative management options (e.g., surveillance until delivery).

We decided to aim at a fetal sirolimus level of 4–7 ng/mL since, in the postnatal therapy of CLMVs, such levels have been found to be as effective as the previously recommended levels of 7–12 ng/mL, while being safer [27–30]. On the basis of the limited reports on fetuses with rhabdomyomas treated in utero with sirolimus, it was assumed that the cord blood drug level at delivery constitutes approximately 100–160% of the maternal sirolimus level [26, 31–33]. However, Seront et al. found that transplacental crossing of sirolimus may be as low as 30%, on the basis of the results of repeated cordocentesis in a mother of a child with cranio-facial lymphatic malformation [16]. Therefore, we tried to maintain the maternal sirolimus trough levels of 8–12 ng/mL, to achieve therapeutic sirolimus levels of 4–7 ng/mL in the fetal circulation while not increasing toxicities for the pregnant women. The maternal dosing of sirolimus of 4–6 mg/day produced the assumed therapeutic sirolimus levels in the umbilical cord blood and newborn’s blood (the latter measured only in patient 1), even though in the first pregnant woman, we did not achieve the target maternal sirolimus blood level. The drug penetration to the fetal circulation seemed to differ between patients—the umbilical cord arterial blood level constituted approximately 59 and 23% of maternal drug level in Case 1 and 2, respectively. The unusually high drug level before delivery in the mother of patient 2 (27.3 ng/mL) could, however, result from obtaining the sample not before the drug dose (when its concentration in the blood is the lowest) but 4 h after the last dose administered, due to unplanned delivery.

In both of our patients, we observed evident therapeutic effects of prenatal sirolimus treatment. In patient 1, an immediate decrease in MCA peak systolic flow was observed, indicating a reduction in bleeding, which was causing anemia and fetal distress. However, this finding should be interpreted with caution, as the initiation of sirolimus alone is unlikely to have caused such a rapid increase in hemoglobin levels. Other mechanisms may have contributed to this phenomenon, such as a “tamponade effect,” in which the cyst, filled with blood, blocks further bleeding.

In patient 2, repeated prenatal ultrasound examinations showed a significant decrease in the size of the CLVM, which was even more evident in relation to the simultaneous growth of the fetus. Unexpectedly, in this patient, a postnatal MRI showed a new CLMV fraction in the abdominal cavity, which was not visible on the MRI in the 27th WOG. As the prenatal MRI was performed 6 weeks before the introduction of sirolimus in the 33rd WOG, we hypothesize that the abdominal fraction might have developed before the start of the treatment.

In both of our cases, the tolerance of the sirolimus treatment by the mothers and fetuses was very good, and no adverse effects were reported, including maternal oral mucositis or infections. In Case 2, this allowed for the provision of the treatment in an ambulatory setting, after a 7-day-long initial inpatient observation.

Limitations

This study had several limitations. Firstly, it included a very small series of patients, which limits generalization of our findings. Moreover, as patient 2 was born unplanned in another obstetrics institution, not all relevant information (such as the sirolimus level in the newborn’s blood) was collected. We also did not measure the albumin levels in the pregnant women, which, as sirolimus is a highly protein-bound compound, could have been utilized to better understand the placental transfer of sirolimus to the fetal circulation. Thus, further preclinical and clinical research is needed to understand how sirolimus levels in the maternal and fetal circulations vary throughout pregnancy. A physiologically based pharmacokinetic (PBPK) model could be used in predicting fetal exposure and minimizing toxicity [34]. Further research, including multicenter collaboration and clinical trials, is needed to better explore the safety and efficacy of sirolimus in pregnancy and to develop recommendations on the management of fetal CLVMs. Comparison of prenatal and postnatal sirolimus initiation could be considered; however, interpreting results of such a study would be difficult owing to extreme heterogeneity of vascular anomalies, including their size, location, and vessels of origin, all possibly affecting the outcome.

Conclusions

Administration of sirolimus during pregnancy with regular maternal blood drug-level monitoring seems to be an effective and relatively safe treatment option that should be considered in high-risk fetal CLVMs. Interdisciplinary cooperation between pediatric oncology, radiology, neonatology, gynecology, obstetrics, and surgery units is crucial for optimal realization of this unprecedented perinatal treatment.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

No external funding was received for conducting this study.

Conflict of interest

Anna Klosowska, Malgorzata Styczewska, Malgorzata A. Krawczyk, Lena Gluszkiewicz, Przemyslaw Adamski, Katarzyna Wartecka-Zielinska, Lukasz Matwiejczyk, Magda Rybak-Krzyszkowska, Daria Dziechcinska-Poletek, Anna Jankowska, Katarzyna Sinacka, Dariusz Wyrzykowski, Anna Taczanowska-Niemczuk, Anna Gabrych, Paulina Kielpinska, Natalia K. Mazur-Ejankowska, Iwona Domzalska-Popadiuk, Magdalena Emilia Grzybowska, Prof. Dariusz G. Wydra, Wojciech Gorecki, Ninela Irga-Jaworska, and Ewa Bien declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Availability of data and material

No public data other than those presented in the article are available. Additional information on the presented patients is available on request from the corresponding author.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Bioethics Committee for Scientific Research of the Medical University

of Gdansk, Poland.

Consent to participate

Both pregnant women signed an informed consent before the off-label sirolimus treatment. Additional separate informed consents were obtained from the mothers to publish the case reports, including photographs of their children.

Code availability

Not applicable.

Consent for publication

Not applicable.

Author contributions

Conceptualization—Anna Klosowska, Malgorzata Styczewska, Malgorzata A. Krawczyk, and Ewa Bien; methodology—Anna Klosowska, Malgorzata Styczewska, Malgorzata A. Krawczyk, and Ewa Bien; formal analysis and investigation—Anna Klosowska, Malgorzata Styczewska, Malgorzata A. Krawczyk, Ewa Bien, Lena Gluszkiewicz, Przemyslaw Adamski, Katarzyna Wartecka-Zielinska, Lukasz Matwiejczyk, Magda Rybak-Krzyszkowska, Daria Dziechcinska-Poletek, Anna Jankowska, Katarzyna Sinacka, Dariusz Wyrzykowski, Anna Taczanowska-Niemczuk, Anna Gabrych, Paulina Kielpinska, Natalia K. Mazur-Ejankowska, and Magdalena E. Grzybowska; writing—original draft preparation—Anna Klosowska, Malgorzata Styczewska, Malgorzata A. Krawczyk, and Ewa Bien; writing—review and editing—Lena Gluszkiewicz, Przemyslaw Adamski, Katarzyna Wartecka-Zielinska, Lukasz Matwiejczyk, Magda Rybak-Krzyszkowska, Daria Dziechcinska-Poletek, Anna Jankowska, Katarzyna Sinacka, Dariusz Wyrzykowski, Anna Taczanowska-Niemczuk, Anna Gabrych, Paulina Kielpinska, Natalia K. Mazur-Ejankowska, Magdalena E. Grzybowska, Ninela Irga-Jaworska, Iwona Domzalska-Popadiuk, Wojciech Gorecki, and Dariusz G. Wydra; resources—Przemyslaw Adamski, Katarzyna Wartecka-Zielinska, Lukasz Matwiejczyk, Magda Rybak-Krzyszkowska, Daria Dziechcinska-Poletek, Anna Jankowska, Katarzyna Sinacka, Dariusz Wyrzykowski, Anna Taczanowska-Niemczuk, Magdalena E. Grzybowska, Ewa Bien, Ninela Irga-Jaworska, Iwona Domzalska-Popadiuk, Wojciech Gorecki, and Dariusz G. Wydra; supervision—Ewa Bien, Ninela Irga-Jaworska, Iwona Domzalska-Popadiuk, Wojciech Gorecki, and Dariusz G. Wydra.