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Congenital fulminant Kaposiform hemangioendothelioma of the leg
Reproductive Toxicology 50 (2014) 1–3
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Short communication
Congenital fulminant Kaposiform hemangioendothelioma of the leg Zivanit Ergaz a,∗ , Benjamin Bar-Oz a , Gilad W. Vainer b , Sinan Abu-Leil a , Natalia Simanovsky c , Orna Diav-Citrin d a
Department of Neonatology, Hadassah Hebrew University Medical Center, Jerusalem, Israel Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Department of Medical Imaging, Hadassah Hebrew University Medical Center, Jerusalem, Israel d The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel b c
a r t i c l e
i n f o
Article history: Received 22 March 2014 Received in revised form 16 September 2014 Accepted 19 September 2014 Available online 30 September 2014 Keywords: Etanercept Kaposiform hemangioendothelioma Kasabach Merritt syndrome Congenital Multi-organ failure
a b s t r a c t Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor associated with Kasabach Merritt syndrome. We present a case of congenital Kaposiform hemangioendothelioma of the leg in a female infant who was born to a mother treated with various medications including etanercept, a TNF antagonist, due to rheumatoid arthritis. The neonate suffered from a fulminant form of Kasabach Merritt syndrome with disseminated intravascular coagulation (DIC) resulting in multi-organ failure which led to her demise. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
2. Case presentation
Kaposiform hemangioendothelioma (KH) is a rare tumor with vascular and lymphatic component. KH is associated with Kasabach Merritt Syndrome (KMS) a condition characterized by profound thrombocytopenia and life-threatening hemorrhage (DIC). Treatments include correction of the anemia and thrombocytopenia, enoxaparin, low dose salicylic acid, steroids, chemotherapy, interferon, irradiation, embolization and excision. In a review of the literature among 33 cases diagnosed at 14 days to 20 years, three died due to the disease and one from unknown reason [1]. The pathogenesis of KH is unclear. We present a case of congenital fulminant KH of the leg that was born to a mother treated with polytherapy for rheumatoid arthritis including prednisone, hydroxychloroquine and etanercept during her pregnancy. Prednisone, hydroxychloroquine [2] and enoxaparine [3] are commonly prescribed and can be safely used during pregnancy, however data concerning maternal etanercept treatment during pregnancy are limited.
A 2740 g female infant was born by cesarean section following 31 + 5 weeks of gestation. The mother, a 25 years old woman at her fourth pregnancy, was previously diagnosed with rheumatoid arthritis. Before pregnancy, she was effectively treated with methotrexate 7.5 mg/week, etanercept 25 mg injection once every 3 days, prednisone 10 mg/d and hydroxychloroquine 200 mg/day. She stopped the methotrexate 4 weeks before her last menstrual period and continued the etanercept until pregnancy validation at 7 weeks from the last menstrual period. At that point, she continued the prednisone and hydroxychloroquine. She was administered enoxaparin 120 mg/d at 3 months gestation because of varicose veins. On admission, she suffered from palpitations, dyspnea and abdominal pain. Fetal ultrasonography revealed hydrops fetalis with right leg and labial hypertrophy. A female neonate was delivered by cesarean section. The APGAR scores were 4 and 8 at 1 min and 5 min, respectively. Physical examination revealed generalized edema, ecchymosis and purpura that covered the whole body, and marked hypertrophy of the right leg and labia with purplebrownish discoloration of the skin (Fig. 1). The neonate suffered from multi-organ failure for which she needed assisted ventilation and continuous inotropic treatment. DIC was treated with recurrent red blood cells, thrombocytes and fresh frozen plasma transfusions. Later she developed hyperbilirubinemia for which she had
∗ Corresponding author at: Department of Neonatology, Hadassah-Hebrew University Hospital, Mount Scopus, Jerusalem 91240, Israel. Tel.: +972 2 5844438; fax: +972 2 5813068. E-mail address: [email protected] (Z. Ergaz). http://dx.doi.org/10.1016/j.reprotox.2014.09.011 0890-6238/© 2014 Elsevier Inc. All rights reserved.
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Z. Ergaz et al. / Reproductive Toxicology 50 (2014) 1–3
Fig. 1. The female neonate intubated at pediatric intensive care unit. This picture clearly illustrates the purple discoloration and hypertrophy of the right lower limb and labia. Note the generalized edema of the neonate. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
six blood exchanges, and coagulase negative staphylococcal sepsis for which she received antibiotic treatment. At day 5 she developed deteriorating oliguria, and became anuric at day 8. Despite intensive medical care, the infant’s condition deteriorated rapidly resulting in death on the 10th day of her life. 3. Methods and results X-ray revealed normal, symmetrical lower limbs and pelvis bony structure. Neonatal color Doppler imaging demonstrated
normal flow in the aorta, femoral arteries, inferior vena cava and left femoral vein, but no visible flow at the right femoral vein. Abdominal ultrasound examination revealed small hyperechoic kidneys, mild dilatation of the renal pelvis and blood clots in the abdominal cavity. Laboratory data showed leukocytosis (44,000/mm3 ), severe anemia (hemoglobin 4.3 gr%), thromobocytopenia (platelets 13,000/mm3 ), and hypofibrinogenemia (97 mg%) with elevated international normalized ratio (INR) up to 1.56. Recurrent abdominal ultrasonography revealed hydronephrosis without focal lesions. An autopsy showed that the immediate cause of death was severe edema with profuse bleeding in the lungs. Bilateral renal pelvis subepithelial bleeding was noted and might explain the deteriorating renal function. Histological examination of the right leg suggested the diagnosis of hemangioma associated with Kasabach–Merritt phenomenon. The vascular lesion extended from the skin, infiltrated through the muscles up to the bone, involving the thigh and shin (Fig. 2). It included spindle cells which were negative for Glut-1, positive for CD34, CD31 and podoplanin (D2-40). This aberrant immunophenotype confirms that the spindle cells express bi-lineage, vascular (CD31) and lymphatic (podoplanin) (Fig. 2D and F, respectively), markers confirming the diagnosis of Kaposiform hemangioendothelioma. 4. Discussion The fulminant course in our case was due to the deteriorating renal function that aggravated the generalized edema caused in utero by the severe anemia, and led to cardio-respiratory failure. KH has a vascular and lymphatic components that has a common origin. The homeobox gene Prox1 which is expressed in a subpopulation of endothelial cells is required for both maintenance of the budding of the venous endothelial cells and differentiation toward the lymphatic phenotype [4].
Fig. 2. Kaposiform hemangioendothelioma. (A, ×2.5 mag.) The epidermis is noted at the upper side of the micrograph. Large, abnormal, thrombosed vessels are present. Bluish areas represent highly cellular spindle cell rich foci can easily identify across the section. (B and C, ×20 and ×40 mag., respectively) One of the foci with ill-formed blood vessel lumina, extravasated red blood cells, and spindle cells. (D–F, ×20 mag.) Immunohistochemical staining shows: (D) strong CD31, (E) strong CD34 and (F) podoplanin immunoreactivity (brown staining of 3,3 -diaminobenzidine tetrahydrochloride indicate positivity). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Z. Ergaz et al. / Reproductive Toxicology 50 (2014) 1–3
The precise mechanism that lead to the blood dyscrasia differentiate the KH from juvenile hemangioma. Lyons et al. hypothesized that the small convoluted capillaries that arise directly from large vessels may cause turbulence that may lead to platelet activation and aggregation. Additionally, they assumed that the epithelioid or glomeruloid islands within the vascular nodules can cause platelet and red blood cells trapping and destruction [1]. Our case is unique because of the association of KH with maternal treatment by etanercept in the beginning of pregnancy, which was not previously reported. When anti mouse TNF-␣ monoclonal antibody was administered to pregnant mice there were no teratogenic effects [5]. Carter et al. described a neonate with VATER association born to a mother who was treated with etanercept during pregnancy [6], and reviewed the TNF antagonist use in pregnancy report to the US Food and Drug Administration. They concluded that maternal treatment with TNF antagonists posed an increased risk for VATER or VACTERL association since out of 22 reports on adverse effects of etanercept during pregnancy 60% had anomalies that are part of the VACTER association [7]. However Koren et al. pointed out numerous methodological problems in this study [8]. In contrast, human pregnancy experience with etanercept has been mostly reassuring, although based on small studies [9–11]. Etanercept is a dimeric fusion protein consisting of the extracellular ligand binding portion of the human 75 kDa (p75) TNF receptor linked to the Fc portion of human IgG1. It has a large molecular weight of approximately 149 kDa, and is, therefore, not expected to cross the human placenta in significant concentration in the first trimester of pregnancy. Placental transfer of etanercept close to term has been documented [12]. Despite maternal treatment with various medications before and during pregnancy, the etiology of the KH in her offspring remains unknown. We cannot conclude that the offspring condition was caused by any of the maternal medications, including etanercept, and the association is possibly incidental. However, the rarity of Kaposiform hemangioendothelioma combined with the uncommon in-utero presentation of the lesion, occurring in association with maternal etanercept treatment, a novel drug that is taken rarely in pregnancy, justifies continuing surveillance and close observation of pregnant women treated with anti TNF-␣ therapy. Indeed, we published a prospective comparative study on pregnancy outcome following gestational exposure to TNF-␣ inhibitors that mentioned this case briefly [13]. Our case is unique due to the in utero full blown presentation of the Kaposiform hemangioendothelioma and the associated Kasabach Merritt syndrome that led to multi-organ failure. An early
3
recognition of vascular tumors associated with Kasabach–Merritt syndrome allows prompt treatment with good prognosis in most cases. Conflict of interest The authors declare that there are no conflicts of interest. Transparency document The Transparency document associated with this article can be found in the online version. References [1] Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Folpe AL, Weiss SW. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 2004;28:559–68. [2] Zrour-Hassen S, Jguirim M, Aouam K, Korbaa W, Younes M, Bejia I, et al. Safety of rheumatic disease drugs at childbearing age. Therapie 2010;65: 465–73. [3] Singh N, Varshney P, Tripathi R, Mala YM, Tyagi S. Safety and efficacy of low molecular weight heparin therapy during pregnancy: three year experience at a tertiary care center. J Obstet Gynaecol India 2013;63:373–7. [4] Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 2002;21:1505–13. [5] Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–8. [6] Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014–7. [7] Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635–41. [8] Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans. J Rheumatol 2009;36:465–6. [9] Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–6. [10] Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers. Scand J Rheumatol 2012;41:196–201. [11] Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, Liote F, Goeb V, et al. Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 2009;76:28–34. [12] Murashima A, Watanabe N, Ozawa N, Saito H, Yamaguchi K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann Rheum Dis 2009;68:1793–4. [13] Diav-Citrin O, Otcheretianski-Volodarsky A, Shechtman S, Ornoy A. Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study. Reprod Toxicol 2014;43:78–84.
Contents lists available at ScienceDirect
Reproductive Toxicology journal homepage: www.elsevier.com/locate/reprotox
Short communication
Congenital fulminant Kaposiform hemangioendothelioma of the leg Zivanit Ergaz a,∗ , Benjamin Bar-Oz a , Gilad W. Vainer b , Sinan Abu-Leil a , Natalia Simanovsky c , Orna Diav-Citrin d a
Department of Neonatology, Hadassah Hebrew University Medical Center, Jerusalem, Israel Department of Pathology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel Department of Medical Imaging, Hadassah Hebrew University Medical Center, Jerusalem, Israel d The Israeli Teratology Information Service, Israel Ministry of Health, Jerusalem, Israel b c
a r t i c l e
i n f o
Article history: Received 22 March 2014 Received in revised form 16 September 2014 Accepted 19 September 2014 Available online 30 September 2014 Keywords: Etanercept Kaposiform hemangioendothelioma Kasabach Merritt syndrome Congenital Multi-organ failure
a b s t r a c t Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor associated with Kasabach Merritt syndrome. We present a case of congenital Kaposiform hemangioendothelioma of the leg in a female infant who was born to a mother treated with various medications including etanercept, a TNF antagonist, due to rheumatoid arthritis. The neonate suffered from a fulminant form of Kasabach Merritt syndrome with disseminated intravascular coagulation (DIC) resulting in multi-organ failure which led to her demise. © 2014 Elsevier Inc. All rights reserved.
1. Introduction
2. Case presentation
Kaposiform hemangioendothelioma (KH) is a rare tumor with vascular and lymphatic component. KH is associated with Kasabach Merritt Syndrome (KMS) a condition characterized by profound thrombocytopenia and life-threatening hemorrhage (DIC). Treatments include correction of the anemia and thrombocytopenia, enoxaparin, low dose salicylic acid, steroids, chemotherapy, interferon, irradiation, embolization and excision. In a review of the literature among 33 cases diagnosed at 14 days to 20 years, three died due to the disease and one from unknown reason [1]. The pathogenesis of KH is unclear. We present a case of congenital fulminant KH of the leg that was born to a mother treated with polytherapy for rheumatoid arthritis including prednisone, hydroxychloroquine and etanercept during her pregnancy. Prednisone, hydroxychloroquine [2] and enoxaparine [3] are commonly prescribed and can be safely used during pregnancy, however data concerning maternal etanercept treatment during pregnancy are limited.
A 2740 g female infant was born by cesarean section following 31 + 5 weeks of gestation. The mother, a 25 years old woman at her fourth pregnancy, was previously diagnosed with rheumatoid arthritis. Before pregnancy, she was effectively treated with methotrexate 7.5 mg/week, etanercept 25 mg injection once every 3 days, prednisone 10 mg/d and hydroxychloroquine 200 mg/day. She stopped the methotrexate 4 weeks before her last menstrual period and continued the etanercept until pregnancy validation at 7 weeks from the last menstrual period. At that point, she continued the prednisone and hydroxychloroquine. She was administered enoxaparin 120 mg/d at 3 months gestation because of varicose veins. On admission, she suffered from palpitations, dyspnea and abdominal pain. Fetal ultrasonography revealed hydrops fetalis with right leg and labial hypertrophy. A female neonate was delivered by cesarean section. The APGAR scores were 4 and 8 at 1 min and 5 min, respectively. Physical examination revealed generalized edema, ecchymosis and purpura that covered the whole body, and marked hypertrophy of the right leg and labia with purplebrownish discoloration of the skin (Fig. 1). The neonate suffered from multi-organ failure for which she needed assisted ventilation and continuous inotropic treatment. DIC was treated with recurrent red blood cells, thrombocytes and fresh frozen plasma transfusions. Later she developed hyperbilirubinemia for which she had
∗ Corresponding author at: Department of Neonatology, Hadassah-Hebrew University Hospital, Mount Scopus, Jerusalem 91240, Israel. Tel.: +972 2 5844438; fax: +972 2 5813068. E-mail address: [email protected] (Z. Ergaz). http://dx.doi.org/10.1016/j.reprotox.2014.09.011 0890-6238/© 2014 Elsevier Inc. All rights reserved.
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Z. Ergaz et al. / Reproductive Toxicology 50 (2014) 1–3
Fig. 1. The female neonate intubated at pediatric intensive care unit. This picture clearly illustrates the purple discoloration and hypertrophy of the right lower limb and labia. Note the generalized edema of the neonate. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
six blood exchanges, and coagulase negative staphylococcal sepsis for which she received antibiotic treatment. At day 5 she developed deteriorating oliguria, and became anuric at day 8. Despite intensive medical care, the infant’s condition deteriorated rapidly resulting in death on the 10th day of her life. 3. Methods and results X-ray revealed normal, symmetrical lower limbs and pelvis bony structure. Neonatal color Doppler imaging demonstrated
normal flow in the aorta, femoral arteries, inferior vena cava and left femoral vein, but no visible flow at the right femoral vein. Abdominal ultrasound examination revealed small hyperechoic kidneys, mild dilatation of the renal pelvis and blood clots in the abdominal cavity. Laboratory data showed leukocytosis (44,000/mm3 ), severe anemia (hemoglobin 4.3 gr%), thromobocytopenia (platelets 13,000/mm3 ), and hypofibrinogenemia (97 mg%) with elevated international normalized ratio (INR) up to 1.56. Recurrent abdominal ultrasonography revealed hydronephrosis without focal lesions. An autopsy showed that the immediate cause of death was severe edema with profuse bleeding in the lungs. Bilateral renal pelvis subepithelial bleeding was noted and might explain the deteriorating renal function. Histological examination of the right leg suggested the diagnosis of hemangioma associated with Kasabach–Merritt phenomenon. The vascular lesion extended from the skin, infiltrated through the muscles up to the bone, involving the thigh and shin (Fig. 2). It included spindle cells which were negative for Glut-1, positive for CD34, CD31 and podoplanin (D2-40). This aberrant immunophenotype confirms that the spindle cells express bi-lineage, vascular (CD31) and lymphatic (podoplanin) (Fig. 2D and F, respectively), markers confirming the diagnosis of Kaposiform hemangioendothelioma. 4. Discussion The fulminant course in our case was due to the deteriorating renal function that aggravated the generalized edema caused in utero by the severe anemia, and led to cardio-respiratory failure. KH has a vascular and lymphatic components that has a common origin. The homeobox gene Prox1 which is expressed in a subpopulation of endothelial cells is required for both maintenance of the budding of the venous endothelial cells and differentiation toward the lymphatic phenotype [4].
Fig. 2. Kaposiform hemangioendothelioma. (A, ×2.5 mag.) The epidermis is noted at the upper side of the micrograph. Large, abnormal, thrombosed vessels are present. Bluish areas represent highly cellular spindle cell rich foci can easily identify across the section. (B and C, ×20 and ×40 mag., respectively) One of the foci with ill-formed blood vessel lumina, extravasated red blood cells, and spindle cells. (D–F, ×20 mag.) Immunohistochemical staining shows: (D) strong CD31, (E) strong CD34 and (F) podoplanin immunoreactivity (brown staining of 3,3 -diaminobenzidine tetrahydrochloride indicate positivity). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Z. Ergaz et al. / Reproductive Toxicology 50 (2014) 1–3
The precise mechanism that lead to the blood dyscrasia differentiate the KH from juvenile hemangioma. Lyons et al. hypothesized that the small convoluted capillaries that arise directly from large vessels may cause turbulence that may lead to platelet activation and aggregation. Additionally, they assumed that the epithelioid or glomeruloid islands within the vascular nodules can cause platelet and red blood cells trapping and destruction [1]. Our case is unique because of the association of KH with maternal treatment by etanercept in the beginning of pregnancy, which was not previously reported. When anti mouse TNF-␣ monoclonal antibody was administered to pregnant mice there were no teratogenic effects [5]. Carter et al. described a neonate with VATER association born to a mother who was treated with etanercept during pregnancy [6], and reviewed the TNF antagonist use in pregnancy report to the US Food and Drug Administration. They concluded that maternal treatment with TNF antagonists posed an increased risk for VATER or VACTERL association since out of 22 reports on adverse effects of etanercept during pregnancy 60% had anomalies that are part of the VACTER association [7]. However Koren et al. pointed out numerous methodological problems in this study [8]. In contrast, human pregnancy experience with etanercept has been mostly reassuring, although based on small studies [9–11]. Etanercept is a dimeric fusion protein consisting of the extracellular ligand binding portion of the human 75 kDa (p75) TNF receptor linked to the Fc portion of human IgG1. It has a large molecular weight of approximately 149 kDa, and is, therefore, not expected to cross the human placenta in significant concentration in the first trimester of pregnancy. Placental transfer of etanercept close to term has been documented [12]. Despite maternal treatment with various medications before and during pregnancy, the etiology of the KH in her offspring remains unknown. We cannot conclude that the offspring condition was caused by any of the maternal medications, including etanercept, and the association is possibly incidental. However, the rarity of Kaposiform hemangioendothelioma combined with the uncommon in-utero presentation of the lesion, occurring in association with maternal etanercept treatment, a novel drug that is taken rarely in pregnancy, justifies continuing surveillance and close observation of pregnant women treated with anti TNF-␣ therapy. Indeed, we published a prospective comparative study on pregnancy outcome following gestational exposure to TNF-␣ inhibitors that mentioned this case briefly [13]. Our case is unique due to the in utero full blown presentation of the Kaposiform hemangioendothelioma and the associated Kasabach Merritt syndrome that led to multi-organ failure. An early
3
recognition of vascular tumors associated with Kasabach–Merritt syndrome allows prompt treatment with good prognosis in most cases. Conflict of interest The authors declare that there are no conflicts of interest. Transparency document The Transparency document associated with this article can be found in the online version. References [1] Lyons LL, North PE, Mac-Moune Lai F, Stoler MH, Folpe AL, Weiss SW. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 2004;28:559–68. [2] Zrour-Hassen S, Jguirim M, Aouam K, Korbaa W, Younes M, Bejia I, et al. Safety of rheumatic disease drugs at childbearing age. Therapie 2010;65: 465–73. [3] Singh N, Varshney P, Tripathi R, Mala YM, Tyagi S. Safety and efficacy of low molecular weight heparin therapy during pregnancy: three year experience at a tertiary care center. J Obstet Gynaecol India 2013;63:373–7. [4] Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J 2002;21:1505–13. [5] Treacy G. Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody. Hum Exp Toxicol 2000;19:226–8. [6] Carter JD, Valeriano J, Vasey FB. Tumor necrosis factor-alpha inhibition and VATER association: a causal relationship. J Rheumatol 2006;33:1014–7. [7] Carter JD, Ladhani A, Ricca LR, Valeriano J, Vasey FB. A safety assessment of tumor necrosis factor antagonists during pregnancy: a review of the Food and Drug Administration database. J Rheumatol 2009;36:635–41. [8] Koren G, Inoue M. Do tumor necrosis factor inhibitors cause malformations in humans. J Rheumatol 2009;36:465–6. [9] Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–6. [10] Viktil KK, Engeland A, Furu K. Outcomes after anti-rheumatic drug use before and during pregnancy: a cohort study among 150,000 pregnant women and expectant fathers. Scand J Rheumatol 2012;41:196–201. [11] Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, Liote F, Goeb V, et al. Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 2009;76:28–34. [12] Murashima A, Watanabe N, Ozawa N, Saito H, Yamaguchi K. Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant’s serum. Ann Rheum Dis 2009;68:1793–4. [13] Diav-Citrin O, Otcheretianski-Volodarsky A, Shechtman S, Ornoy A. Pregnancy outcome following gestational exposure to TNF-alpha-inhibitors: a prospective, comparative, observational study. Reprod Toxicol 2014;43:78–84.