Portal de Periódicos da CAPES

Prenatal Risk Factors for Infantile Hemangioma Development

2016; Elsevier BV; Volume: 137; Issue: 4 Linguagem: Inglês

10.1016/j.jid.2016.10.047

1523-1747

Manrup Hunjan, Jennifer J. Schoch, Katelyn Anderson, Christine M. Lohse, Mary L. Marnach, Jennifer L. Hand, Dawn Marie R. Davis, Megha M. Tollefson,

Teratomas and Epidermoid Cysts

Previous studies determined that multiple gestation, female sex, low birth weight, prematurity, use of certain prenatal medications, invasive antepartum procedures, and placental abnormalities increase infant risk for infantile hemangiomas (IH) (Anderson et al., 2016Anderson K.R. Schoch J.J. Lohse C.M. Hand J.L. Davis D.M. Tollefson M.M. Increasing incidence of infantile hemangiomas (IH) over the past 35 years: Correlation with decreasing gestational age at birth and birth weight.J Am Acad Dermatol. 2016; 74: 120-126Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, Chen et al., 2013Chen X.D. Ma G. Chen H. Ye X.X. Jin Y.B. Lin X.X. Maternal and perinatal risk factors for infantile hemangioma: a case-control study.Pediatr Dermatol. 2013; 30 ([Erratum appears in Pediatr Dermatol. 2013 Sep-Oct;30(5):664]): 457-461Crossref PubMed Scopus (35) Google Scholar, Drolet et al., 2008Drolet B.A. Swanson E.A. Frieden I.J. Hemangioma Investigator GInfantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants.J Pediatr. 2008; 153: 712-715Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, Haggstrom et al., 2007Haggstrom A.N. Drolet B.A. Baselga E. Chamlin S.L. Garzon M.C. Horii K.A. et al.Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics.J Pediatr. 2007; 150: 291-294Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, Munden et al., 2014Munden A. Butschek R. Tom W.L. Marshall J.S. Poeltler D.M. Krohne S.E. et al.Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies.Br J Dermatol. 2014; 170: 907-913Crossref PubMed Scopus (187) Google Scholar). We sought to explore maternal prenatal risk factors associated with IH in a systematic fashion. After Institutional Review Board approval, the Rochester Epidemiology Project (REP) was used to obtain 869 maternal records for the 999 infants <1 year of age with IH diagnosed between 01 January 1976 and 31 December 2010 identified in our previous study (Anderson et al., 2016Anderson K.R. Schoch J.J. Lohse C.M. Hand J.L. Davis D.M. Tollefson M.M. Increasing incidence of infantile hemangiomas (IH) over the past 35 years: Correlation with decreasing gestational age at birth and birth weight.J Am Acad Dermatol. 2016; 74: 120-126Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). The REP is a medical records linkage system allowing for access to records for nearly all patient encounters in Olmsted County, Minnesota, since the 1960s (St Sauver et al., 2012St Sauver J.L. Grossardt B.R. Yawn B.P. Melton 3rd, L.J. Pankratz J.J. Brue S.M. et al.Data resource profile: the Rochester Epidemiology Project (REP) medical records-linkage system.Int J Epidemiol. 2012; 41: 1614-1624Crossref PubMed Scopus (438) Google Scholar). Case mother-infant pairs were matched to control mother-infant pairs without IH from the same geographically defined population, by age of the mother at delivery, and birth date and sex of the infant. Each of the medical records was reviewed by one of the primary authors. Comparisons between the case and control mother-infant pairs were evaluated using conditional logistic regression to account for the paired nature of the data and summarized with odds ratios and 95% confidence intervals. Statistical analyses were performed using version 9.3 of the SAS software package (SAS Institute, Cary, NC). P-values <0.05 were considered statistically significant. There were 561 (65%) girls and 308 (35%) boys among the 869 case infants and the 869 control infants. There were no significant differences in maternal age at delivery or race between the case and control mother-infant pairs. All associations of the features studied with the development of IH were reported (Table 1) and then adjusted for gestational age at birth and multiple gestation, both of which are known risk factors for the development of IH (Anderson et al., 2016Anderson K.R. Schoch J.J. Lohse C.M. Hand J.L. Davis D.M. Tollefson M.M. Increasing incidence of infantile hemangiomas (IH) over the past 35 years: Correlation with decreasing gestational age at birth and birth weight.J Am Acad Dermatol. 2016; 74: 120-126Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar; Table 2). Our study confirmed several previously identified prenatal risk factors for IH development, including maternal progesterone use, gestational hypertension (GHTN), and preeclampsia (Dickison et al., 2011Dickison P. Christou E. Wargon O. A prospective study of infantile hemangiomas with a focus on incidence and risk factors.Pediatr Dermatol. 2011; 28: 663-669Crossref PubMed Scopus (97) Google Scholar, Haggstrom et al., 2007Haggstrom A.N. Drolet B.A. Baselga E. Chamlin S.L. Garzon M.C. Horii K.A. et al.Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics.J Pediatr. 2007; 150: 291-294Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, Chen et al., 2013Chen X.D. Ma G. Chen H. Ye X.X. Jin Y.B. Lin X.X. Maternal and perinatal risk factors for infantile hemangioma: a case-control study.Pediatr Dermatol. 2013; 30 ([Erratum appears in Pediatr Dermatol. 2013 Sep-Oct;30(5):664]): 457-461Crossref PubMed Scopus (35) Google Scholar), while also describing several associations that, to our knowledge, have not been reported previously, particularly gestational diabetes mellitus (GDM).Table 1Summary of prenatal risk factors1Univariable analysis (N = 869:869 for controls:cases unless otherwise indicated).Prenatal risk factors (N= control: cases)OR (CI 95%)P-valueDelivery type (N=867:866) Vaginal1.0 (reference) Cesarean1.37 (1.07-1.75)0.013 Vaginal vacuum-assisted0.90 (0.54-1.52)0.70 Vaginal forceps-assisted1.50 (1.08-2.09)0.017Fertility treatment Medication1.55 (0.88-2.72)0.13 Assisted reproductive technology3.09 (1.57-6.10)0.001 OtherNE2NE (not evaluated), as there were fewer than 5 patients with the feature listed.NE Any of the above2.07 (1.32-3.25)0.002Maternal medication Progesterone2.35 (1.60-3.45)<0.001 Tocolytic2.50 (1.53-4.10)<0.001Nifedipine (N=869:866)NENEIndomethacin (N=869:866)5.00 (1.10-22.82)0.038Terbutaline (N=869:866)2.67 (1.47-4.83)0.001Magnesium sulfate (N=869:866)0.08 (0.00-0.40)0.003Other tocolytic (N=869:866)24.00 (3.25-177.40)0.002 Beta-blocker3.00 (0.61-14.86)0.18 Non–beta-blocker antihypertensive2.50 (0.49-12.89)0.27 Corticosteroid3.05 (1.86-4.99)<0.001 Any of the above2.47 (1.84-3.32)<0.001Invasive antepartum procedures Amniocentesis1.33 (0.90-1.94)0.15 Chorionic villus sampling3.50 (0.73-16.85)0.12 OtherNENE Any of the above1.52 (1.05-2.21)0.027Placental abnormalities Single umbilical artery1.50 (0.25-8.98)0.66 Placenta previa1.50 (0.42-5.32)0.53 Placenta accreta/percreta/incretaNENE Placental abruption2.56 (1.18-5.52)0.017 Other1.50 (0.72-3.11)0.28 Any of the above2.13 (1.31-3.45)0.002Maternal complications Twin gestation3.18 (1.84-5.48)<0.001 Triplet gestation4.00 (0.45-35.79)0.22 Twin or triplet gestation3.22 (1.90-5.47)<0.001 Gestational diabetes2.00 (1.20-3.34)0.008 Preexisting diabetes1.80 (0.60-5.37)0.29 Gestational hypertension1.65 (1.02-2.69)0.043 Preexisting hypertension2.50 (0.78-7.97)0.12 Anemia0.93 (0.66-1.30)0.66 Preeclampsia/eclampsia2.71 (1.14-6.46)0.024 Gestational hypertension or preeclampsia1.90 (1.22-2.96)0.004 HELLP syndrome1.33 (0.30-5.96)0.71 Hypothyroidism1.13 (0.65-1.98)0.67 PPROM5.13 (2.40-10.93)<0.001 IUGR3.40 (1.25-9.22)0.016 Breech presentation1.81 (1.17-2.80)0.008 Vaginal bleeding1.32 (0.93-1.86)0.12 Oligohydramnios3.20 (1.17-8.74)0.023 Polyhydramnios1.14 (0.41-3.15)0.80 UTI1.40 (0.91-2.16)0.13 Tobacco use1.22 (0.90-1.66)0.19 Alcohol use0.60 (0.14-2.51)0.48 Other substance use3.00 (0.81-11.08)0.099 Other1.77 (1.38-2.27)<0.001 Any of the above1.63 (1.33-1.99)<0.001 Any of the above excluding other1.54 (1.27-1.86)<0.001Type of gestational diabetes (N=868:869) None1.0 (reference) 1 – diet controlled2.23 (1.16-4.29)0.016 2 – medication including insulin1.88 (0.80-4.42)0.15Abbreviations: CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, low platelet count; IUGR, intrauterine growth restriction; NE, not evaluated; OR, odds ration; PPROM, premature rupture of membranes; UTI, urinary tract infection.1 Univariable analysis (N = 869:869 for controls:cases unless otherwise indicated).2 NE (not evaluated), as there were fewer than 5 patients with the feature listed. Open table in a new tab Table 2Summary of prenatal risk factors after adjusting for multiple gestation and gestational agePrenatal risk factorOR (CI 95%)P-valueDelivery type Vaginal1.0 (reference) Cesarean1.10 (0.84-1.43)0.49 Vaginal vacuum-assisted0.94 (0.54-1.62)0.81 Vaginal forceps-assisted1.45 (1.03-2.05)0.035Fertility treatment Medication1.27 (0.70-2.32)0.44 Assisted reproductive technology1.90 (0.90-3.98)0.091 OtherNENE Any of the above1.50 (0.92-2.44)0.10Maternal medication Progesterone2.25 (1.50-3.38)<0.001 Tocolytic1.30 (0.75-2.25)0.35NifedipineNENEIndomethacin1.15 (0.22-5.98)0.87Terbutaline1.56 (0.82-2.95)0.18Magnesium sulfate0.05 (0.00-0.25)<0.001Other tocolytic7.32 (0.95-56.48)0.056 Beta-blocker2.41 (0.47-12.31)0.29 Non–beta-blocker antihypertensive2.09 (0.37-11.87)0.41 Corticosteroid1.33 (0.74-2.40)0.34 Any of the above1.88 (1.36-2.58)<0.001Invasive antepartum procedures Amniocentesis1.05 (0.70-1.57)0.80 Chorionic villus sampling4.41 (0.90-21.69)0.068 OtherNENE Any of the above1.27 (0.86-1.88)0.23Placental abnormalities Single umbilical artery1.29 (0.20-8.33)0.79 Placenta previa0.87 (0.24-3.20)0.83 Placenta accrete/percreta/incretaNENE Placental abruption1.68 (0.75-3.78)0.21 Other1.37 (0.63-3.02)0.43 Any of the above1.62 (0.97-2.73)0.068Maternal complications Gestational diabetes1.79 (1.06-3.02)0.029 Preexisting diabetes1.43 (0.47-4.39)0.53 Gestational hypertension1.38 (0.83-2.29)0.22 Preexisting hypertension1.72 (0.51-5.79)0.38 Anemia0.87 (0.60-1.25)0.44 Preeclampsia/eclampsia3.43 (1.24-9.45)0.017 Gestational hypertension or pre/eclampsia1.71 (1.07-2.74)0.025 HELLP syndrome1.02 (0.20-5.07)0.98 Hypothyroidism1.04 (0.58-1.87)0.88 PPROM2.10 (0.92-4.76)0.077 IUGR2.20 (0.79-6.13)0.13 Breech presentation1.09 (0.67-1.78)0.72 Vaginal bleeding1.14 (0.79-1.64)0.49 Oligohydramnios2.58 (0.91-7.36)0.076 Polyhydramnios0.57 (0.18-1.85)0.35 UTI1.39 (0.88-2.21)0.16 Tobacco use1.20 (0.87-1.64)0.27 Alcohol use0.60 (0.14-2.56)0.49 Other substance use3.01 (0.76-11.86)0.12 Other1.64 (1.26-2.13)<0.001 Any of the above1.36 (1.10-1.69)0.005 Any of the above excluding other1.26 (1.03-1.55)0.027Type of gestational diabetes None1.0 (reference) 1 – diet controlled1.95 (1.00-3.80)0.049 2 – medication including insulin1.74 (0.72-4.20)0.22Abbreviations: CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, low platelet count; IUGR, intrauterine growth restriction; NE, not evaluated; OR, odds ration; PPROM, premature rupture of membranes; UTI, urinary tract infection. Open table in a new tab Abbreviations: CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, low platelet count; IUGR, intrauterine growth restriction; NE, not evaluated; OR, odds ration; PPROM, premature rupture of membranes; UTI, urinary tract infection. Abbreviations: CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, low platelet count; IUGR, intrauterine growth restriction; NE, not evaluated; OR, odds ration; PPROM, premature rupture of membranes; UTI, urinary tract infection. Maternal progesterone use was previously described as a risk factor for IH development in an Asian population (Chen et al., 2013Chen X.D. Ma G. Chen H. Ye X.X. Jin Y.B. Lin X.X. Maternal and perinatal risk factors for infantile hemangioma: a case-control study.Pediatr Dermatol. 2013; 30 ([Erratum appears in Pediatr Dermatol. 2013 Sep-Oct;30(5):664]): 457-461Crossref PubMed Scopus (35) Google Scholar); however, the generalizability of this has been thus far unknown. In this study, after adjusting for gestational age and multiple gestations, maternal progesterone use remained an independent risk factor in the development of IH. The mechanism by which exposure to progesterone increases risk of IH development is not understood, but warrants further investigation. Previous studies suggest that preeclampsia may play a role in IH development (Haggstrom et al., 2007Haggstrom A.N. Drolet B.A. Baselga E. Chamlin S.L. Garzon M.C. Horii K.A. et al.Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics.J Pediatr. 2007; 150: 291-294Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, Drolet and Frieden, 2010Drolet B.A. Frieden I.J. Characteristics of infantile hemangiomas as clues to pathogenesis: does hypoxia connect the dots?.Arch Dermatol. 2010; 146: 1295-1299Crossref PubMed Scopus (72) Google Scholar). In our study, mothers of babies who had IH were more likely than controls to carry the diagnosis of preeclampsia. There is often lack of clear delineation between preeclampsia and GHTN; when preeclampsia and GHTN were considered as a single entity, the likelihood of IH development increased 1.71-fold. Notably, the use of antihypertensive drugs was not significantly associated with IH, suggesting under-treatment of patients with GHTN and preeclampsia, failure to capture all medication use in the data set, or lack of power due to the relatively small size of this population subset. One possible explanation for increased risk with preeclampsia or GHTN is consistent with the theory that IH may be stimulated by a hypoxic environment in utero (Drolet and Frieden, 2010Drolet B.A. Frieden I.J. Characteristics of infantile hemangiomas as clues to pathogenesis: does hypoxia connect the dots?.Arch Dermatol. 2010; 146: 1295-1299Crossref PubMed Scopus (72) Google Scholar, Janmohamed et al., 2015Janmohamed S.R. Brinkhuizen T. den Hollander J.C. Madern G.C. de Laat P.C. van Steensel M.A. et al.Support for the hypoxia theory in the pathogenesis of infantile haemangioma.Clin Exp Dermatol. 2015; 40: 431-437Crossref PubMed Scopus (14) Google Scholar). Conditions that propagate a hypoxic environment stimulate the release of hypoxia inducible factor-1 alpha, which promotes production of vascular endothelial growth factor A. Increased levels of hypoxia inducible factor-1 alpha and vascular endothelial growth factor A have been observed in blood samples of children with IH, supporting the plausibility of hypoxia as an influential factor in the development of IH (Kleinman et al., 2007Kleinman M.E. Greives M.R. Churgin S.S. Blechman K.M. Chang E.I. Ceradini D.J. et al.Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma.Arterioscler Thromb Vasc Biol. 2007; 27: 2664-2670Crossref PubMed Scopus (175) Google Scholar, Drolet et al., 2008Drolet B.A. Swanson E.A. Frieden I.J. Hemangioma Investigator GInfantile hemangiomas: an emerging health issue linked to an increased rate of low birth weight infants.J Pediatr. 2008; 153: 712-715Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). GDM was a newly identified significant risk factor for IH. Many known fetal complications of GDM are thought to be a result of placental abnormalities that occur in the presence of GDM (Jarmuzek et al., 2015Jarmuzek P. Wielgos M. Bomba-Opon D. Placental pathologic changes in gestational diabetes mellitus.Neuro Endocrinol Lett. 2015; 36: 101-105PubMed Google Scholar), including villous immaturity, fibroid necrosis, and ischemic changes. The presence of placental nucleated fetal red blood cells, a hallmark of chronic fetal hypoxemia, is also seen in these patients (Daskalakis et al., 2008Daskalakis G. Marinopoulos S. Krielesi V. Papapanagiotou A. Papantoniou N. Mesogitis S. et al.Placental pathology in women with gestational diabetes.Acta Obstet Gynecol Scand. 2008; 87: 403-407Crossref PubMed Scopus (133) Google Scholar). Both placental abnormalities and placental hypoxia are factors implicated in the development of IH (Drolet and Frieden, 2010Drolet B.A. Frieden I.J. Characteristics of infantile hemangiomas as clues to pathogenesis: does hypoxia connect the dots?.Arch Dermatol. 2010; 146: 1295-1299Crossref PubMed Scopus (72) Google Scholar, Janmohamed et al., 2015Janmohamed S.R. Brinkhuizen T. den Hollander J.C. Madern G.C. de Laat P.C. van Steensel M.A. et al.Support for the hypoxia theory in the pathogenesis of infantile haemangioma.Clin Exp Dermatol. 2015; 40: 431-437Crossref PubMed Scopus (14) Google Scholar), thus suggesting that hypoxia may explain the association between IH and GDM. Another possible theory for the association between GDM and IH development involves the expression of glucose transporter 1. Glucose transporter 1 is a highly specific marker for IH, used to discriminate IH from other vascular malformations (North et al., 2000North P.E. Waner M. Mizeracki A. Mihm Jr., M.C. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas.Hum Pathol. 2000; 31: 11-22Crossref PubMed Scopus (656) Google Scholar). A 40% increase in glucose transporter 1 expression was seen in placentas of mothers with diabetes, with up-regulation occurring almost exclusively in the first trimester (Jansson et al., 1999Jansson T. Wennergren M. Powell T.L. Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes.Am J Obstet Gynecol. 1999; 180: 163-168Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). Limitations of this study include that the population of Olmsted County is a predominantly white population, which may lead to population bias. Further, the retrospective nature of this study may limit the ability to accurately delineate some maternal risk factors. Strengths of this study include the ability to use the REP to identify a population within a well-defined geographical area and to pair each case with an age-matched and sex-matched control from the same population. As well as establishing previously identified potential maternal risk factors for IH, we describe the association between GDM and IH. Prospective studies are necessary to further explore this relationship, which may be clinically relevant to prenatal education and may also provide valuable insight into the pathogenesis of IH. The authors state no conflict of interest. This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.