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Evaluation of maternal history of miscarriage, infertility andin vitrofertilization as associated factors in PHACE

Year: 2017

Type: article

Abstract: Dear Editor, The aetiology of PHACE (posterior fossa anomalies, haemangioma, arterial anomalies, coarctation of the aorta and eye anomalies) is unknown. A genetic aetiology has been proposed but there are no published reports of heritability in families of children with PHACE. PHACE has a female predominance, although preliminary X‐inactivation studies have not demonstrated significant skewing in affected female patients or their mothers.1 Copy‐number variation studies have yet to identify a common pathogenic variant.2 We sought to determine whether there is an increased prevalence of miscarriage, infertility and/or use of in vitro fertilization (IVF) in the mothers of children with PHACE. Several studies have suggested that the incidence of imprinting disorders is increased in patients undergoing IVF. Imprinting disorders occur when either the paternal or maternal normal allele is epigenetically silenced (imprinted) and a mutated allele from the other parent is expressed. Previous studies indicate that IVF may not be the sole cause of imprinting disorders, but rather that the genetic background of subfertile parents plays an important role.3 It has been proposed that IVF may bypass a natural selection mechanism to allow for an imprinting disorder to occur.4 The PHACE Syndrome International Clinical Registry was established in 2006 and had 218 families enrolled at the time of this study. Information regarding maternal history of miscarriage and infertility was available for only 174 families at the time of enrolment. To investigate further the rates of maternal history of miscarriage, infertility and IVF in the registry, an electronic survey was designed using SurveyMonkey Platinum (https://www.surveymonkey.co.uk) and sent to registry participants for whom e‐mail contact information was available (114 families). Fifty‐four responses were gathered from 14 December 2014 to 4 February 2015. The χ2‐test was used to calculate P‐values when comparing survey results with rates in the U.S.A. for miscarriage, infertility and IVF use. Known or suspected history of miscarriage was reported in 59 of 174 families in the registry database (33·9%) compared with 22 of 54 survey respondents (41%). This difference likely represents an ascertainment bias. Both rates were statistically significantly higher than the estimated miscarriage rate of 10–20% in the U.S.A., P <0·001 (Fig. 1a).5 Of the 22 survey respondents, eight reported a history of two or more pregnancy losses. (a) Miscarriage rates in PHACE, (b) infertility rates and (c) infertility service rates. Fifteen per cent of survey respondents reported a history of infertility (eight of 54). This rate was not statistically different from the U.S. infertility rate of 12%, P =0·67 (Fig. 1b).6 Thirteen per cent (seven of 54) of survey respondents reported receiving fertility therapy for the pregnancy related to the child with PHACE. This is comparable with the 11·9% of women in the U.S.A. receiving infertility services, P =0·97 (Fig. 1c).7 More mothers of children with PHACE had miscarriages when compared with U.S. data. Miscarriage is defined as the spontaneous loss of a known pregnancy before 20 weeks of gestation, and recurrent pregnancy loss has been defined as two or more failed consecutive pregnancies.5 Aetiologies include cytogenetic abnormalities in the miscarriage tissue (50% for spontaneous pregnancy loss and 35% for recurrent pregnancy loss), anatomical uterine anomalies (20%), autoimmune and alloimmune causes (i.e. antiphospholipid antibody syndrome, 15–20%) and parental genetic abnormalities (3–5%).5 Because cytogenetically abnormal miscarriages may result from a mechanism that impairs chromosome segregation, it is possible that PHACE syndrome results from a similar cause such as smaller, more viable cytogenetic abnormalities (e.g. duplications and deletions) or other molecular aberrations. Anatomical factors such as uterine or placental anomalies may also play a role in the pathogenesis of PHACE. There was not an increased incidence of hypercoagulability disorders in mothers of children with PHACE per maternal report; however, mothers may not have been routinely tested for these. In contrast, rates of infertility and IVF use did not differ substantially between our study cohort and U.S. national rates, making the hypothesis of PHACE as an imprinting disorder less likely. Limitations to the study include recall and ascertainment biases and lack of control for confounding factors such as maternal age given the survey‐based design, parental reporting and underpowering. Another limitation was that the study was not designed to include a severity scale. The clinical features of PHACE in the children of the respondents were similar to those in the registry as a whole, with no significant differences in severity except for a trend towards higher rates of cardiac anomalies in the survey group. Population data were used for comparison, where the cohort may have included individuals with various diseases. In summary, our study demonstrated higher rates of miscarriage in mothers of children with PHACE. Rates of infertility and IVF use between the PHACE cohort and the U.S. population did not differ significantly. Larger studies will be beneficial to elucidate the aetiology of PHACE. We are grateful for the contributions of the participants to this study and to the PHACE Syndrome Community for their support. Funding sources: this publication was made possible with support from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) under award number 1R01AR064258. Conflicts of interest: none declared.

Source: British Journal of Dermatology

DOI: 10.1111/bjd.15341