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Recommendations on pregnancy, childbirth and aftercare in epidermolysis bullosa: a consensus‐based guideline*

2021; Oxford University Press; Volume: 186; Issue: 4 Linguagem: Inglês

10.1111/bjd.20809

1365-2133

Danielle Greenblatt, Elizabeth Pillay, Karen Snelson, Rebecca Saad, Mauricio Torres Pradilla, Suci Widhiati, Anja Diem, Caroline L. Knight, Kim M. Thompson, Nazzareno Azzopardi, Mia Werkentoft, Zena Moore, Declan Patton, K. M. Mayre‐Chilton, Dédée F. Murrell, Jemima E. Mellerio,

Dermatological and Skeletal Disorders

Optimizing outcomes for pregnant women with genetic disease has received increasing attention.1 Improved early diagnosis and management of genetic disease, together with access to prenatal diagnostics, has meant that more women are reaching reproductive age and are able to make informed choices about pregnancy and childbirth.2 Despite these advances, the management of pregnancy, childbirth and aftercare in epidermolysis bullosa (EB) has been infrequently evaluated in the literature. EB encompasses a group of rare, heterogeneous, inherited disorders characterized by skin and variable mucosal fragility. In response to friction or mechanical trauma, the skin layers cleave, resulting in blistering and erosions forming within the skin and mucosae. Four major subtypes are characterized, based on the level of ultrastructural cleavage within the skin: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB (KEB).3 Patients with EB have variable disease severity, both within and between subtypes. Patients with mild forms of EBS, for example, may experience a limited impact on daily function and have a normal life expectancy, while patients with severe recessive DEB (RDEB) have significant morbidity and experience life-limiting complications of their disease.4 This article summarizes recommendations reached following a systematic literature review and expert consensus on the management of pregnancy, birth and postnatal care in women with EB. This guideline is intended to inform and support women with EB and their partners, and aid decision-making by clinicians managing patients with EB. Intended guideline users include women with EB and their partners, dermatologists, obstetricians, anaesthetists, neonatologists, paediatricians, nurses, allied health professionals, family practice physicians and psychologists. The CPG development process established three broad clinical questions pertinent to the guideline scope. A: Preconception and antenatal management Can preconception and antenatal management advice support a positive pregnancy experience for women living with EB? B: Labour and management of delivery What is best practice for maternal assessment and management during labour for women living with EB? C: Postnatal care and management Are there specific postnatal care recommendations and interventions to optimize a positive pregnancy experience, including breastfeeding, in women living with EB? For further information on the CPG methodology, see Appendix S1 (see Supporting Information) with reference to the Critical Appraisal Skills Programme (CASP), GRADE and the AGREE II instrument.5-8 The search identified 415 papers of possible relevance (Figure 1); 22 were included in the appraisal (Table S1; see Supporting Information). The selected articles were then allocated to the three clinical questions and outcomes. The evidence quality overview of the appraised papers can be found in Tables 1 and 2. Additional references relating to other aspects of EB care or obstetric management were added during the iterative process of guideline development from expert consensus. A: Preconception and antenatal management Pregnancies have been reported in women with all EB subtypes.9 Fertility is not typically affected in milder forms of EB; however, comorbid medical problems in severe EB subtypes, for example nutritional compromise and low body mass index (BMI), may have an impact on ovulation.10 As medical supportive care improves and patients transition into adulthood, more women are able to make decisions about starting a family.11 However, in severe EB subtypes complicated by mucosal fragility (e.g. RDEB, JEB and KEB), vulvovaginal involvement may result in pain during sexual intercourse and, rarely, vaginal stenosis;12 these factors may impact on sexual function.13 Use of water-based lubricants may be helpful for women with vulvovaginal involvement. Vaginal dilators are occasionally prescribed. R1 ↑↑ Discuss and evaluate vulvovaginal manifestations of EB, where appropriate and dependent on EB subtype, as part of routine care.14-16 For women with severe vaginal stenosis and dyspareunia, consider referral to an assisted conception unit. A.1 Access to diagnostics, genetic counselling and prenatal testing R2 ↑↑ Offer standard preconception care to women with EB, and provide access to genetic counselling where available.17-19 Depending on the inheritance pattern (autosomal recessive, autosomal dominant) the risk assessment for the pregnancy can be estimated and prenatal testing offered.11, 18-26 Couples at reproductive risk of severe forms of EB may wish to pursue prenatal or preimplantation genetic testing, accounting for family preferences, religious/cultural beliefs and national regulations. Carrier screening of an unaffected and unrelated partner may be offered according to the individual situation and national regulations, after genetic counselling.22 A.2 Optimizing health pre-pregnancy Optimizing diet and nutrition pre-pregnancy may improve maternal and perinatal outcomes via effects on BMI or correction of micronutrient deficiencies.27, 28 R3 ↑↑ Follow standard preconception care guidelines for women with EB planning a pregnancy. Attention should be given to supplementing folate, managing iron and vitamin D levels, and supplementing zinc and selenium, if needed. R4 ↑↑ Offer management of severe anaemia, chronic infection, malnutrition and oral health in women with severe EB subtypes.29 Some patients with EB may be predisposed to gingivitis and oral ulceration.30, 31 Hormonal fluctuations in pregnancy may exacerbate gingival disease.32 A.3 Medication review Many women with severe subtypes of EB will be established on chronic medication such as analgesia (including opiates) and proton pump inhibitors. R5 Good practice point (GPP) Review all active prescription and over-the-counter medicines and supplements in the context of a woman planning or establishing a pregnancy. Drugs should only be prescribed in pregnancy if anticipated benefit to the mother with EB outweighs risk to the fetus. Where possible, avoidance of medication during the first trimester is a sensible approach. A.4 Physiological changes in pregnancy Important physiological and anatomical adaptations occur during pregnancy, allowing a pregnant woman to meet the metabolic demands of the developing fetus. With rising levels of human chorionic gonadotropin in early pregnancy, many women suffer from morning sickness or hyperemesis gravidarum. Gastric acidity is increased and oesophageal sphincter tone relaxed, making reflux oesophagitis and heartburn symptoms common throughout pregnancy.33 This is challenging for patients with EB, who may already suffer with chronic gastro-oesophageal disease.34 Vomiting may cause oesophageal blistering and scarring. Furthermore, a bloated sensation and constipation can develop during pregnancy,35 and may exacerbate pre-existing gastrointestinal complications of EB. R6 ↑↑ Monitor and treat pregnancy-related nausea and vomiting, particularly in women with pre-existing gastroesophageal reflux disease or known oesophageal strictures.24 If antisecretory/mucosal protectant prophylaxis is required for reflux management, only agents safe in pregnancy should be offered.36 (Note the ranitidine recall by the US Food and Drugs Administration and Medicines and Healthcare products Regulatory Agency due to the ongoing investigation of a possible contaminant, N-nitrosodimethylamine.37) R7 ↑↑ Assess and manage constipation in women with EB. Patients may benefit from regular exercise, improved hydration and dietary modification. Iron supplementation may need review. Osmotic laxatives, in particular, may be helpful.38 R8 ↑↑ Monitor gravid distention of the abdomen for impact on EB wounds. Although skin involvement does not routinely worsen during pregnancy in EB,9, 12, 39-41 there have been occasional reports of wound deterioration related to abdominal distention.42-45 A.5 Clinical examination of pregnant women during antenatal visits R9 ↑↑ Engage the multidisciplinary team (MDT) early during pregnancy for patients with complex forms of EB. Where available, a team consisting of midwife, obstetrician, dermatologist, clinical nurse specialist, anaesthetist, occupational therapist and psychologist will improve pregnancy management.9, 19, 29, 43, 46 If an infant with EB is expected, timely involvement of the neonatal team and paediatric EB nurse is needed. R11 ↑↑ Exercise caution during examination when assessing for fundal height, to prevent unintended skin trauma. Lubricant or emollient may need to be applied to gloves and the patient's skin before examination; a layer of Mepitel® Film may help to protect vulnerable skin.24 If a speculum or vaginal examination (VE) is required for assessment, generous lubrication should be used. A.6 Planning delivery, including anaesthetic assessment R12 GPP Offer pregnant women with EB information to enable informed decision-making about the mode of childbirth, as part of woman-centred care.47 Encourage women with EB to prepare a birth plan. R13 GPP Provide antenatal care and plan delivery close to the patient's home wherever possible. This will enable involvement of the patient's partner, family and carers. The role of the specialist EB team is to advise local obstetric services. Phenotypic variability both between and within EB subtypes necessitates an individualized approach when considering and planning a woman's delivery. The EB team caring for the patient will be able to advise about risks to the baby and potential complications associated with each form of EB and how this may impact on labour and/or birth choices. Having a diagnosis of EB is not a contraindication to vaginal birth.9, 12, 19 In some cases, there may be a strong maternal preference for caesarean section (e.g. owing to fear and anxiety regarding trauma to the birth canal resulting in blistering/wounds); the benefits and risks of all options should be discussed with an obstetrician and dermatologist ideally, and an individualized birth plan agreed. R14 ↑↑ Vaginal birth should be offered as the preferred mode of delivery for women with all EB subtypes. Vaginal birth does not appear to increase the risk of subsequent vaginal scarring or stenosis, even in patients with severe RDEB.9, 42, 48 There are reports of women with RDEB giving birth to more than one child vaginally, confirming the patency of the vaginal canal postdelivery.9, 42 Women with dominantly inherited forms of EB [e.g. EBS or dominant DEB (DDEB)] have a 50% chance of having a baby with EB. Prenatal testing in many such cases is not routinely performed as the conditions are not life limiting. In mothers expecting to deliver a baby with EB, normal vaginal delivery remains the preferred mode of delivery.9 Antenatal engagement with the neonatal team is critical in these pregnancies. R16 ↑↑ Arrange an anaesthetic assessment antenatally in women with a known difficult airway, restricted mouth opening or extensive wounds involving the lower back, the latter of which precludes regional anaesthesia.11, 21, 29, 49 An airway, dental and skin assessment should be undertaken, and anaesthetic plans documented. Planning should involve epidural, spinal and general anaesthetic options (e.g. for emergencies or in the setting of lower back wounds). In women with chronic pain requiring baseline opioids, planning intrapartum analgesia requirements should be undertaken. A.7 Longer-term planning R18 ↑↑ Offer ongoing routine EB skin monitoring and surveillance for skin cancer throughout pregnancy and the postpartum period in patients at greatest risk of EB-related squamous cell carcinoma.51 See Table 3 for a summary of the recommendations in pre-conception/antenatal planning. Recommendation Offer genetic counselling pre-conception, to women with EB Boria et al.,18 Shah et al.,19 Bianca et al.,20 Büscher et al.,21 Vendrell et al.23 ⇨Has et al.,22 Pillay24(Sybert,17 Fassihi and McGrath,25 Pfendner et al.)26 Baloch et al.29 ⇨Kramer et al.30,b b Reference contained no EB population. (Kramer,31 Ressler-Maerlender et al.)32 ⇨Pillay,24 RCOG36,b b Reference contained no EB population. (Fine and Mellerio,34 Body and Christie)35,b b Reference contained no EB population. Intong et al.,9 Araujo et al.46 ⇨Pillay24 B: Labour and birth B.1 Advance preparations R19 ↑ Consider sourcing a 'dressings pack' from the EB specialist team for the woman and/or baby. This could include an accessible supply of suitable dressings and silicone medical adhesive remover spray (MARS) during and after labour. R20 GPP The patient's handheld notes should include information about EB subtype, delivery plan and contact details for the EB specialist team. These should be accessible in case of an emergency delivery. B.2 Engagement of neonatal team R21 ↑↑ Liaise early with the neonatal team if there is a possibility that the baby may be born with EB (e.g. in dominantly inherited forms of EB such as EBS or DDEB, or when prenatal testing results are available). To minimize skin damage, neonates should be handled with extreme care. Vigorous rubbing to stimulate the neonate at delivery should be avoided; if oropharyngeal suction is necessary, small, well-lubricated catheters should be used.52 B.3 Monitoring and skincare during labour and delivery R22 ↑↑ Ensure abdominal examinations are carried out gently, to reduce potential skin damage to the woman; lubricated gloves should be worn. Fetal monitoring equipment such as tight cardiotocography (CTG) belts may cause friction and blistering (see R24).12, 19 R23 ↑↑ Ensure lubrication of the speculum and/or gloves when carrying out speculum or VEs.24 Internal examinations should only be performed when absolutely necessary.19 R24 ↓↓ Unless the baby is known to be unaffected by EB, avoid fetal scalp electrodes and fetal blood sampling. B.4 Skincare management during labour and birth B.5 Pressure relief R26 ↑↑ Offer pressure relief adaptations throughout labour. Frequent position changes will reduce potential pressure damage to the skin.19, 29, 49 Consider use of pressure-relieving mattresses or pillows (e.g. Repose or international alternative); portable and inflatable options are available for the patient to bring in. To minimize perspiration, the labour room should be kept cool, particularly if the patient is lying on an occlusive surface. Air conditioning or fans may help, but can worsen dryness of the eyes. B.6 Catheterization R27 ↓↓ Avoid unnecessary urinary catheterization, which may damage the urethral lining of patients with severe EB subtypes. If needed, the smallest possible silicone urinary catheter should be selected. This should be well lubricated prior to insertion.24 B.7 Cannulation and securing intravenous lines Intravenous access may be challenging, particularly in women with more severe EB.46 R28 GPP If venous access is difficult, offer ultrasound-guided cannulation, where available.19 Skin preparation should involve gently dabbing, rather than rubbing, the skin with cleansing solution.12, 29, 49 Cannulas should be secured with low-adherent film, where available. If sticky film is used, MARS should be used for its removal.24, 29, 53 B.8 Analgesia B.9 Anaesthetic management Ideally, anaesthetic assessment should take place antenatally for women with complex forms of EB, such as RDEB.29 R30 ↑↑ If a caesarean section is planned, regional anaesthesia (spinal or epidural) should be offered, where possible.9, 19, 29, 46, 49, 54 Rarely, patients with extensive skin involvement involving the back, precluding neuraxial anaesthesia, may need assessment for general anaesthetic (GA).55 B.10 Inducing labour R33 ↑ Consider induction of labour if needed, as this is not contraindicated in EB.21, 39 Care should be taken to avoid vaginal/perineal trauma when rupturing membranes and/or introducing vaginal pessaries. When carrying out speculum or VE, inserting or removing pessaries, or rupturing membranes, gloves should be well lubricated and the procedure conducted as gently as possible.24 B.11 Birth setting R34 Θ Hydrotherapy during labour and water birth may be considered in EB. Although home birth may be feasible, it should not be considered if there is risk of an affected neonate. B.12 Instrumental delivery R35 ↓↓ Avoid instrumental delivery, including vacuum suction or forceps-assisted delivery, where possible, both to minimize skin trauma to the mother's vulvovaginal surface and perineum, as well as to a potentially affected neonate.9, 19, 24 B.13 Caesarean section B.14 Episiotomy and tears R37 ↑ The decision to undertake episiotomy should be directed by obstetric indication and may be offered in EB. Episiotomies and tears heal well in EB.9, 12, 19, 39, 41, 42, 56 Stitches should be applied following standard obstetric practice and removed within the recommended timescale. B.15 Anti-thromboembolism management R38 ↓↓Avoid the use of compression stockings as friction caused by their application and removal may damage the skin.12, 29 B.16 Mother–infant bonding/skin-to-skin R39 GPP Encourage direct skin-to-skin contact where possible. See Table 4 for a summary of the recommendations for labour/delivery in women with EB. Recommendation Bolt et al.,12 Shah et al.19 ⇨Pillay24 Shah et al.19 ⇨Pillay24 Intong et al.9 Shah et al.,19 Baloch et al.,29 Araujo et al.46 ⇨Pillay24 Choi et al.,39 Berryhill et al.55 ⇨Pillay,24 Denyer and Pillay53 Intong et al.,9 Shah et al.19 ⇨Pillay24 Bianca et al.20 ⇨Pillay24 ↑↑ ↓↓ C: Postnatal care and management C.1 Perineal care C.2 Care of caesarean section wound R41 ↑↑Offer nonadherent dressings and MARS for caesarean section wounds. These generally heal well;9, 11, 12, 19, 29, 40, 41, 46, 48, 56 however, blistering of the scar site has been described.9, 20, 56 C.3 Prevention of venous thrombosis R42 ↓↓ Avoid compression stockings for women with severe EB due to the unavoidable shearing forces associated with use.12, 29 Patients with EB do not appear to be at greater risk for venous thromboembolism during pregnancy/postpartum, compared with other pregnant women.29 However, in women at high risk of a thromboembolic event, low-molecular-weight heparin can be given as per local guidelines.29 C.4 Infant feeding R43 GPP Assess factors such as the woman's EB subtype, social support structures, condition of wounds on breasts or hands, and pain management when supporting a woman in deciding how to feed her baby. C.5 Support for breastfeeding and breast care C.6 Formula feeding and mixed feeding R45 ↑↑ Plan support for women with pseudosyndactyly who may need assistance with the preparation of formula. If formula feeding or mixed feeding is chosen, management of infant formula should be included in the postnatal care plan. C.7 Planning discharge R46 ↑↑ In general, women with EB do not need longer postnatal hospital admission. See Table 5 for a summary of the recommendations in postnatal care. Recommendation Intong et al.,9 Bolt et al.,12 Boria et al.,18 Baloch et al.,29 Hanufusa et al.,42 Mallipeddi et al.,44 Colgrove et al.,48 Broster et al.54 ⇨Pillay24 Women with EB should be encouraged in their reproductive choices. With the appropriate genetic counselling, and a planned approach to care, positive pregnancy experiences and outcomes for mothers with EB and their babies can be achieved. Despite the limited evidence base, it is clear that women with EB can have successful pregnancies and deliveries, even in more severe EB subtypes. MDT input is critical to ensuring sustained quality of care. Future research should include the establishment of an international registry for pregnant women with EB. Collection of real-world data on pregnancies and postnatal outcomes in women with EB would better direct future guideline development and more accurately refine advice, stratified according to EB subtype. This would help standardize EB pregnancy management internationally. There is a dearth of information regarding the psychological aspects of maternal and partner health related to family planning, and this should be explored. EB is a rare condition, posing challenges to the conduct of research. Substantial clinical heterogeneity exists between subtypes, limiting the generalizability of advice for different patient groups. Most of the available literature relates to prenatal diagnosis of severe forms of EB, as well as affected neonatal management, but specific guidance on antenatal, intra- and postpartum management has not been comprehensively explored.9 These CPG recommendations are supported largely by low-level evidence, and therefore we have relied heavily upon expert panel consensus. The authors would like to thank Kattya Mayre-Chilton for invaluable support and guidance in coordinating this guideline. We are grateful to DEBRA International and DEBRA UK for initiating the guideline and providing financial support. We also thank DEBRA Switzerland for hosting the panel in Zermatt during the International DEBRA Congress in 2018, and the EB2020 world congress organizers for hosting our recommendation panel meeting in London. Danielle Talia Greenblatt: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Funding acquisition (equal); Investigation (equal); Methodology (equal); Supervision (equal); Writing-original draft (lead); Writing-review & editing (equal). Elizabeth Pillay: Conceptualization (equal); Data curation (equal); Investigation (equal); Writing-original draft (equal); Writing-review & editing (equal). Karen Snelson: Conceptualization (equal); Data curation (equal); Investigation (equal); Writing-original draft (equal); Writing-review & editing (equal). Rebecca Saad: Investigation (equal); Methodology (equal); Writing-original draft (equal); Writing-review & editing (equal). Maurico Torres Pradilla: Conceptualization (equal); Investigation (equal); Methodology (equal); Writing-original draft (equal); Writing-review & editing (equal). Suci Widhiati Riza: Conceptualization (equal); Investigation (equal); Writing-original draft (equal); Writing-review & editing (equal). Anja Diem: Conceptualization (equal); Investigation (equal); Writing-review & editing (equal). Caroline Knight: Conceptualization (equal); Writing-review & editing (equal). Kerry Thompson: Conceptualization (equal); Investigation (equal); Writing-review & editing (equal). Nina Azzopardi: Conceptualization (equal); Investigation (equal); Writing-review & editing (equal). Mia Werkentoft: Conceptualization (equal); Investigation (equal); Writing-review & editing (equal). Zena E. H. Moore: Data curation (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Writing-review & editing (equal). Declan Patton: Data curation (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Writing-review & editing (equal). Kattya Mayre-Chilton: Conceptualization (equal); Formal analysis (equal); Funding acquisition (equal); Methodology (equal); Project administration (equal); Writing-review & editing (equal). Dedee F Murrell: Conceptualization (equal); Data curation (equal); Investigation (equal); Writing-review & editing (equal). Jemima Mellerio: Conceptualization (equal); Investigation (equal); Supervision (equal); Writing-original draft (equal); Writing-review & editing (equal). Table S1 Appraisal tool. Appendix S1 Stakeholder involvement and peer review, and methodology. Appendix S2 Strength of recommendations rating. Appendix S3 External review panel. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.