Expert Opinions on Managing Fertility and Pregnancy in Patients With Mucopolysaccharidosis

Stewart, Fiona; Bentley, Andrew; Burton, Barbara K; Guffon, Nathalie; Hale, Susan L.; Harmatz, Paul R.; Kircher, Susanne G.; Kochhar, Pavan K.; Mitchell, John J.; Plöckinger, Ursula; Semotok, Jennifer; Graham, Sue; Sande, Stephen; Sisic, Zlatko; Johnston, Tracey A.

doi:10.1177/2326409816669375

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Journal of Inborn Errors of Metabolism and Screening

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Review • J. inborn errors metab. screen. 4 • 2016 • https://doi.org/10.1177/2326409816669375 copy

Expert Opinions on Managing Fertility and Pregnancy in Patients With Mucopolysaccharidosis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The mucopolysaccharidosis (MPS) disorders are rare genetic diseases caused by deficiencies in lysosomal enzymes involved in the degradation of glycosaminoglycans, leading to pulmonary, cardiac and neurological dysfunctions, skeletal anomalies, impaired vision, and/or hearing and shortened life spans. Whereas in the past, few individuals with MPS reached adulthood, better diagnosis, multidisciplinary care, and new therapies have led to an increasing number of adult patients with MPS. Therefore, fertility and pregnancy questions in this patient population are becoming more important. Management of fertility issues and pregnancy in patients with MPS is challenging due to the lack of documented cases and a dearth in the literature on this topic. This review presents multidisciplinary expert opinions on managing fertility and pregnancy based on case studies and clinical experience presented at a meeting of MPS specialists held in Berlin, Germany, in April 2015. An overview of the existing literature on this subject is also included.

Keywords
mucopolysaccharidoses; pregnancy; fertility; expert opinions; adult

MPS Type		Deficient Enzyme		Storage Material(s)		Disease Manifestations
MPS I (Hurler [MPS		α-L-iduronidase		Dermatan sulfate,		Dysostosis multiplex, joint stiffness, short
	IH], Hurler-Scheie				heparan sulfate		stature, cardiorespiratory disease, cognitive
	[MPS IHS], Scheie						decline (Hurler, Hurler-Scheie), corneal
	[MPS IS])						clouding, organomegaly
MPS II (Hunter)		Iduronate-2-sulfatase		Dermatan sulfate,		Dysostosis multiplex, joint stiffness, short
					heparan sulfate		stature, organomegaly, cognitive decline
							(severe form), cardiorespiratory disease, organomegaly
MPS III (Sanfilippo)		A: heparan N-sulfatase’ B: α-N-		Heparan sulfate		Profound cognitive decline, behavioral
			acetylglucosaminidase; C: acetyl-CoA: α-				problems, hyperactivity, relatively mild
			glucosaminide acetyltransferase; D: N-				somatic manifestations
			acetylglucosamine 6-sulfatase
MPS IV (Morquio)		A: N-acetylgalactosamine 6-sulfatase; B: β-		A: keratan sulfate,		Dysostosis multiplex, joint hypermobility/
			galactosidase		chondroitin		stiffness, dwarfism with short trunk and neck,
					sulfate; B:		cardiorespiratory disease, corneal clouding,
					keratan sulfate		atlantoaxial instability, organomegaly
MPS VI (Maroteaux-		Arylsulfatase B		Dermatan sulfate,		Dysostosis multiplex, joint stiffness, short
	Lamy)				chondroitin		stature, cardiorespiratory disease, corneal
				sulfate			clouding, organomegaly
MPS VII (Sly)		β-Glucuronidase		Dermatan sulfate,		Dysostosis multiplex, cognitive decline, corneal
					heparan sulfate,		clouding, organomegaly; wide spectrum of
					chondroitin		severity, including fetal and neonatal form
					sulfate

MPS Type	ERT			EU Label		USLabel
MPS I	Laronidase		Pregnancy	Aldurazyme should not be used during pregnancy		Pregnancy Category B ^a a Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women. ; Aldurazyme should be
		(Aldurazyme)			unless clearly necessary		used during pregnancy only if clearly needed
			Lactation	Because there are no data available in neonates		Calution should be exercised when Aldurazyme
					exposed to laronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment		is administered to a nursing woman
MPS II	Idursulfase		Pregnancy	There are no data or limited amount of data from		Pregnancy Category C ^b b Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. ; Elaprase should be used
		(Elaprase)			the use of idursulfase in pregnant women. As a precautionary measure, it is preferable to avoid the use of Elaprase during pregnancy		during pregnancy only if clearly needed
			Lactation	A decision must be made whether to discontinue		Caution should be exercised when Elaprase is
					breast-feeding or to discontinue/abstain from Elaprase therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman		administered to a nursing woman
MPS IVA	Elosulfase alfa		Pregnancy	It is preferable to avoid use of Vimizim during		Pregnancy Category C ^b b Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. ; Vimizim should be used
		(Vimizim)			pregnancy, unless clearly necessary		during pregnancy only if the potential benefit justifies the potential risk to the fetus
			Lactation	Vimizim should only be administered to breast-feeding		Exercise caution when administering Vimizim to
					women if the potential benefit is considered to outweigh the potential risk to the infant		a nursing mother
MPS VI	Galsulfase		Pregnancy	Naglazyme should not be used during pregnancy		Pregnancy Category B ^a a Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women. ; Naglazyme should be
		(Naglazyme)			unless clearly necessary		used during pregnancy only if clearly needed
			Lactation	It is not known whether galsulfase is excreted in		Caution should be exercised when Naglazyme is
					milk, therefore breast-feeding should be stopped during Naglazyme treatment		administered to a nursing mother

Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br

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[1] Corresponding Author: Fiona Stewart, Northern Ireland Regional Genetics Centre, Belfast City Hospital, 51 Lisburn Road, Belfast BT9 7AB, Northern Ireland, United Kingdom. Email: fiona.Stewart@belfasttrust.hscni.net

Before pregnancy
•	Involve a multidisciplinary team in advance (metabolic specialist, high-risk/maternal medicine obstetrician orgynecologist, pulmonologist, ear-nose-throat specialist, cardiologist, anesthesiologist, critical care physician, and psychologist) managed and guided by the physician who cares for the patient on a regular basis (metabolic physician, geneticist or pediatrician).
•	Assess cardiovascular/respiratory function and anesthetic risk: arterial blood gas, full blood count, biochemistry (renal function, liver function), cervical spine imaging, electrocardiography, echocardiography, and pulmonary function tests as indicated. Previous anesthetic records may indicate potential difficulties. Due to the heterogeneity of MPS, potential issues differ from patient to patient. Determining risk solely based on disease phenotype (e.g., slowly vs rapidly progressing disease) should be avoided.
•	Review drugs and modify for pregnancy if required. Discuss risks and benefits of using/continuing ERT during pregnancy. Notify pharmacovigilance if continuing ERT and/or registry (if available).
•	Prepare a comprehensive documented management plan covering all aspects of care to share with the team and the patient and with a local unit for cases of emergency.
During pregnancy
•	Schedule the patient for consultation in a unit with tertiary level maternal and neonatal care, ideally with inherited metabolic disease support on-site or colocated.
•	Refer the patient to the specialist involved in prepregnancy planning early during pregnancy.
•	Confirm management plan, review drugs if needed, and distribute the care plan to the multidisciplinary team and the patient.
•	Assess cardiovascular/respiratory function and anesthetic risk as early as possible (if not done before pregnancy), plan for regular review of the fetus, cardiovascular/respiratory and anesthetic risk factors, preeclampsia, diabetes, and cholestasis.
•	Patients should have an emergency card with contact information of care providers and general instructions regarding their condition and for anesthesia.
•	Noninvasive ventilation (NIV)/continuous positive airway pressure (CPAP) may be required in patients with or developing respiratory failure. Respiratory compromise as gestation advances often dictates timing of delivery.
•	Consider the size of the baby relative to the mother; in case of a severe disproportion, assess risks/benefits of early delivery.
Delivery
•	The baby should not be delivered prematurely unless there are issues with the maternal health.
•	Consider steroids for lung maturity and magnesium sulfate for neuroprotection dependent on gestational age.
•	Spontaneous vaginal delivery is advised, if appropriate. If this is not possible (eg, in case of cephalopelvic disproportion or after bilateral hip joint endoprosthesis) or if the anesthetic issues are such that emergency cesarean section may not be safe or achievable, elective cesarean section must be considered as a better option. Emergency cesarean section should be avoided as lack of preparation may lead to adverse outcomes. Delivery options should be discussed with the expectant parents.
•	Involve an anesthesiologist from the beginning to anticipate problems during delivery.
•	Prepare an individualized anesthetic plan for mode of anesthesia in advance. Regional anesthesia (spinal, combined spinal-epidural, or de novo epidural) is preferable but be prepared for conversion to general anesthesia for emergency cesarean section. Regional anesthesia is contraindicated in patients with spinal cord compression and may be difficult due to skeletal deformities, short stature, or inability to lie flat.
•	In patients with established or potential respiratory failure, the use of NIV and neuraxial (epidural) anesthesia should be considered.
•	Consideration should be given to maintain spontaneous ventilation. Use muscle relaxants with great caution as loss of airway tone after paralysis may totally occlude the airway. Consider securing the airway awake with a fiber-optic technique.
•	A difficult airway should be expected, and specialist equipment should be available to deal with a variety of airway situations. The use of videolaryngoscopes has been shown to be very useful in these types of cases.
Postdelivery
•	Delivery should take place in a unit where neonatal and maternal critical care facilities are available.
•	Evaluate and minimize the risk of postpartum hemorrhage
•	Monitor for cardiac decompensation; thromboprophylaxis will be a key consideration.
•	In patients with or developing respiratory failure, consider NIV or CPAP and sputum clearance techniques after delivery with general anesthesia to reduce the risk of early failed extubation requiring reintubation and atelectasis postanesthetic.
•	Consider increased risk of poor wound healing and incisional hernias.
•	Try to keep mother and child together with increased assistance due to physical handicap.
•	Close monitoring to provide follow-up care for the mother and newborn are essential to address any ongoing medical issue as well as to provide social and psychological support in the postpartum period.
•	Support from family, partner, and social services after delivery is very important for both time in hospital and at home. It can be challengingfor an individual with marked short stature and/or other physical issues such as stiffness ofthe hands to manage a small baby at home.

•	Provide ongoing education to patients about their disease, genetics, and inheritance
•	Start discussions about genetics and inheritance during teens. Explore relationship status and fertility desires from the time of transition from pediatric to adult health-care onward as part of an ‘‘annual review.’’ All patients of reproductive age, also those who are not in relationships, should be aware that pregnancy is possible with MPS. Further discuss genetics, fertility, and pregnancy with patients after expressing interest (at least before pregnancy)
•	Give contraceptive advice to those who are not planning a pregnancy, with special focus on those in vulnerable situations
•	Discuss the importance of multidisciplinary prepregnancy review and counseling and optimization of maternal health before pregnancy (including review of medications, evaluation of spinal problems, treatment of underlying cardiac issues, etc). Provide options of surrogacy, adoption, or to have no children if maternal health cannot support pregnancy
•	Inform women with MPS about anticipated issues in pregnancy before they get pregnant or before starting an assisted reproductive program. These include significant weight gain relative to body size, exacerbation of symptoms (eg, cardiac and respiratory problems, spinal cord compression, skeletal dysplasia, see ‘‘Evidence from literature’’), preterm delivery in case of very short stature or restrictive lung disease, likelihood of cesarean section, risks of emergency cesarean section and anesthesia, problems with wound healing and infection, risk of postpartum hemorrhage and incisional hernias, and potential long-term impact on health
•	Encourage involvement of the partner in pregnancy planning discussions if available and appropriate. Discuss recurrence risks and, if the partner does not have the same MPS, review availability of carrier testing for the partner. Discuss the risks, benefits, and limitations of prenatal testing options (including options if the fetus is affected) and preimplantation genetic diagnosis (if available) if the partner is a carrier
•	Assess family history, provide standard genetic preconception counseling, and discuss prevention of sexually transmitted diseases and general prenatal care