Speaker Disclosure: Maternal Genetic Conditions Affecting Pregnancy and the Fetus Nothing to Disclose Ben Li, MD University of California, San Francisco, Department of Obstetrics, Gynecology & Reproductive Sciences, San Francisco, CA June 9, 2016 Outline Background • Background Advances in early detection (i.e.: newborn screening), • Learning objectives medical care and artificial reproductive technology have • Key points allowed conception in an increasing number of women • Disorders who in previous generations • Things to think about during pregnancy (and would have been unable to before pregnancy!) reach childbearing age or have the ability to become pregnancy • Summary points 3 4
Background Learning Objectives • Understand the influence of some of the more • The number of women with various genetic common disorders on both the mother and fetus syndromes who are undergoing pregnancy is increasing • Be able to recognize potentially serious medical issues specific to each disorder • This represents an important issue for obstetric care providers • Understand that the fetus may face issues related to risk for inheritance of the genetic disorder itself, as • Potentially serious complications exist for the mother well as risks related to the chronic disease status of and fetus the mother 5 6 Marfan Syndrome Key Points • Preconception counseling • Autosomal dominant (AD) • FBN1 gene • Baseline evaluations and surveillance during pregnancy • Occurs in 2-3 per 10,000 individuals • Multidisciplinary team approach � MFMs and OBs • Skeletal: long bone overgrowth causing tall stature, � Anesthesiologists anterior chest deformity, loose joints � Subspecialists � Geneticists and Genetic Counselors • Ocular: ectopia lentis � Cardiologists � Hematologists • Cardiovascular: valve dysfunction, aortic � Etc aneurysm/dilation 7 8
What is the most serious pregnancy Marfan Syndrome complication of Marfan Syndrome? A. Preterm labor 95% B. Aortic dissection C. Postpartum hemorrhage 3% 1% 9 10 Marfan Syndrome Marfan Syndrome Management considerations: Potential pregnancy issues: • Beta blocker • Significant morbidity due to cardiovascular complications • Cardiology consultation with close echo surveillance • Risk for maternal mortality increases significantly if • Anesthesia consultation aortic root diameter > 40 mm, with 10% risk for dissection (ESC Task Force) • Trial of labor and vaginal delivery ok if stable aortic root diameter < 40 mm (Rossiter 1995) • Need echocardiogram to evaluate aortic root size and evidence of valvular abnormality • Risk of having affected child is 50% 11 12
Ehlers-Danlos Syndrome (EDS) • Heterogeneous group of connective tissue disorders • Various inheritance patterns and differing genetic mutations • Occurs in 1 per 5000 as a group • Cardinal manifestations include joint hypermobility, skin hyperextensibility, connect tissue fragility • Risk factor for cervical incompetence, aortic root dilation 13 14 Ehlers-Danlos Syndrome 3 (EDS 3) EDS 3 Potential pregnancy issues: • EDS type 3, most common type, and least severe • Subluxations and dislocations are common; they • EDS type 3 has AD inheritance may occur spontaneously or with minimal trauma and can be acutely painful • Causative gene has not been identified in the majority of cases • Risk factor for cervical incompetence, aortic root dilation 15 16
EDS 3 Ehlers-Danlos Syndrome 4 Management considerations: (EDS 4) • Cardiology consultation with close surveillance • EDS type 4 carries significant risk for obstetric • Anesthesia consultation complications due to fragility of arteries, intestines, uterus • Peripartum risks include postpartum hemorrhage and abnormal wound healing and scarring • Characteristic translucent skin and easy bruising • Safe to have a spontaneous vaginal delivery and • EDS type 4 has AD inheritance there is no clear advantage to vaginal versus cesarean delivery • COL3A1 gene • Risk of having affected child is 50% 17 18 What is the most serious pregnancy complication of EDS 4? EDS 4 59% Potential pregnancy issues: A. Preterm labor • Pregnancy mortality with EDS type 4 ~12% due to B. Uterine rupture 36% uterine or great vessel rupture during labor (Pepin C. Postpartum hemorrhage 2000, Murray 2014) • Risk factor for cervical incompetence and PTL, aortic 5% root dilation, vessel aneurysms, PPH, poor wound healing 19 20
EDS 4 Achondroplasia Management considerations: • Most common form of short limbed dwarfism • Cardiology consultation with close surveillance • AD inheritance • Anesthesia consultation • FGFR3 gene • Increased risk of uterine rupture has contributed to • Occurs in 1 per 26,000 individuals general recommendation for cesarean delivery before onset of labor • Skeletal: short stature, short extremities, macrocephaly, frontal bossing • Risk of having affected child is 50% 21 22 Achondroplasia Achondroplasia Management considerations: Potential pregnancy issues: • Baseline pulmonary function testing • Respiratory difficulties related to decreased functional residual capacity from increased uterine • Anesthesia consultation size and kyphoscoliosis • Cesarean delivery advised • Narrowed nasal passages and hypoplasia of the pharynx and maxilla contributing to difficult • Risk of having affected child is 50% if one affected endotracheal intubation (Kuczkowski 2003) parent • Shortened anteroposterior diameter of pelvic inlet • If both parents affected, 25% chance of having child results in risk for cephalopelvic disproportion with homozygous achondroplasia, a perinatal lethal (Allanson 1986) condition 23 24
Turner Syndrome Turner Syndrome Potential pregnancy issues: • Increased risk of preeclampsia, GDM, and thyroid • Complete or partial absence of the second X dysfunction (Boissonnas 2009) chromosome • Increased risk of aortic dilation and • Affects approximately 1 in 2500 live-born females dissection/rupture (2%) • Congenital heart defects, growth failure, primary • Coarctation, aortic size index > 25 mm/m 2 , infertility suggested as contraindications to pregnancy (Beauchesne 2001) • Pregnancy rates are similar to other women who undergo infertility treatments (Bondy 2007) • Short stature increases risk for cephalopelvic disproportion (Hadnott 2011) 25 26 Phenylketonuria (PKU) Turner Syndrome • Maternal deficient activity of the enzyme phenylalanine hydroxylase ( PAH gene), responsible Management considerations: for hydroxylation of the amino acid phenylalanine to • Cardiology consultation with close echo surveillance tyrosine • Anesthesia consultation • Accumulation of phenylalanine and its metabolites are neurotoxic • Number of reported spontaneous pregnancies is low and precise risk of transmission to offspring is • Autosomal recessive (AR) unknown • Occurs in 1 per 10,000 individuals of Northern European descent 27 28
What is the most important preconception PKU goal for PKU? Potential pregnancy issues: A. Metabolic genetics/nutritionist consult • Phenylalanine is teratogenic: congenital heart defect, to optimize nutrition in preparation for microcephaly, neurodevelopmental disability pregnancy 96% B. Strict adherence to a phenylalanine • Progressive mental retardation and irreversible restricted, low protein diet with neurologic impairment supplementation C. Goal for phenylalanine levels (2-6 • In untreated pregnancies in which the maternal blood mg/dL) to begin at least 3 months phenylalanine concentration was ≥ 20 mg/dL, 1% 2% 0% before conception microcephaly and intellectual disability occurred in D. All of the above 73 to 92% of the offspring, 12% had CHD, 26% IUGR (Platt 2000) 29 30 PKU PKU Management considerations continued: Management considerations: • Fetal echocardiogram given risk for CHD • Metabolic genetics consultation • Ultrasound growth surveillance given risk for fetal • Metabolic nutritionist consult to optimize adequate growth restriction pregnancy weight gain • Maternal decompensation during times of stress, • Strict adherence to a phenylalanine restricted, low prolonged fasting, or over-restriction of protein -> protein diet with supplementation catabolic state • Goal for phenylalanine levels (2-6 mg/dL) to begin at • If partner is carrier, 25% chance of having affected least 3 months before conception (Koch 2000) child 31 32
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