Handbook of Genetic Counseling/Trisomy 13 - Advanced Maternal Age - Occupational Exposures

Trisomy 13 - Advanced Maternal Age - Occupational Exposures

Introduction

 * Discuss the reason for referral
 * AMA
 * Occupational exposures
 * Medication for migraines
 * Elicit prior knowledge
 * Trisomy 13
 * AMA
 * Exposures
 * Assess concerns and set goals for the session.
 * Provide overview of topics for counseling session
 * Pregnancy & family history
 * Address risks for the pregnancy
 * Introduce testing options

Client & Partner Information

 * Medical history
 * Any other chronic illnesses?
 * Migraines
 * Information about your husband:
 * Name, age, occupation?
 * Any exposures?
 * Any chronic illnesses?
 * Psychosocial assessment
 * Loss of prior pregnancy
 * Guilt about termination
 * Mourning for loss of fetus
 * Anxiety about future pregnancies
 * Self-blame
 * Did you name the fetus?
 * Do you have anything from the fetus such as ultrasound photos?
 * Support system
 * Friends and family in the area
 * Who did you tell about the condition?
 * What did you tell people about the loss?
 * How has it affected your marriage?
 * Future reproductive plans
 * Has it changed your future plans?
 * Would you again choose prenatal diagnosis?
 * How do the recurrence risk numbers feel to you?

Elicit History

 * Construct pedigree:
 * Abnormal # miscarriages, stillbirths, infant deaths?
 * Previous children with chromosome abnormality, Down syndrome, birth defects, mental retardation?
 * Consanguinity? Ethnicity? Other concerns/risk factors?

What is AMA?

 * Woman is age 35 & above at expected date of delivery.
 * As maternal age increases, risks of birth defects increase.
 * Women do not make new eggs like males make sperm.
 * They are born will all the eggs they will have in their life and these eggs mature with age.
 * There are procedures that can be done to assess the risk, but there are also risks associated with the procedures.
 * As women age, their risk of having a child with a chromosomal difference increases. Advanced maternal age begins at 35 years of age because a woman's risk of having a child with a chromosomal difference at 35 is equal to the risk of having a miscarriage via an amniocentesis (both risks are equal to 1 in 200).
 * The background risk for major birth defects for women of all ages is 3-5%.

Explain Chromosome Abnormalities

 * Explain genes and chromosomes
 * Show karyotypes
 * Show karyotype of fetus
 * Explain nondisjunction
 * Be prepared to explain meiosis in males versus females
 * Nondisjunction has not been found to be associated with environmental factors such as occupational exposures.
 * Show abnormal karyotypes (trisomy 13)
 * Give a general description of the clinical features and prognoses.
 * Trisomy 18 & 13 are most severe with most affected dying before the age of 1 year
 * Trisomy 21 is more mild; characteristic physical features and mild to moderate MR
 * Turner and Kleinfelter's syndromes are sex chromosome anomalies. Also usually mild.

What is Trisomy 13?

 * A chromosomal disorder resulting in a syndrome characterized by specific (midline) dysmorphic features and organ malformations
 * Pathogenesis:
 * A single defect during the first 3 weeks of development of the mesoderm
 * Leads to morphologic defects of the midface, eyes and forebrain
 * Natural History
 * Very poor prognosis
 * Median survival is 2.5 days
 * 82% die within the first month
 * 5% survive the first 6 months
 * Survivors show:
 * Severe mental defects
 * Seizures
 * Failure to thrive
 * Life-sustaining emergency surgery to a newborn with trisomy 13 may be inappropriate
 * Clinical Manifestations
 * Dysmorphic Features
 * Facial
 * Microcephaly
 * Wide sagittal sutures and fontanelles
 * Microphthalmia or anophthalmia
 * Cleft lip, cleft palate, or both
 * Abnormal or low-set ears often with deafness
 * Skeletal
 * Thin posterior or missing ribs
 * Simian crease
 * Flexion of the fingers
 * Camptodactyly
 * Polydactyly
 * Organ Malformations
 * Central Nervous System
 * Severe mental retardation
 * Holoprosencephaly (lack of the septation of the forebrain)
 * Apnea
 * Seizures
 * Cardiovascular
 * Coarctation, ASD, PDA, VSD, dextroposition
 * Gastrointestinal
 * Inguinal or umbilical hernia
 * Omphalocele
 * Genitourinary
 * Polycystic kidneys
 * Males: cryptorchidism, abnormal scrotum, ambiguous genitalia
 * Females: bicornuate uterus
 * Etiology
 * Trisomy 13
 * Occurs in 75% of cases
 * Due to meiotic nondisjunction
 * Translocation
 * 20% of cases
 * May be de novo or familial
 * Mosaicism
 * 5% of cases
 * Due to postzygotic mitotic nondisjunction
 * Usually less severe than full trisomy 13, but is variable
 * Incidence
 * 1/5000 - 1/12,000 live births
 * AMA is a risk factor
 * The prevalence of unbalanced chromosomal abnormality in the whole newborn population is about 1/250
 * Recurrence
 * Trisomy 13
 * There is not accurate empiric recurrence risk data for trisomy 13
 * It remains to be shown whether a true increased risk, taking maternal age into account, really exists
 * But, presumed that likelihood for recurrence is of "very low magnitude" for full trisomy 13 cases
 * Several studies have found no recurrences following approximately 100 pregnancies with trisomy 13
 * Prenatal diagnosis may be offered for reassurance
 * Maternal Serum Screening
 * CVS
 * Amniocentesis
 * Level II ultrasound

Quote Risks
Exposures in Pregnancy
 * Show charts to figure risk of chromosome abnormalities.
 * Give age-specific risks:
 * Age at EDD: ____________
 * Trisomy 13: 1 in ________
 * Down syndrome: 1 in _______ ( %)
 * Any CA: 1 in ________ ( %)
 * Types of studies done to assess safety in pregnancy
 * Animal studies
 * Case reports
 * Population studies
 * Explain what empirical data are
 * Occupational
 * Work with your employer to optimize safety conditions
 * Proper ventilation
 * Mask
 * Gloves
 * Lab coat
 * Cidex (Glutaraldehyde)
 * Chemical used in sterilization of medical instruments
 * Animal data
 * Was not teratogenic when administered in large doses to pregnant mice and rats
 * Human data
 * Questionnaire of women who sterilize instruments in hospitals found increase in miscarriage as compared to controls and compared to staff who were not involved in this activity during pregnancy
 * 16.7% in sterilizing staff, 10.6% in controls, 6.0% in sterilizing staff not exposed
 * BUT…when adjusted for age and other exposures, the significant increase in the miscarriage rate did not persist for glutaraldehyde (it did for ethylene oxide)
 * No information on birth defects was reported
 * Endozime
 * Bacteriostatic dual enzyme cleaner produced by Ruhof Corporation
 * No data on Reprotox
 * Migraine Medication
 * Must weigh the risk: benefit ratio
 * Asses the potential fetal risks
 * Determine the value of the medication to management of the mother's condition
 * Should speak to prescribing physician for recommendations
 * Imitrex (Sumatriptan)
 * A sulfonamide derivative used as a vasoconstrictor
 * Animal data
 * RATS
 * Did not impair fertility or reproductive success in rats at unspecified dose
 * No embryolethality at plasma levels 50x those in humans
 * No increase in congenital anomalies at unspecified subcu dose
 * Rabbits
 * Embryolethality occurred in pregnant rabbits treated at doses close to those producing maternal toxicity
 * This is 3x higher than dose attained in therapy for humans
 * Fetal
 * Human data
 * 15% of a single dose crosses the placenta as shown by in vitro studies
 * GlaxoSmithKline has a registry for exposure during pregnancy
 * 194 exposed pregnancies showed increase in adverse pregnancy outcome to be 3.1% which is the rate expected in the general population
 * There is a low level of excretion in breast milk, but this should not pose a risk because it is administered as a single dose at infrequent intervals
 * Zomig (Zolmitriptan)
 * Serotonin 1D agonist used as an antimigraine drug
 * Animal data
 * Administration to rats did not impair fertility
 * At plasma concentrations 5000x humans, there was an increase in embryolethality in rats
 * At 11x human dose in rabbits, embryolethality was also seen
 * Maternal toxicity occurred in these studies
 * Human data
 * There are no published references on human reproductive effects
 * Method of action is similar to Imitrex
 * Phenergan (Promethazine)
 * A phenothiazine with antihistaminic activity
 * Has been used as an antiemetic for morning sickness and an adjunct to narcotic analgesia during labor
 * Human data
 * Isolated reports of abnormalities have appeared, but have included other drugs and lacked proper control groups.
 * Better designed studies have shown no association with birth defects
 * For example the Collaborative Perinatal Project
 * Readily crosses the placenta when given near term
 * There are conflicting reports on neonatal respiratory depression after administration
 * There is no data on breast milk excretion
 * Demerol (Meperidine)
 * One of the most commonly used opioid analgesics
 * Animal Data
 * Increased incidence of exencephaly, cranioschisis, and other lesions in the hamster
 * Human Data
 * No association between use in the first trimester and abnormal morphologic development
 * Crosses the placenta and enters fetal circulation
 * Commonly used during parturition to sedate parturient and neonate (inadvertently)
 * Excreted into breast milk in small amounts; no adverse effects identified in nursing infants

Chorionic Villus Sampling (CVS)

 * What is it?
 * The chorionic villi are wisps of fetal tissue or finger-like projections that attach the pregnancy sac to the uterine wall
 * CVS is the technique in which this sample of placental tissue is obtained
 * It is unique because it is used to diagnose certain birth defects in the 1st trimester of pregnancy rather than later in the pregnancy like amniocentesis
 * It is usually performed at 10-12 weeks gestation
 * What can it NOT tell me?
 * CVS cannot detect neural tube defects such as spina bifida
 * For this reason, it may be useful to measure the amount of AFP in the maternal serum at 15-18 weeks gestation
 * Also, follow-up with US at 18-20 weeks is recommended
 * It cannot detect all birth defects or mental retardation
 * For example, congenital heart defects, cleft lip & palate cannot be seen.
 * Also the severity of the defect cannot be known from CVS
 * Exactly what does the procedure involve?
 * Show figures of CVS
 * Transcervical CVS:
 * Done at 10-12 weeks gestation
 * Gentle suction is applied to the tube to remove the villi
 * Discomfort is often minimal, perhaps similar to a pap smear
 * Transabdominal CVS:
 * Done at 10 weeks gestation or later
 * Using US to guide, a spinal needed is inserted through the abdomen into the uterine wall and into the placenta
 * The needle is moved back and forth several times through the placenta
 * Suction is used to remove the villi sample
 * CVS takes approximately 5-7 minutes (not including prep time)
 * The baby's heartbeat is monitored by US
 * The collected sample is examined under the microscope to confirm that fetal tissue and not maternal tissue was collected
 * If maternal cells were collected, the CVS will be repeated
 * The sample is sent to the lab
 * Results are available in approximately 10 days
 * What are the risks?
 * The background rate of pregnancy loss at 10-12 weeks is 2-3%
 * CVS increases the risk of miscarriage by 1/100 (1%) in women with a normal uterus
 * Reinforce that 99% of women will have a healthy baby
 * Some studies indicate an increased risk for limb defects when CVS is done before 10 weeks gestation
 * When performed at 10-12 weeks, most recent studies do not report an increased risk because limbs have already formed at this point
 * The risk is approximately 1/3000 (0.0003%)

Amniocentesis

 * What is it?
 * Procedure used to obtain a small sample of fluid from the fluid-filled sac that surrounds the fetus
 * Performed at 15 weeks gestation or later
 * 15-18 weeks is optimal because it leaves the patient with options
 * 22 weeks is probably the latest it can be done leaving the option of elective abortion
 * Amniotic fluid contains the fetus's urine as well as other cells from the skin, throat, and digestive tract
 * Fluid is studied in the lab for abnormalities
 * Exactly what does the procedure involve?
 * Show figure of amniocentesis.
 * You will lie down on your back with hands behind your head.
 * Your abdomen will be cleaned with alcohol or iodine.
 * A local anesthetic may be applied to your stomach.
 * Ultrasound will be used to locate the position of the baby and the placenta and to find a safe spot for the needle.
 * A long, thin needle will be inserted through the skin, into the uterus.
 * Then a small amount (about 1-2 tablespoons) of fluid is removed and the needle is withdrawn.
 * The procedure itself usually takes ~5 minutes.
 * The baby will quickly replace the fluid that is removed.
 * The baby's heartbeat will be monitored by ultrasound.
 * Fluid will be sent to the lab and results are available in 1-2 weeks.
 * What are the risks?
 * The risk of miscarriage is between 1/400 and 1/200.
 * This means that the added risk for pregnancy loss attributable to the procedure is 0.5% or less.
 * There is a risk of uterine infection but this is less than 1 in 1,000
 * There is a remote chance that birth defects can be caused by the amnio (0.1%).
 * There are special considerations for mothers who are Rh negative. They need to take RhoGam after the amnio procedure.

Offer Resources

 * March of Dimes information on prenatal diagnosis
 * www.modimes.org
 * 1-888-MODIMES


 * GlaxoSmithKline registry for Imitrex exposures during pregnancy
 * 1-800-336-2176


 * Reach out to Grieving Parents Support Group