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

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Trisomy 13 - Advanced Maternal Age - Occupational Exposures

Introduction[edit]

  • 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[edit]

  • 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[edit]

  • 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?[edit]

  • 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[edit]

  • 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?[edit]

  • 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[edit]

  • 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 ________ ( %)

Exposures in Pregnancy

  • 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 glutaraldehye (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

Discuss the Screening Options for Chromosome Abnormalities[edit]

Chorionic Villus Sampling (CVS)[edit]

  • 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[edit]

  • 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[edit]

  • 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

Review and summarize major points[edit]

Elicit final questions and concerns[edit]

References[edit]

  • Smith's p 18-19
  • Gardner, R.J. McKinlay, and Grant R. Sutherland. Chromosome Abnormalities and Genetic Counseling. 1996. pp325-335, 252, 356-358, 362-364.
  • Reprotox at reprotox.org
  • Pediatric Database (PEDBASE) http://pedbase.org
  • Support Organization for Trisomy 18, 13, and Related Disorders. www.trisomy.org

Notes[edit]

The information in this outline was last updated in 2002.