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

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 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

Discuss the Screening Options for Chromosome Abnormalities

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

Review and summarize major points

Elicit final questions and concerns

References

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

The information in this outline was last updated in 2002.