# 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

## 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

## 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.