What is the Risk of Chromosomal Abnormalities in Women of Advanced Maternal Age?

Patient Presentation
A 35-year-old gravida 2, para 1, female came to clinic with her spouse and 2 year old daughter for a prenatal appointment. She was only 15 weeks into her pregnancy but had recently moved and wanted to establish care. She was scheduled for an amniocentesis next week and was very anxious because a first cousin’s son was recently diagnosed with a “genetic problem,” where he is expected to have mental retardation.
The mother has no other information about this infant, but that her cousin has been devastated by the news.
The family history revealed heart disease and stroke in relatives in their 70’s on the mother’s side. The father’s side of the family had lung cancer and diabetes. The two year old sibling was well and her medical records were being transferred.
The family had no other specific concerns and the rest of the interview revealed no specific concerns about the physical, mental or psycho-social health of the family.
The family was counseled to try to find out more information about the affected infant cousin – most importantly the name of the problem and how it was diagnosed. The family was also told that depending on the particular problem that other information may also be helpful such as obtaining medical records. Once this information was known, the family was told to discuss it with their obstetrician who could then make
appropriate arrangements to have them counseled prior to the amniocentesis and arrange for specific testing of the “genetic problem” if it is available. The pediatrician also offered to help review the medical information with the family and assist in the decision-making process if they wished.

Early prenatal care has been shown to improve the obstetrical and pediatric outcomes for families. As part of routine prenatal care, the mother has numerous tests performed to determine risk factors for screening of potentially harmful health problems.

Indications for referrals for prenatal diagnosis include:

    Child or Family members with

    • Multiple malformations in a child or a family history of such a problem
    • Mental retardation or developmental delays or family history of such a problem
    • Known or suspected metabolic disorder such as neonatal deaths, failure to thrive, organomegaly or loss of developmental milestones
    • Birth defects such as cleft lip/palate, clubfoot, congenital heart disease, or neural tube defects
    • Unusual looking child especially if he/she also has failure to thrive, developmental delays or mental retardation
    • Known chromosomal abnormality
    • Known hereditary disorders and/or where the family has questions about recurrence risks
    • Family history of hearing loss, blindness, neurodegenerative disorders, short stature, premature heart disease, immune deficiency, abnormalities of the hair, skin, bones, or cancer
    Parents with

    • Primary amenorrhea, aspermia, infertility or abnormal sexual development in the parents
    • Recurrent pregnancy loss or stillbirth (usually two or more)
    • Advanced parental age – mother > 35 years, father >55 years
    • Related closely by blood
    • Member of a specific ethnic group with an increased risk of a specific genetic disease
    • Questions about prenatal diagnosis for any disorder
    Mother with

    • Exposure to potential teratogens
    • A hereditary disorder who is considering a pregnancy
    • Abnormal prenatal testing such as multiple marker screening or fetal ultrasound

Testing can include chromosomal analysis (which tests the total numbers or large parts of chromosomes, examples include Down Syndrome and Trisomy 18), molecular genetic studies (which tests single gene changes or small parts of chromosomes, examples include Duchenne muscular dystrophy or Fragile X) or biochemical studies (tests for an over- or under-production of a specific biochemical, examples include Smith-Lemli-Opitz or Tay-Sachs Disease).

Prenatal diagnostic techniques include:

  • Amniocentesis is usually performed at 15-18 weeks gestation by removing a small amount of amniotic fluid. Risks include fetal loss (0.5% overall), chorioamnionitis, fetal injury and maternal Rh sensitization.
  • Chorionic villus sampling is usually performed at 10-12 weeks gestation by removing a small amount of the placenta transcervically. The risks include a higher rate of fetal loss than amniocentesis and limb reduction abnormalities.
  • Fetal blood sampling is performed by inserting a spinal needle into the umbilical artery or vein. The risks include fetal loss of 1-2%.
  • Preimplantation genetic diagnosis is performed on invitro fertilized eggs at an early stage of development. This is only performed in a limited number of centers.
  • Ultrasound can be performed at any gestational age, but usually around 18-22 weeks of gestation for a wide variety of indications. The risks include over- or under-diagnosis of physical abnormalities.
  • Magnetic resonance imaging can be performed in the second and third trimesters to follow-up abnormalities seen on ultrasound. This can be useful for central nervous system problems but is limited because of fetal movement.
  • Fetal echocardiography is performed generally after 20 weeks gestation.

The pediatrician’s role in prenatal diagnosis may include:

  • Counseling the family about risks and benefits
  • Being familiar with local and regional resources for diagnosis
  • Care coordination with other healthcare providers obstetricians, maternal-fetal medicine specialists, clinical geneticists or genetic counselers, and neonatologists
  • Reviewing the information provided by other health care providers
  • Assisting in, and supporting the family in the decision-making process

Learning Point
The risk for chromosomal abnormalities and Down Syndrome specifically increases with increased maternal age. According to the American College of Obstetricians and Gynecologists, women with a singleton pregnancies who will be 35 years of age or more at birth should be offered prenatal diagnosis for chromosomal abnormalities.

The risks for chromosomal abnormalities from a 1983 article in JAMA are:

Maternal Age at Delivery   Risk for All Chromosomal  Risk for Down
				Abnormalities		Syndrome
	33 			1/345			1/602
	34			1/270			1/485
	35			1/213			1/376
	36			1/169			1/289
	37			1/132			1/224
	38			1/103			1/174
	39			1/81			1/136
	40			1/64			1/106
	41			1/50			1/82
	42			1/39			1/63
	43			1/31			1/49
	44			1/24			1/38
	45			1/19			1/30
	46			1/15			1/23
	47			1/12			1/18
	48			1/9			1/14
	49			1/7			1/11

Questions for Further Discussion
1. What are the current recommendations for prenatal screening for cystic fibrosis?
2. What are the current recomendations for prenatal screening for parents of Eastern European Jewish heritage?
3. What changes are being considered for post-natal universal screening of infants for metabolic diseases?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Birth Defects.

To view current news articles on this topic check Google News.

Hook EB, Cross PK, Schreinemachers, DM. Chromosomal abnormality rates at amniocentesis and in live-born infants. JAMA. 1983:249(15);2034-38.

ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol. 2001 May;97:suppl 1-12. Available from the Internet at: http://www.guideline.gov/summary/summary.aspx?doc_id=3976&nbr=3115&string=Prenatal+AND+diagnosis+AND+fetal+AND+chromosomal+AND+abnormalities (cited 6/2/05).

American Academy of Pediatrics Clinical Report. Prenatal Screening and Diagnosis for Pediatricians. Pediatrics. 2004:114:889-894. Available from the Internet at: http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=5741 (rev. 9/2004, cited 5/23/05).

University of Washington. GeneTests. Available from the Internet at: http://www.geneclinics.org/servlet/access?id=8888891&key=KSDx8qL4ONueK&fcn=y&fw=vVyI&filename=/concepts/primer/primerwhoshould.html (rev. 2005, cited 5/23/05).

Mountain States Genetic Network. Indications for Genetic Counseling Referrals. Available from the Internet at: http://www.mostgene.org/dir/indicate.htm (cited 5/23/05).

Donna M. D’Alessandro, MD
Associate Professor of Pediatrics, Children’s Hospital of Iowa

July 18, 2005

How Does Acute Leukemia Present?

Patient Presentation
A 16-year-old female came to the emergency room after tripping on a loose piece of carpeting and falling down several stairs hitting her head. Her mother was concerned after the girl stated she was dizzy after the fall. The dizziness stopped on the way to the hospital. She had no loss of consciousness, or other mental status changes and she remembered all events before and after the fall.
Her past medical history, family history, and review of systems were normal.
The pertinent physical exam showed her mental status examination to be alert and oriented to time, place, person and situation. Her neurological examination was normal. Her skin showed some petechiae on her calves where she had had tight fitting socks.
As her presentation was identified as a trauma visit, she had a basic laboratory evaluation completed. The physician was surprised when the laboratory called and said the complete blood count had many atypical lymphocytes that all looked the same on the blood smear. The platelet count was also decreased at 100,000 /mm2.
After reviewing the blood smear, the physician was suspicious that the atypical lymphocytes were blast cells.
She arranged for transfer to a local children’s hospital where the diagnosis of acute lymphoblastic leukemia was confirmed.

The diagnosis of acute leukemia used to be a death sentence for the patients and families. According to some of the pre-eminant oncologists of the 20th century, Drs. Blackfan, Diamond and Leister,
“The course of leukemia varies widely from the most acute form in which symptoms progress rapidly to a fatal termination in within one to four weeks, to the subacute and chronic forms which may continue for weeks to months or rarely for a few years.”
“Because the disease is uniformly fatal, treatment should be directed toward modifying the symptoms so that the patient may enjoy relative comfort.”

Today, thanks to years of productive research and clinical trials, ~80% of children and adolescents with acute lymphoblastic leukemia, and ~50% of those with acute myeloid leukemia can be cured.

After the diagnosis of acute leukemia is made, the prognostic risk factors must be defined as they will determine the type of treatment necessary so the patient is not under- or over-treated.
These major risk factors include clinical features, genetic abnormalities in the leukemic cells, pharmacodynamics, pharmacogenetics, and early treatment response.

On the basis of prognostic factors, patients generally are assigned to one of three risk groups – standard risk, high risk or very high risk. Some groups advocate for a fourth group – very low risk. The group assigned generally determines the intensity of post-remission treatment the patient receives including the possibility of bone marrow transplantation.
Male sex and black race are associated with a higher risk but the reasons for this appear to be multifactorial and the effectiveness of treatment for these groups appears to be improving.

B-Cell Acute Lymphoblastic Leukemia Risk Factors

  • Favorable
    • Hyperdiploidy (> 50 chromosomes)
    • TEL-AML1 fusion
    • Trisomies 4,10, and 17
  • Unfavorable
    • Poor early response
    • MLL rearrangement in infants
    • Philadelphia chromosome
    • Leukocyte count > 50 x 109/L
    • Age > 10 years at diagnosis

T-Cell Acute Lymphoblastic Leukemia Risk Factors

  • Favorable
    • HOX11 overexpression
    • t(11;19) with MLL-ENL fusion
  • Unfavorable
    • Poor early response
    • Low dose-intensity chemotherapy

Learning Point
Presenting symptoms and signs of acute leukemia include:


  • Anorexia
  • Bleeding manifestations – bleeding, bruising, petechiae, purpura
  • Dyspnea
  • Fainting
  • Fever
  • Headache
  • Infection
  • Mass – secondary to metastasis
  • Mental status changes
  • Oliguria or anuria
  • Pain – abdominal, bone, joint
  • Pallor
  • Palpitations
  • Skin changes – nodules, urticaria
  • Seizures
  • Superior vena cava syndrome
  • Visual changes
  • Weight loss


  • Anemia
  • Cranial neuropathies
  • Disseminated intravascular coagulation,
  • Hepatosplenomegaly
  • Hyphema
  • Idiosyncratic
  • Lymphadenopathy
  • Mediastinal mass
  • Neutropenia
  • Papilledema
  • Renal failure
  • Thrombocytopenia

Questions for Further Discussion
1. What are the presentations for intracranial malignancies?
2. What are the presentations for abdominal malignancies?
3. What are the presentations for thoracic malignancies?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Leukemia.

To view current news articles on this topic check Google News.

Atlas of the Blood in Children. Blackfan KD, Diamond LK, Leister CM. The Commonwealth Fund. 1944;119-120.

Stockman JA. Corden TE. Kim JJ. Pediatric Book of Lists. Mosby-Year Book, St. Louis, MO. 1991:233.

Cohen PS. Cancer in Children in Pediatrics A Primary Care Approach. Berkowitz CD. edit. W.B. Saunders, Philadelphia, PA. 1996:445-451.

Pui C, Schrappe M, Ribeiro RC, Niemeyer CM. Childhood and Adolescent Lymphoid and Myeloid Leukemia. Hematology. 2004:118-45. Available from the Internet at: http://www.asheducationbook.org/cgi/content/full/2004/1/118.

Donna M. D’Alessandro, MD
Associate Professor of Pediatrics, Children’s Hospital of Iowa

July 12, 2005

What are the Indications for a Tonsillectomy?

Patient Presentation
An 8-year-old female came to clinic with acute onset of severe sore throat, fever and malaise for 1 day. Streptococcal pharyngitis is in her school and the community.
The past medical history reveals that she has had two prior streptococcal pharyngitis episodes documented by throat culture in the past year. She had two documented streptococcal pharyngitis episodes 1 year ago. She has had several viral upper respiratory infections and pharyngitis in the past two years.
The pertinent physical exam reveals a child in mild discomfort because of pain. She has a temperature of 38.5 degrees Celsius. Her tonsils are swollen just beyond the tonsillar pillars bilaterally, with enlarged crypts and white exudate on them. There are palatal petechiae.
She had mild cervical adenopathy and her ears are normal. The rest of her examination is normal.
The laboratory evaluation shows a positive rapid streptococcal antigen test.
The diagnosis of streptococcal pharyngitis is made and she is going to be treated with Penicillin V. During the discussion her father asks if she can have her tonsils out to prevent future streptococcal infections.
The general indications for tonsillectomy were discussed as well as the relative effectiveness of tonsillectomy for preventing infection. The father says he wants to discuss this more with his wife but still may want a referral to otolaryngology.

Streptococcal pharyngitis is caused by Group A, Beta-hemolytic Streptoccus pyogenes (GAS). GAS is a common illness for people of all ages, but especially in children and adoelscents. The incubation period for strep throat is 2-5 days, and the diagnosis is made by rapid antigen testing and culture. The treatment of choice is Penicillin V, with Erythromycin or an oral Cephalosporin as alternatives for people allergic to penicillin.
Prior to effective antibiotics, and for some patients left untreated, complications of GAS can occur including abscesses of the peritonsillar and retropharyngeal areas, cervical adenitis, otitis media and sinusitis.

Nonsupprative sequelae of GAS include acute rheumatic fever and acute glomerulonephritis. GAS can cause numerous invasive infections also such as pneumonia, endocarditis, osteomyelitis, sepsis and toxic shock syndrome, to name a few.

Management of a patient with repeated frequent episodes of acute pharyngitis with positive laboratory testing for GAS can be problematic. Pharyngeal carriage of GAS is common.

To determine pharyngeal carriage the following factors must be considered:

  • Were the clinical findings of the episodes more suggestive of GAS or viral infection?
  • Were the community epidemiological factors during the episodes more suggestive of GAS or viral infection?
  • What was the clinical response to antimicrobial therapy (usually very rapid for GAS)?
  • Are laboratory tests positive for GAS between episodes of acute pharyngitis?
  • Has a serological response to GAS antigens, such as Antistreptolysin O, occurred?

Antibiotics are not indicated for GAS carriers and carriage can be difficult to eradicate. The Academy of Pediatrics has recommendations for possible carriage eradication and suggested antibiotic regimens (See To Learn More below).

Treatment for tonsillitis has changed over the years. In 1896, one of the United States’ premier pediatricians, Thomas Morgan Rotch said that the treatment for acute follicular tonsillitis “should be entirely symptomatic.” “I am in the habit of having the throat kept
throughly clean with mild solutions of chlorate of potassium or borate of sodium. Holding pieces of cracked iced in the mouth often affords considerable relief.” For chronic tonsillitis, he said, “The most thorough and certain way of curing the disease is, however, by excision. This should be done with the tonsillotome, and it is best to etherize the child for the operation.”Tonsillectomy was much more common in the earlier part of the 20th century, but with the widespread use of effective antibiotics, tonsillectomies for recurrent GAS pharyngitis have decreased.

One meta-analysis found adenotonsillectomy to decrease sore throat episodes (caused by all organisms) by 1.2 episodes per year, to decrease school absence due to sore throats by 2.8 days per year and to decrease upper respiratory infections by 0.5 episodes per year.

Learning Point
After searching the National Guideline Clearinghouse, the American Academy of Pediatrics website, and several other databases and national organization websites, the following evidence-based indications for tonsillectomy were found from the Finnish Medical Society.
These indications are categorized as level C evidence, i.e. limited research-based evidence with at least one adequate scientific study.
They are:

  • Recurrent, confirmed bacterial tonsillitis ( > 4 times/year), irrespective of the type of bacteria
  • Complications of acute tonsillitis such as peritonsillar abscess or septicemia originating from the tonsils
  • Peritonsillar abscess in a patient < 40 years of age
  • Suspected malignancy including marked asymmetry or ulceration
  • Airway obstruction caused by tonsils, sleep apnea, or disorder of dental occlusion
  • Chronic tonsillitis is a relative indication. It is indicated if the patient continuously has bad breath, sore throat, and gagging, and if the symptoms do not decrease during follow-up.

Questions for Further Discussion
1. What is the youngest age that a child generally can get the nonsupprative complications of GAS?
2. Should a child who is too young to get the nonsupprative complications of GAS still receive antibiotic treatment?
3. What is the relative sensitivity and specificity of rapid antigen tests?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Strep Throat / Strep Tonsillitis.

To view current news articles on this topic check Google News.

Rotch TM. Pediatrics. 1st Edition. J.B. Lippincott and Co. Philadelphia, PA. 1895;810-815.

American Academy of Pediatrics. Clinical Practice Guideline: Diagnosis and Management of Childhood Obstructive Sleep Apnea Syndrome. Pediatrics 2002 Apr;109(4):704-1. Available from the Internet at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;109/4/e69

American Academy of Pediatrics. Group A Streptococcal Infections, In Pickering LD, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th edit. Elk Grove Village, IL: American Academy of Pediatrics; 2003;573-584.

Finnish Medical Society Duodecim. Sore throat and Tonsillitis. In: EBM Guidelines. Evidence-Based Medicine [CD-ROM]. Helsinki, Finland: Duodecim Medical Publications Ltd.; 2004 May 13
A summary is available from the Internet at http://www.guideline.gov/ (rev. 05/13/04, cited 5/5/05).

van Staaij BK,et. al. Adenotonsillectomy for Upper Respiratory Infections: Evidence Based? Arch Dis Child. 2005 Jan;90(1):19-25.

Donna M. D’Alessandro, MD
Associate Professor of Pediatrics, Children’s Hospital of Iowa

July 5, 2005