Tag Archives: pregnancy

Reproductive Medicine – First Trimester Aneuploidy Screening – Part 2

© 2018, GENASSIST, Inc.    

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

OVERVIEW: We have known for years that children with chromosomal abnormalities and some structural abnormalities may demonstrate subtle differences on clinical examination.

Likewise, the mother’s age at conception, and the mode of conception [i.e. Invitro Fertilization (IVF) and the use of frozen eggs] can affect the calculated risk for a child with a chromosomal abnormality.

Just as the ethnic background can affect the likelihood of specific disorders (i.e. Cystic Fibrosis, Sickle Cell Anemia, Tay Sachs, Thalassemia etc) these differences can affect the ultrasound findings (e.g. biochemical blood results and fetal nasal bone).

Even with the introduction of Maternal Fetal DNA testing, “Markers” will continue to be useful for early fetuses at “risk” in addition to screening for aneuploidy.

MINOR MARKERS:

  • Choroid Plexus Cysts (cysts in the baby’s brain blood supply)
  • Echogenic Cardiac Focus/Echogenic Papillary Muscle (bright ultrasound echo in one or both large chambers of the baby’s heart)
  • Hydronephrosis/Pyelectasis (fluid in the baby’s kidneys)

Minor markers are found more commonly in fetuses with chromosomal abnormalities than in normal fetuses.

However, most fetuses with “minor markers” only, usually have normal chromosomes. The absence of any “ultrasound markers”, minor or major is reassuring and multiple minor markers or the presence of one or more minor markers in association with a major marker(s) increases the risk.

Except for the association of Choroid Plexus Cyst(s) in Trisomy 18 or less likely Trisomy 21, the other minor markers are associated most with Trisomy 21.

MAJOR MARKERS:

  • Atrial Septal Defect/ASD (hole in the septum that divides the small chambers of the baby’s heart). ASD increases the risk for Trisomy 21.
  • Diaphragmatic Hernia (defect in the diaphragm that separates the fetal chest from the abdomen). Diaphragmatic Hernia increases risk for Trisomy 18.
  • Exomphalos (hernia of baby’s bowel into umbilical cord). Exomphalos increases risk for Trisomy 13 & 18.
  • Holoprosenencephaly (abnormal frontal brain development of the baby). Holoprosenencephaly increases risk for Trisomy 13

Multiple abnormalities in a fetus increase the likelihood of Trisomy 13 and Trisomy 18 more than Trisomy 21.

BIOCHEMICAL MARKERS:

  • Free Beta HCG may be increased in Trisomy 13 or Trisomy 18 and is usually increased in Trisomy 21. In Triploidy (due to ovum defects), beta HCG may be low. If due to paternal etiology, beta HCG is usually increased. Beta HCG levels are usually normal in sex chromosomal abnormalities.
  • Pregnancy Associated Plasma Protein-A (PAPP-A) is usually low in Trisomy 13, Trisomy 18, Trisomy 21, sex chromosomal abnormalities and Triploidy. Maternal Triploidy may show the lowest PAPP-A values. Low PAPP-A (less than 0.3 MoM’s) are associated with preterm delivery, fetal growth restriction and fetal death.

Preeclampsia and Fetal Intrauterine Growth Restriction (IUGR).

Preeclampsia is more common in nulliparous and black women, women with a history of hypertension, preeclampsia in a prior pregnancy and women with a high Body Mass Index (BMI).

Combining maternal history with uterine artery doppler pulsatility index and PAPP-A at 11-14 weeks may help detect up to 80% of women who will develop preeclampsia before 34 weeks gestation and 40% of women who will develop later preeclampsia.

This compares with 30% detection using maternal history alone. These values can also be used to help predict IUGR.

ANALYSIS:

1st Trimester Aneuploidy Screening & “Markers” are still important non-invasive prenatal testing [NIPT] tools for the healthcare provider.

1st Trimester screening should continue to be used to help evaluate the “low risk” patient who is not a candidate for Maternal Fetal DNA testing and the “high risk” patient who declines having invasive testing, (i.e. CVS or amniocentesis), even when indicated.  

Maternal Fetal DNA testing usually will not identify structural problems unrelated to a chromosomal abnormality.

Reproductive Medicine – Viability Ultrasound

© 2018, GENASSIST, Inc.    

By Keith S. Wexler, MBA, CFO, Business Development Director, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

 OVERVIEW:

The ease and convenience of urine pregnancy test kits that are available across the counter may become positive as early as 6 days after fertilization. This has allowed a woman to know that she is “pregnant” even before she misses a period. Once a woman knows that she has a positive pregnancy test, it can be confirmed with a maternal serum blood Beta HCG test.

We are getting calls from patients in their third or fourth week of pregnancy, many times even before they have seen their healthcare provider, to have a Viability Ultrasound.

Although patients are anxious to see the baby’s heartbeat so they can be reassured about the health of the pregnancy, a Viability Ultrasound is usually deferred until at least 5 weeks 3 days from a last menstrual period. Often the heartbeat may not be visible until after 6 weeks gestation. Additionally, when a viability ultrasound is performed prior to 6 weeks gestation, a vaginal ultrasound is often the only way to confirm a heartbeat.

ANALYSIS:

We have to weigh the patient’s anxiety and excitement against the technological limitations of the ultrasound equipment. We tell patients that even with Invitro Fertilization (IVF), when we know exactly when fertilization took place, we do not know exactly when implantation of the embryo took place. Especially with infertility patients and multiple miscarriage patients, we usually want to wait until 6 1 / 2 weeks to 7 weeks gestation.

With all of the Non Invasive Prenatal Testing [NIPT] options available to the pregnant patient, more pressure is being placed on the healthcare provider to get a size and dates ultrasound early in pregnancy so that NIPT tests can be done as soon as possible. Some offices are delaying seeing a patient until 10 to 12 weeks gestation, leaving many patients in early pregnancy uncertain about the welfare of the pregnancy.

Many insurance companies will only pay for two ultrasounds in pregnancy. Healthcare providers usually choose a First Trimester Aneuploidy Ultrasound at 11 to 14 weeks gestation and a second ultrasound (a Level II Ultrasound) at 18 to 22 weeks gestation. Many insurance companies will NOT pay for a viability ultrasound unless there is a medical indication (e.g. bleeding in pregnancy).

A fetal heart may be seen with a transvaginal ultrasound when the fetal pole, usually seen attached to a yolk sac, measures greater than 2 mm. However, the fetal heart should be seen when the fetal pole measures 7 mm or greater.   Usually the heart beat is greater than 100 beats per minute by 6.3 weeks gestation and greater than 110 to 119 beats per minute by 6.4 to 7 weeks gestation.

When discussing weeks of gestation, dates are calculated from the first day of the patient’s last menstrual period (LMP). This is often confusing for patients since they are not pregnant on the first day of their LMP. The patient always expects that she is approximately 2 weeks less pregnant than the weeks gestation calculated by her healthcare provider which adds the approximately 2 weeks prior to ovulation when conception actually took place.

Patients talk about a pregnancy being 9 months long but medically a full term pregnancy is 40 weeks or 10 four week months from the LMP.

Occasionally a slow fetal heart rate (Fetal Bradycardia) will be detected early in pregnancy (e.g. less than 90 beats per minute before 6.3 weeks gestation from the LMP). Miscarriage rates appear to be increased in these cases (20% to 25%) compared with the miscarriage rate of only (5% to 10%) when fetal heart rates are in the normal range.

Some studies have suggested a possible increased risk for pregnancies with a slow fetal heart rate to have a slightly greater risk for a child with a chromosomal abnormality or heart defect whereas other studies have failed to show this relationship.

When a slower heart rate is detected in early pregnancy, the healthcare provider will often request a repeat ultrasound in 1-2 weeks to recheck the heart rate and ensure continued fetal viability. Additional testing may be recommended if the pregnancy continues.

Reproductive Medicine – West Nile & Zika

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background: Colorado has seen a recent surge in West Nile virus disease transmitted by the mosquito species called Culex Tarsalis. The virus is usually transmitted from infected birds to mosquitos. The virus can then be transmitted to horse and humans who do Not pass the virus to other mosquitos.

Human to human transmission does not occur. The greatest risk is from May through September with August and September having the greatest number of cases.

Incubation time is approximately 5-15 days.

With all of the media attention on the Zika virus, at risk states for West Nile virus need to focus not only on possible Zika cases but also the possibility of West Nile virus cases in pregnancy.

Many individuals exposed to the West Nile virus have no symptoms. Symptoms may include fever and can progress rarely to meningitis or encephalitis. Serious illness or death is rare but has been reported. Treatment is primarily supportive. Interferon therapy is currently being investigated.

The problem for the healthcare provider is that West Nile and Zika are acquired and can occur any time before, during or after the pregnancy,

The Zika Virus RNA-NAT (Nucleic Acid Test) is most informative 6 weeks after exposure. Beginning at 18-22 weeks, CDC recommendations in 2018 are for ultrasound every 3-4 weeks with specific attention to:

  • Growth
  • Fetal Anatomy
  • Particularly Neuroanatomy

*Microcephaly is defined as greater than 2 standard deviations below age appropriate head measurements.

More recent studies suggest that up to 20% of exposed infants may not demonstrate *microcephaly and the fetal impact in uncertain in these cases.

Pediatric evaluation should include age appropriate physical exam including hearing, vision testing and more complete evaluations for infants with positive Zika laboratory tests or birth defects.

The sensitivity, specificity, positive and negative predictive values for ultrasound in pregnancy is still uncertain. Ultrasound findings vary from time of exposure, with most studies suggesting most findings occurred approximately 18 weeks post onset of symptoms.

Analysis: Concern about the Zika virus is beginning to rise in the United States with increasing reports of the disease in the continental United States, not simply in patients who recently traveled to areas known to have reported cases of the disease [Brazil, Puerto Rico, Mexico, Southeast Asia (Micronesia), French Polynesia, South America and West Africa].

Although the discussion of Zika in the United States had only gained attention in the last 1-2 years, the Arbor Virus from the Flaviviridae family is transmitted by the same mosquito responsible for several other viral diseases.

Zika was first reported in Uganada in 1947 and isolated from Rhesus monkeys. Aedes Africanus mosquitos were identified as vectors in the Zika forest in Tanzania and Nigeria. At least 20 mosquito species have been identified as vectors with the genus Aedes being the main one.

Colorado gained some notoriety in 2008 as the first probable sexual transmission of the virus after a husband returned home from Senegal where he had become ill with the Zika infection.

In December 2015, the first case of locally acquired Zika infection was reported in Puerto Rico and in January 2016 the first reported case of intrauterine transmission of the virus to the fetus was associated with microcephaly (small head) in Brazil with the virus being identified in the amniotic fluid.

In February 2016 Suriname reported an increase in Guillain Barré cases dating back to 2015 in patients who tested positive for the Zika virus. Deaths occurred in primarily older males with underlying disease or other risk factors.

The two most common Aedes species are Aedes Aegypti (also known as the Yellow Fever mosquito) and Aedes Albopictus (also known as the Asian Tiger mosquito) that are primarily responsible for the transmission of :

  • Yellow Fever
  • Tick Borne Encephalitis
  • Chikungunya
  • Dengue Fever
  • West Nile
  • Zika

26 states in the Unites States have reported the Aedes Aegypti mosquito and 40 states and the District of Columbia reported the presence of the Aedes Albopictus mosquito. Locally occurring cases have been reported in Florida and Texas.

The Zika virus may be anticipated to occur in other areas of the United States, not including sexually transmitted disease.

Signs and Symptoms of Zika are usually mild and include fever, rash, joint pain and conjunctivitis.

Approximately 20% of patients manifest symptoms but many patients who have been identified as having been infected by laboratory diagnosis did not report symptoms.

Although microcephaly has been described in multiple newborns exposed to the Zika virus in the 1st and 2nd Trimester, it is estimated that as many as 20% of newborns identified as having been exposed to the Zika virus in pregnancy did Not manifest microcephaly. The future impact on this group of newborns to the Zika exposure is not yet known.*

As of August 1, 2016, blood testing is now available for determination of prior Zika infection whether or not typical symptoms were present or absent. Testing is slightly different for exposure before or after 30 days and care must be taken for “positive tests” that must be distinguished from other diseases which can cross react with some of these tests.

No specific treatment has been shown to be effective in preventing the viremia. Approximately 18 laboratories are pursuing a vaccine and testing was recently begun in the United States using up to 80 volunteers. It is hoped that a vaccination will be available by the end of 2017 or early 2018.

*The problem for the healthcare provider is that West Nile and Zika are acquired and can occur anytime during the pregnancy. When a pregnancy tests positive for the Zika virus, or the West Nile virus, it is recommended that serial ultrasounds be performed at 4-6 week intervals throughout the pregnancy to monitor fetal growth and well-being with particular attention to head measurements and cerebral findings.

 

 

 

 

 

 

 

 

 

Ultrasound Markers – Patau Syndrome

© 2018, GENASSIST, Inc.    

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Patau Syndrome (Trisomy 13) is characterized by three copies of chromosome #13 instead of the expected

two copies.  

The incidence of Patau Syndrome is approximately 1 in 2000 to 1 in 5000 births.

Ultrasound performed in pregnancy after 15 weeks gestation can help identify some babies with Trisomy 13.

Patau Syndrome Ultrasound “Markers:

  • Small Head
  • Small Orbits
  • Sloping Forehead
  • Low Set Ears
  • Cleft Lip/Cleft Palate
  • Extra Fingers and/or Toes
  • Possible Ambiguous Genitalia
  • Occasional Deficiency Development of the Front of the Brain
  • Excess Fluid Accumulation
  • Diaphragmatic Hernia
  • Hernia of Abdominal Wall
  • Heart Defect(s)

(1) The American College of Obstetricians & Gynecologists, Committee Opinion Number 545 December 2012, Publications Committee, “NonInvasive Prenatal Testing for Fetal Aneuploidy”.  The American College of Obstetricians and Gynecologists Committee on Genetics, The Society For Maternal-Fetal Medicine 

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