Prenatal Screening

Question 1

General Considerations for Prenatal Screening

Answer 1

• All women should be offered the option for prenatal screening for aneuploidy and major congenital anomalies. Certain factors and signs change the risk of fetal aneuploidy/congential abnormalities.

1. Maternal history: Age, previous aneuploidy pregnancy, maternal or paternal chromosomal rearrangements (Increase risk for chromosomal imbalance), history of congenital abnormalities, recurrent spontaneous abortions of unknown cause.
2. First trimester (11-13 weeks) ultrasound can provide information on various factors, including major structural anormalities and aneuploidy screening (NT).
3. Second trimester (18-22 weeks) ultrasound can be used to assess for structural abnormalities
4. First and/or second trimester maternal serum aneuploidy screening - using placental and fetal biochemical analytes with or without NT, as part of first trimester screening, or IPS.
5. NIPT (non-invasive prenatal testing) using circulating maternal plasma cfDNA (cell free DNA)

Question 2

Nuchal Translucency

Answer 2

• This is a screening test done during the first trimester ultrasound.
• This is a collection of fluid found under the back of the fetus via ultrasound. Fetus’s with this are more likely to have Downs.
• An NT above 3.5mm is associated with congenital heart disease, fetal akinesia, structural malformations, certain single gene disorders, chromosomal abnormalities, and poor pregnancy outcomes.

Question 3

Prenatal Aneuploidy Screening

Answer 3

• Current screening protocols for T21, T18, and T13 are based on maternal serum biochemical markers +/- NT.

1. Enhanced First Trimester Combined Screening(eFTS)
   
   • Available to all women between 11 weeks and 13 weeks 6 days. In eFTS 4 measurements are used together, along with age, to estimate risk. Results are available in the first trimester.
     
     • NT ultrasound
     • Maternal blood test - measures 4 substances
       
       • ↓ Pregnancy assoicated plasma protein A
       • ↑ Beta hGC
       • ↓ alpha fetoprotein
       • ↓Placental growth factor
2. Integrated Prenatal Screening (IPS). Results available in second trimester.
   
   • Frist Trimester = NT and PAPP-A
   • Second Trimester = AFP, BhCG, ↓uES (unconjugated estriol)
3. Serum Integrated Prenatal Screening. Results available in second trimester.
   
   • Frist Trimester = PAPP-A
   • Second Trimester = AFP, BhCG, uES, ↑DIA Idimeric inhibin A)
4. Quadruple Screening. Results available in second trimester.
   
   • Second Trimester = AFP, hCG, uEs, DIA

Question 4

cfDNA

Answer 4

• cfDNA is a screening test for aneuploidy. This is a good option for high risk patients who don’t want invasive testing.
• cfDNA are degraded cell fragments of the fetus that circulate in the maternal blood. It originates from the placental trophoblast. These fragements are ~200bP in length, which is significantly smaller than maternal DNA fragments.
• Invasive diagnostic testing with chorionic villus sampleing (CVS) or aminocentesis is recommended after a positive cfDNA.

Question 5

Fetal Sex Determination

Answer 5

• DNA sequences specific to the Y chromosome allow for determination of fetal sex by 7th postmenstrual week.
• Can due PCR testing in maternal blood for these sequences. The clinical indication for this is to determine risk for transmission of X-linked genetic disorder (Duchenee muscular dystrophy, X-linked hemophilia).
• Testing for this will also reveal potential disovery of sex chromosome aneuploidy. Women with + test results should be given option of invasive testing.

Question 6

Prenatal Screening Ultrasound Soft Markers

Answer 6

• There are 5 second trimester ultrasound soft markers that indicate increases risk for aneuploidy including enlarged nucheal folds, echogenic bowel, mild ventriculomegaly, echogenic heart focus, and choroid plexus cysts.
• These markers should not be used in isolation and should be used cautiously if effective first or second trimester aneuploidy screening has been carried out. It should not be used if cfDNA screening has been done.

Question 7

Screening algorithm

Answer 7

Question 8

Teratogen

Answer 8

• Any agent that can produce a birth defect or increase the incidence of a defect in the population
• Causes 7-10% of birth defects

Question 9

When do teratogens cause the most damage?

Answer 9

• Organs are most sensitive to effects of teratogens during periods of rapid differentiation (critical period).
  
  • Biochemical differentiation occurs before morphologic differentiation and thus the time when strucutures can be influences by teratogens occurs before visible development.
• During the first 2 weeks, teratogens don’t have an effect due to the lack of cellular differentiation (may result in death of embryo, but won’t cause defects).

Question 10

Critical Period

Answer 10

• The stage of embryological development when an agent is present determines its susceptibility to teratogens.
• Most criterial periods occur when cell division, cell differentiation, and morphogenesis are at their peak.
• Development of the embryo is most easily disturbed when tissues and organs are forming. During this oranogenetic period (4-8weeks), teratogens can cause major birth defects. Exposure later is more likely to result in less severe defects.
• Ex. Critical period brain: 3-16 weeks. However, the brain continues differentiating and growing even after birth and thus teratogens can still cause damage past this point.

Question 11

Medications as Teratogens

Answer 11

• 40-90% of women consume at least one drug during pregnancy. However, less than 2% of birth defects are caused by drugs or chemicals.
  
  • It is best to avoid using all medications during the first trimester unless there is a strong indication for use.

Question 12

Smoking as a teratogen

Answer 12

• Well established cause of intrauterine growth restricition. Also X2 risk of premature delivery and low birth weight.
• Nicotine restricits uterine blood vessels causing a decrease in uterine blood flow - this reduces O₂ and nutrients available to the fetus. May result in chronic fetal hypoxia affect fetal growth and development.

Question 13

Alcohol as a teratogen

Answer 13

• Moderate and high levels of alcohol during early pregnancy may result in alternations in growht and morphogenesis of the fetus/embryo.
  
  • Fetal alcohol spectrum disorder - range of physical and neurodevelopmental problems that can result from prenatal alcohol exposure.

Question 14

Infectious agents as teratogens

Answer 14

• Rubella - if it crosses the placenta in the first trimester it may infect the embryo/fetus and result in congenital rubella syndrome - cataracts, cardiac defects, and deafness.
• Herpes simplex - maternal infection in early pregnancy increases the risk of abortion. Infection after the 20th week is associated with higher rate of prematurity.
• Varicella - infection during first two trimester can result in teratogenic effects. After 20 weeks there is no teratogenic effect.
• Toxoplasmosis - parasite. Maternal infection can be acquired by eating raw meat or close contract with infected domestic animals (cats). Parasite can cross the placenta and lead to damage of brain and eyes.
• Syphilis - rapidly crosses the placental membrane and can infect the fetus at any stage of pregnancy.

Question 15

Venous thromboembolism (VTE) in Pregnancy

Answer 15

• Pregnancy and the post-partum period are well established risk factors for VTE.
  
  • Can manifest as lower extremity DVT or a clot can break off and lead to PE.
  • Thromobotic risk is highest in te first 6 week postpartum, but risk persists until 12 weeks postpartum.

Question 16

Pathogenesis of VTE in pregnancy

Answer 16

• Pregnancy and the postpartum period has all 3 compoents of virchows triad.

1. Statsis - venous stasis of lower extremities occurs in pregnacy due to changes in venus capacitance and compression of large veins by uterus.
   
   • Even before uterus has substantially enlarged, hormonally induced dilation of capacitance veins leads to venous pooling and valvular incompotence.
2. Endothelial injury - delivery is associated with vascular injury and changes at uteroplacental surface.
3. Hypercoagulability - pregnancy results in increase in certain coagulation factors + resistance to activated protein C is observed in the second and third trimester.

Question 17

Antiphosopholipid Syndrome (APS)

Answer 17

• A systemic autoimmune disorder characterized by venous of arterial thrombosis and/or pregnancy morbidity in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL).
• Clinical criteria: One or more of the following.
  
  • One or more episodes of vascular thromobosis
  • Pregnancy morbidity

Question 18

Prenatal Care -Vitamins and Minerals

Answer 18

• Standard prenatal vitamin with iron and folic acid satifies daily vitamin and mineral requriements
  
  • Iron - to prevent anemia
  • Folic acid - to reduce risk of open neural tube defect

Question 19

Prenatal care - diet and exercise

Answer 19

• Diet - shoud encourage appropriate weight gain
  
  • BMI <24.9 = 1-4lbs in first trimester & 1 lb/week after
  • BMI>25 = 1-4lbs in first trimester & .5 lb/week after
  • Underweight women are at increased risk of having small babies and overweight women have increase risk of a large baby
• Calories
  
  • First trimester = no change
  • Second trimester = increase daily intake by 340 calories
  • Third trimester = increase daily intake by 450 calories