Frequently Asked Questions for health care providers

Questions about:

The purpose of prenatal screening
Nuchal translucency (NT) ultrasound and the Integrated Prenatal Screen (IPS)
Amniocentesis
Multiple gestation pregnancies
Prenatal screen reports and results
Explaining screen results
Pregnancy dating and screen reinterpretation
Family history, smoking, IVF, and ethnicity

The Purpose of Prenatal Screening

What is the purpose of the screening?
Primary purpose is to screen for Down syndrome (trisomy 21), trisomy 18, and open neural tube defects (ONTDs).

Do the results of serum screening provide information other than risk for Down syndrome, trisomy 18 and open neural tube defects?
An unexplained low PAPP-A (≤ 0.4 MoM) in the first trimester or, in the second trimester, an unexplained elevation of maternal serum AFP (≥ 2.5 MoM), hCG (≥ 3.0 MoM) and/or inhibin-A (≥ 3.0 MoM) or a decreased level of unconjugated estriol (≤ 0.4 MoM) is associated with an increased frequency of adverse obstetrical outcomes such as pre-eclampsia, intrauterine growth restriction and abruption. Consultation with a maternal fetal medicine specialist or an obstetrician is recommended for these women. Targeted ultrasound assessments (including uterine artery Doppler) can be useful in refining the risks.

Screening will flag pregnancies at increased risk of Smith Lemli Opitz syndrome (SLOS) predominantly because of a low unconjugated estriol (uE3). Although the screen is reported as "increased risk for SLOS", the most common explanations are incorrect dating, fetal demise and X-linked ichthyosis. Low estriol may also result from adrenal insufficiency. Rarely is it SLOS but the software is designed to report it in this way.

Other chromosomal disorders (e.g. trisomy 13, Turner syndrome, triploidy) may also be diagnosed in pregnancies that screen positive for Down syndrome, trisomy 18 or SLOS.

Nuchal Translucency (NT) Ultrasound and the Integrated Prenatal Screen (IPS) (back to top)

What is the benefit of adding a nuchal translucency (NT) ultrasound measurement for women 35 years and older?
Although the serum integrated prenatal screen (SIPS) is associated with a high detection rate for Down syndrome, the combination of serum screening and NT (integrated prenatal screen or IPS) reduces the false positive rate.

What accommodation has been made in the guidelines for communities with limited/no access to NT?
• As of April 2010, 13 NT sites are operational across the province. Eligible women able to travel may be accommodated at any NT site.
• Additional NT sites will be created over the next 12 months. (It takes time to train and certify sonographers and sonologists.)
• IPS for women 35 – 39 years old is being phased-in as NT capacity is developed within the province. Notification will be sent when the eligible age is reduced from 36 to 35 years old.
• As of January 2010, eligibility for NT includes women (a) ≥ 36 years old at EDD; (b) with multiple gestation pregnancies; (c) who have a history of a previous child or fetus with Down syndrome, trisomy 18 or trisomy 13; (d) ≥ 35 years old with 3 or more miscarriages; (e) who are HIV positive; and (f) with pregnancy conceived by IVF with ICSI.
• The risk cut-off for SIPS has been adjusted to enable the same detection rate for Down syndrome in women 35 years and older as IPS (NT and serum integrated biochemistry). False positive rates will be higher for women who have not had an NT.
• Detection and false positive rates for SIPS and Quad screening meet the recommendations of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and the Canadian College of Medical Geneticists (CCMG).

What if a woman qualifies for an NT ultrasound measurement but cannot get it because there is no NT centre nearby that provides this service or the nearby centre is fully booked?
• If the woman is able to travel, she may be accommodated at any NT site in the province; OR
• Offer SIPS. This is a good alternative as it provides an equivalent high detection rate for Down syndrome and the only downside is that the false positive rate is higher than with the integrated prenatal screen (SIPS plus NT ultrasound).
• For women 40 or older with a singleton pregnancy or 35 or older with a multiple gestation pregnancy, amniocentesis should be offered as an option.

Why is IPS not offered to women 35 years and younger as part of the BC Prenatal Genetic Screening Program?
• SIPS and Quad screens are available to women of all ages and are high quality screens that meet recommended national and international standards for prenatal screening.
• The capacity in BC for NT ultrasound measurement is limited (due to technological and medical expertise) and NT is reserved for women who would benefit most.
• The chance of a false positive result is higher for women 35 and older, thus, women in that age group can benefit most.
• NT is also offered where the woman or her partner has had a previous child or fetus with Down syndrome, trisomy 18 or trisomy 13 (trisomy 13 increases the risk of Down syndrome), women with multiple gestations, women who are HIV positive, and women with a pregnancy conceived by IVF with ICSI.

If a woman does not qualify for IPS but wishes to pay privately, is this service available?
In some parts of the province, NT ultrasound measurement is available on a private pay basis. If a woman wishes to pay privately for the NT and have the SIPS done through the public system, the NT measurement can be used in the risk calculation if the NT was measured by a provider who is accredited by the Fetal Medicine Foundation (provincially-recognized quality control organization). In such cases, the provider ordering the prenatal screen should send a copy of the NT ultrasound report to the Prenatal Biochemistry Laboratory at C&W at fax number 604-875-3008.

If a woman wants to know her risk of Down syndrome in the first trimester, is that an option?
• First trimester screening (PAPP-A + free beta-hCG serum biochemistry + NT ultrasound) is not available through the public system.
• In some parts of the province, first trimester screening is available on a private pay basis.
• If a woman is looking for a private pay service for first trimester screening, consider the following to ensure a reliable result:
• Ensure that the provider who takes the NT measurement is accredited by the Fetal Medicine Foundation (provincially-recognized quality control organization).
• Ensure that the biochemistry tests (PAPP-A + free beta-hCG) are performed in a DAP – accredited laboratory or a laboratory that has accreditation by a comparable organization.
• Note that the first trimester screen does not screen for open neural tube defects. A second trimester maternal serum AFP screen is required in addition to the second trimester detailed fetal ultrasound scan.

Amniocentesis (back to top)

Why has the minimum age for amniocentesis without prior screening been changed from 35 to 40 years old for singleton pregnancies?
• The availability of new screening tests with high detection rates for Down syndrome make it best practice to offer all women non-invasive screening prior to deciding on amniocentesis. The option of CVS/amniocentesis remains available for women 40 years or older, as within this age group the risk of sex chromosomal aneuploidies (47, XXX; 47, XXY) not detected by the screening tests is equal or greater to 1 in 200.
• Limiting the number of CVS/amniocentesis to those at highest risk will reduce the number of normal pregnancies lost due to CVS/amniocentesis.
• Eligibility for amniocentesis is consistent with recommendations of the SOGC and the CCMG.

Why has the minimum age for amniocentesis without prior screening been changed from 32 to 35 years old for multiple gestation pregnancies?
Previously, the presence of two fetuses was predicted theoretically to increase the risk of Down syndrome in the pregnancy by 1.67. More recent studies have shown that the prevalence of Down syndrome is only 3% higher in multiples than singletons (Cuckle, 1998).

Why are there different qualifying ages for amniocentesis without prenatal screening in singleton and multiple gestation pregnancies?
Prenatal screening tests for Down syndrome are less sensitive in pregnancies with multiple gestations as compared to singleton pregnancies. Therefore, women with twin / triplet pregnancies who have a higher risk of Down syndrome based on age (≥35 years old) have the option of choosing a definitive test (amniocentesis) to rule out Down syndrome.

What if twins or triplets have an NT measurement that is discordant – should both twins/all triplets be tested by amniocentesis?
Yes. Given the possibility that the twins or two or three of the triplets can be identical, the finding of an increased NT measurement in one twin/triplet justifies cytogenetic testing of all babies.

Will the results of a detailed ultrasound be used to reduce the eligibility of women for amniocentesis?
No. While research suggests that an 18-20 week ultrasound without any soft markers or anomalies is capable of reducing the estimated risk of Down syndrome by approximately 50%, this information can be used in counselling of the patient but will not be used to change the eligibility criteria for amniocentesis. It will be the woman's choice to have or not to have an amniocentesis.

Are women who screen positive for Down syndrome, trisomy 18, or ONTDs in a previous pregnancy eligible for an amniocentesis in their current pregnancy?
• No, not unless they meet one of the eligibility criteria for amniocentesis in their current pregnancy (e.g. 40 years or older and/or screen positive result).
• The risk for one of these conditions is no higher for these women than other women.

What is the risk of pregnancy loss with CVS and amniocentesis?
The rate of loss following CVS is estimated to be approximately 1 – 2% (1 or 2 in 100) and the risk following amniocentesis is approximately 0.5% (1 in 200).

A recently published study (Eddleman, 2006) suggests that the risk of post-procedure loss after amniocentesis is not as high as previously identified. Is that true?
• There were significant issues associated with the design of the study.
• A more recent expert committee review (Wilson, 2007) reported that the best estimated range to consider for an increased rate of pregnancy loss attributable to amniocentesis is 0.6% to 1.0% (1:175 or 1:100) but may be as low as 0.19% or as high as 1.53% on the basis of the confidence intervals (CI) seen in the various studies. The best risk estimate for twin pregnancies was identified as 1.6% (CI 0.3-3%) (Wapner, 1993). The review concludes that amniocentesis continues to be associated with a non-negligible risk of pregnancy loss.

Multiple Gestation Pregnancies (back to top)

What is the rationale for offering biochemistry tests to women less than 35 years old with twin pregnancies who do not have access to NT?
• Women with twin pregnancies will be offered IPS if available. Women 35 years and older who do not have access to NT will also be offered the option of amniocentesis. Women younger than 35 years who do not have access to NT will be offered SIPS or Quad depending on their gestational age.
• While the best screen for Down syndrome and trisomy 18 for women with twin pregnancies is a screening test that includes NT, biochemistry alone continues to be a viable option for women at lower risk for these conditions. While the detection rates are lower for twin pregnancies than singletons, the detection rates achieved justify offering the test to women who wish screening for Down syndrome (Bush, 2005).

Prenatal Screen Reports and Results (back to top)

Two of my patients, one who had Quad and the other SIPS, had the same Down syndrome risk but one was called a screen negative and the other was called a screen positive. How can this be?
The Quad screen cut-off is 1:385 (risk for delivering a Down syndrome baby at term) while the SIPS cut-offs is 1:300 and the IPS cut-off is 1:200.

Why has the report format changed? Why are screen results no graphically displayed? How has report delivery changed?
Prenatal screening tests are being interpreted using new software (Alpha). The software has a different reporting format that does not easily enable graphical display of the screen results. Further, inclusion of a graphical display would make the report longer than a single page.

Why is the trisomy 18 risk no longer displayed on the reports?
The new software does not display the risk for Trisomy 18 unless it is above screen cut-off.

Explaining Screen Results (back to top)

In practical terms, what does the detection rate of a screening test mean?
The detection rate is the chance that an affected pregnancy will be detected by the screening test. For example, SIPS in women less than 35 years has a detection rate for Down syndrome of 79%. This means that the screen will detect 79% of pregnancies with Down syndrome in women less than 35 years of age. It also means that if a woman less than 35 years of age has a fetus with Down syndrome, there is a 79% chance that she will screen positive.

In practical terms, what does the screen positive rate mean?
• The screen positive rate is the chance that a test will be above the screen cut-off and the result will be reported as screen positive. This rate includes both false positives and true positives. A false positive means that the screen is positive but the baby is unaffected whereas a true positive means that the pregnancy screens positive and the baby is affected. The screen positive rate varies for the different tests and for women of different ages. However, for all tests and all age groups, the majority of women who screen positive have an unaffected pregnancy.
• For example, women less than 35 years of age, who choose SIPS, have a 3.7% chance of having a screen positive result. Of those women who screen positive, 97% of them will have an unaffected pregnancy. These women have a false positive screen result.

In practical terms, once a woman has a positive screen result, should she be counselled as per the risk estimate on the report?
• Yes. The risk estimate provided on her report is the best estimate of her risk for having an affected pregnancy based on the combination of her age, the results of her blood test(s) and, if available, the nuchal translucency measurement. The patient’s calculated risk as indicated on her report should be used in the counselling.
• For example, the 32 year old woman who had SIPS and screens positive with a risk of Down syndrome of 1 in 240 should be counselled that the best estimate of her risk is 1 in 240. This means that for 240 women with this same risk, one will have an affected baby and 239 will not.

Pregnancy Dating and Screen Reinterpretation (back to top)

The report says that my patient had her blood drawn too early. Her last menstrual period dates her at 15 weeks and her ultrasound agrees dating her at 14 weeks 3 days, so her due date doesn’t change. Why does she need to have her blood redrawn?
Dating for serum screening is preferentially based on ultrasound, as measurement of the biparietal diameter or crown rump length is the most precise method of gestational age assessment on a population basis.

Should the Prenatal Biochemistry Laboratory at C&W be contacted regarding soft markers on the 18-20 week ultrasound?
No. The Prenatal Biochemistry Laboratory will no longer be amending reports based on soft markers.

Should the Prenatal Biochemistry Laboratory be contacted if dating by second trimester ultrasound differs from the original dates calculated by LMP?
Yes, if dating by second trimester ultrasound differs by more than seven days from original dates, fax the ultrasound report to the Prenatal Biochemistry Laboratory at C&W (fax 604-876-3008) for possible recalculation of risk. The only exception would be when a screen result is positive for trisomy 18. In these cases, the screen will not be recalculated (because trisomy 18 is frequently associated with intrauterine growth restriction).

Family History, Smoking, IVF, and Ethinicity (back to top)

Does a family history of Down syndrome in a relative other than the woman/partner’s child increase the risk of having a baby with Down syndrome?
If the karyotype of the affected family member (other than child) is 47,XX, +21 or 47, XY, +21, the woman is not at increased risk of having a pregnancy with Down syndrome.

Why is smoking status requested for women having a serum screen?
• The maternal serum level of inhibin-A is significantly influenced by any maternal smoking.
• Providing this information on the patient requisition will allow for adjustments to the risk calculation to be made, improving the accuracy of the screen result.

Is the risk assessment adjusted for IVF pregnancies?
• The literature consensus is that biochemistry results differ slightly in IVF pregnancies when compared to non-IVF pregnancies leading to relatively higher screen positive rates in IVF pregnancies.
• In order to prevent this effect, IVF specific adjustment factors are applied to biochemistry results from IVF pregnancies prior to their use in determining the Down syndrome risk.

Why is the patient’s ethnicity needed for the risk assessment?
Each biochemical marker shows slight ethnic differences. A woman’s marker levels are compared to other women of the same ethnicity as part of the risk calculation. If the ethnic group is not indicated, the calculation will be less accurate as marker levels will be compared to the overall population of women being screened, regardless of ethnic group.

References (back to top)

Bush MC, Malone FD. 2005. Down syndrome screening in twins. Clin Perinatol 32 (2): 383-386.
Cuckle H. 1998. Down's syndrome screening in twins. J Med Screen 5: 3-4.
Eddleman KA, Malone FD, Sullivan L. et al. 2006. Pregnancy loss rates after mid-trimester amniocentesis. Obstet Gynecol 108: 1067-1072.
Wapner RL, Johnson A, Davis G. et al. 1993. Prenatal diagnosis in twin gestations: a comparison between second trimester amniocentesis and first trimester chorionic villus sampling. Obstet Gynecol 82: 29-56.
Wilson RD, Langlois S, Johnson JA. 2007. Mid-trimester amniocentesis fetal loss rate. J Obstet Gynaecol Can 29 (7)L 586-590.