While every attempt has been made to ensure that the information contained herein is clinically accurate and current, Perinatal Services BC and the BC Prenatal Screening Program acknowledge that many issues remain controversial, and therefore may be subject to practice interpretation.# 
Prenatal genetic screening estimates the chance of Down syndrome, trisomy 18, and open neural tube defect. The results will assist in determining the need for further testing. The screening tests offered will vary according to the gestational age at the time of presentation, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation.
BC has adopted a serum-based approach to prenatal genetic screening, with nuchal translucency (NT) ultrasound added for women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with twin pregnancies. Non-Invasive Prenatal Screening (NIPS) is now also an option for some higher risk women/individuals. This guideline refers to screening options that are available in the public health care system. In BC, Serum Integrated Prenatal Screen (SIPS) is available and should be offered to all pregnant women/individuals. The following women/individuals are eligible for NT ultrasound as a component of Integrated Prenatal Screen (IPS = SIPS in combination with NT):
a) Women/individuals  35 years old at expected date of delivery (EDD) 1 ;
b) Women/individuals with twin pregnancies; c) Women/individuals pregnant following in vitro fertilization with intracytoplasmic sperm injection (IVF with ICSI) without PGT-A.
Certified (Fetal Medicine Foundation -UK) nuchal translucency ultrasound sites are established in all BC health authorities.
For women/individuals 40 years or older with a singleton pregnancy, or 35 years or older with a multiple gestation pregnancy, amniocentesis is also an option.
Provincially funded NIPS is available for the following eligible women/individuals: a) Women/individuals with a positive screen result from IPS, SIPS, or Quad; b) Women/individuals who have a documented history of a previous child or fetus with Down syndrome, trisomy 18, or trisomy 13; c) Women/individuals whose chance of Down syndrome is equal to or greater than 1/300 based on the finding of ultrasound marker(s) and results of SIPS / IPS / Quad.
The purpose of prenatal genetic screening is to identify pregnancies at increased chance of chromosome disorders or structural anomalies. Serum integrated prenatal screen (SIPS), integrated prenatal screen (IPS), quad marker screen (Quad), NIPS, and a detailed second trimester ultrasound 2 are some of the options available for prenatal genetic screening. IPS involves measurement of first trimester serum PAPP-A and a nuchal translucency (NT) ultrasound and second trimester serum quad markers (AFP, uE3, hCG and inhibin-A). The blood tests are collected as per the timing for SIPS and the NT measurement is done between 11 -13 +6 weeks (best at 12 -13 +3 weeks). Given that NT must be performed by a certified sonographer or sonologist, this test is available only in a select number of publicly funded centres 4 located around BC and use of the service is prioritized to serve those at higher chance of having a fetus with Down syndrome or trisomy 18 and women/individuals with multiple gestations. IPS test results are available within 10 days after the second blood test. If the NT measurement is high and results in a positive screen, counselling and further testing are offered (such as NIPS, chorionic villi sampling (CVS), or amniocentesis) prior to completing the second blood test. 

# Counselling
Women/individuals should understand that it is their choice to undertake genetic screening. Information about prenatal screening for Down syndrome, trisomy 18, and open neural tube defects should be given to pregnant women/individuals at the first contact with a healthcare professional. This should occur in the first trimester, ideally prior to 10 weeks gestational age in order to ensure that the appropriate early tests are performed, if desired. Women/individuals who choose screening should ideally be sent for the blood test #2 (SIPS/IPS) or the Quad as early as possible within the allotted (14 -20 +6 weeks) timeframe.
Although blood test #2 can be collected and analyzed up to 20 +6 weeks, the ideal time is much earlier (best at 15 -16 weeks) to allow for earlier results and follow-up (NIPS or amnio) testing if necessary.
To assist women/individuals and their families with prenatal screening information, patient brochures in multiple languages, decision aids, and a video are available at bcprenatalscreening.ca.

# Specific counselling information should include:
The age-based a priori risk for each woman/individual for having a fetus with a chromosomal abnormality (Appendix 1)
The available tests for each woman/individual (Table 2)
The screening pathway for both screen positive and screen negative results
The decisions that need to be made at each point along the pathway and their consequences
The fact that screening does not provide a definitive diagnosis
The fact that women/individuals with a positive screen will have the option of further screening or testing such as funded NIPS, chorionic villi sampling (CVS), or amniocentesis (further testing options offered will be dependent on the woman's/individual's estimated chance of Down syndrome or trisomy 18 from the positive screen) 1. Introduction, cont'd  A.
After a discussion of the pros and cons, all pregnant women/individuals regardless of age should be offered prenatal screening for Down syndrome, trisomy 18, and ONTDs. Ideally this discussion needs to occur prior to 10 weeks gestational age (GA) so that the best possible screen for the patient is available. After receiving the information, it is the woman's/individual's choice to proceed with or decline screening. Discussion of prenatal screening and the result should be documented on the BC antenatal record.
B. The prenatal screen offered will depend upon the woman's/individual's gestational age at their first prenatal visit, their previous pregnancy history, maternal age at the time of delivery, and whether the pregnancy is a singleton or twin gestation. NT ultrasound assessment is available only to women/individuals at higher chance of having a fetus with Down syndrome or trisomy 18 8 and women/individuals with multiple gestations.
C. Women/individuals with an increased chance of having a fetus with a chromosomal abnormality 9 should be referred early in their pregnancy to Medical Genetics in Vancouver or Victoria for genetic counselling regarding their screening and diagnostic options. 

# E.
For women/individuals who choose to have (private-pay) NIPS as a first tier screen, IPS / SIPS is not indicated and should not be offered. An NT ultrasound scan should not be done if the woman/ individual is having NIPS, given the limited utility of NT measurement in pregnancies with a negative NIPS result and limited NT resources.

# F.
CVS and amniocentesis for fetal karyotyping will not be offered without prior screening except for women/individuals 40 years or older at expected date of delivery, women/individuals at increased chance of having a fetus with a chromosomal abnormality, 11 and women/individuals with multiple gestations who are  35 years old at expected date of delivery.
G. For women/individuals of any age found to have an NT measurement of 3.0 mm or greater, a calculation will be made based on NT only (or NT and PAPP-A if available). If the result is 1/300 or greater, a report will be issued without waiting for SIPS part 2 (blood test #2). The woman/individual should then be offered further testing: either funded NIPS or CVS / amnio. If the screen result is less than 1/300 based on NT alone (or NT and PAPP-A), no report will be generated, and the woman/individual will continue with serum screening (blood test #2) and the full IPS risk result will be reported 10 days after the collection of blood test #2.
H. The finding of an NT measurement  3.5 mm increases the chance of congenital heart defects, genetic syndromes, and chromosomal abnormalities other than the common aneuploidies.
A referral to Medical Genetics in Vancouver or Victoria is recommended.
I.
If a screen result is positive for Down syndrome and the screen was calculated based on last menstrual period (LMP), gestational age should be confirmed by ultrasound as soon as possible (see points J and K).

# J.
Although dating ultrasounds in the first trimester are not required for screening, ultrasound is the preferred method for calculating gestational age, as opposed to using LMP. If a first trimester ultrasound is done, the calculated gestational age from the scan should be provided to the Prenatal Biochemistry Laboratory at C&W (by attaching the scan report if available to the lab serum requisition or by faxing the scan report to 604-875-3008) to ensure most accurate screen results.
If an NT ultrasound is done, the calculated gestational age from this scan will be used.

# K.
For any screen calculated based on LMP, if dating by second trimester ultrasound differs by eight days or more from original dates, fax the ultrasound report to the Prenatal Biochemistry Laboratory at C&W for recalculation of chance (fax 604-875-3008). The only exception would be when a screen result is positive for trisomy 18 and dating by LMP and second trimester ultrasound differ. In these cases, the screen will not be recalculated (because trisomy 18 is frequently associated with intrauterine growth restriction).

# L.
If the SIPS / IPS / Quad prenatal screen result is positive for Down syndrome (assuming gestational dating is confirmed) or trisomy 18, women/individuals should be counselled by their health care provider and offered further testing. All women/individuals with a positive screen for trisomy 18 should be offered funded NIPS or amniocentesis. For women/individuals with a positive screen for Down syndrome and a result between 1:900 and 1:301, only funded NIPS should be offered.
For women/individuals with a positive screen for Down syndrome and a result equal or greater than 1:300, the option of funded NIPS or amniocentesis should be offered.
NIPS is a blood test which analyzes cell free fetal DNA circulating in maternal blood and tests for Down syndrome, trisomy 18, trisomy 13, and sex aneuploidy. The detection rate for Down syndrome is approximately 98% with less than 0.1% false positives; the detection rate for trisomy 18 is around 85% with less than a 0.1% false positive rate. For more information on NIPS, how it compares to amniocentesis, and how to access testing, go to www.bcprenatalscreening.ca/NIPT.
M. Women/individuals with a positive NIPS result should be referred to Medical Genetics in Vancouver or Victoria for counselling and diagnostic testing. The positive predictive value of a positive NIPS result varies depending on the patient's prior chance of a trisomy. Amniocentesis is recommended for diagnostic confirmation of the positive NIPS result prior to any irrevocable obstetrical decision.
Women/individuals with a positive IPS / SIPS / Quad screen result who then go on to have a negative NIPS result would no longer qualify for amniocentesis. The woman/individual should be reassured, as the negative predictive value of NIPS is very high. Refer to www.bcprenatalscreening.ca for more details including an algorithm for obstetrical management.
O. If the prenatal screen result is positive for an open neural tube defect, and dating is confirmed, a detailed ultrasound should be immediately done, even if less than 19 weeks gestation. Management of the pregnancy will be dependent on the results of the detailed ultrasound. See Appendix 4 for follow-up of elevated MSAFP.

# P.
A detailed second trimester ultrasound (18 -20 weeks) to assess fetal anatomy and growth should be offered to all pregnant women/individuals. An 18 -20 week ultrasound without soft markers or anomalies is capable of reducing the estimated chance of Down syndrome by approximately 50% (Smith-Bindman, 2007).
Q. Soft markers or anomalies on the 18 -20 week ultrasound increase the chance of aneuploidy and should be interpreted in conjunction with the prenatal screening (SIPS, IPS, or Quad) result. See Appendix 5 for detailed soft marker information.
R. Women/individuals who are found on cytogenetic analysis of amniocytes or chorionic villi to carry a fetus with a chromosomal abnormality may be referred to the Vancouver or Victoria Medical Genetics departments for counselling.

# BC Prenatal Genetic Screening Program Website
The 12 Performance of screening tests applies to singleton pregnancies. 13 The detection rates listed are based on the small cohort of Down syndrome pregnancies in BC.
SIPS, IPS, and Quad are screening tests so may not have 100% detection rate. 14 Higher false positive rate of IPS reflects that this test is done in women/individuals who are at a higher a priori risk. 15 May be higher if ultrasound abnormalities present.
Prenatal Genetic Diagnostic Testing (CVS and Amniocentesis) Chorionic Villus Sampling (CVS) 16 Amniocentesis 5. All patients with MSAFP that is not explained by a fetal abnormality should be considered at increased chance of adverse obstetrical outcome and followed as per following algorithm:

# Soft Markers Identified on Detailed Ultrasound
Several markers identified on second-trimester ultrasound examination are associated with increased chance of Down syndrome. The markers are not equally suggestive of Down syndrome. Based on the presence or absence of these markers, positive or negative likelihood ratios can be applied to the calculation of chance of Down syndrome from SIPS / IPS / Quad or maternal age allowing modification of a patient's chance 10 . Some markers are also indicative of increased chance of condition(s) other than Down syndrome.
Markers that significantly increase the chance of Down syndrome include: Markers that increase the chance of condition(s) other than Down syndrome include:  
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Offer ultrasound at 28 -30 weeks to assess fetal growth and amniotic fluid volume. If abnormality detected, recommend consultation with Obstetrician or Maternal Fetal Medicine specialist.
Consider starting ASA 81 mg qhs if patient is less than 20 weeks GA;
Supplement with Calcium 1g/day if daily intake is < 600mg/day.
Recommend consultation with Obstetrician or Maternal Fetal Medicine specialist to establish a fetal surveillance plan which may include ultrasound monitoring and pre-eclampsia blood work every 2 -4 weeks. 

# Appendix 5
If NTh is between 6 -7mm and cardiac views are reported as not well seen, in addition to recalculation of the chance of Down syndrome using the Trisomy21 calculator, a prompt reassessment of the cardiac views is needed. For patients from VCH, NHA, IHA, this can be facilitated through referral to Medical Genetics at BCWH; for patients from FHA, referral to the Jim Pattison Maternal Fetal Medicine Service is recommended; for VIHA patients, referral to Medical Genetics at Victoria General Hospital is recommended.
If NTh is 7mm or greater, referral to Medical Genetics (Vancouver or Victoria) is recommended.

# If ultrasound detects echogenic bowel:
If associated dilated bowel loops, referral to the Fetal Diagnosis Service (FDS) is recommended.

# If isolated echogenic bowel as bright as bone:
Chance of an intrauterine infection is increased. Recommend serology IgM and IgG for CMV, Toxoplasmosis and Parvovirus.
Chance of Down syndrome is increased. If patient had negative NIPS, chance of Down syndrome remains low. If patient had SIPS/IPS/Quad or no screen, the chance of Down syndrome should be recalculated using the Trisomy21 calculator (www.perinatalservicesbc.ca/healthprofessionals/professional-resources/screening/ prenatal-genetic/trisomy-21-risk-calculator). Medical Genetics can be consulted for help with calculation as needed. If revised chance of Down syndrome is greater than 1 in 300, patient qualifies for amniocentesis or funded NIPS. If patient chooses funded NIPS, contact medical genetics for NIPS code.
Chance of cystic fibrosis is increased for Caucasian couples. Offer CF carrier screening on patient and partner (requisition available at www.genebc.ca). For midwifery patients, this can be facilitated through referral to Medical Genetics.
Risk of developing IUGR in third trimester is increased. A follow up ultrasound around 30 -32 weeks gestation is recommended.
- If ultrasound detects isolated pyelectasis, abnormal femur/foot ratio (0.9) or echogenic intracardiac focus (EICF), and the Down syndrome screen (SIPS /IPS /Quad or NIPS) showed a negative screen (low chance), no further prenatal testing is recommended. If no screening has been done and patient is less than 21 weeks and 6 days gestation, Quad screening should be offered. For patients with an ultrasound finding of pyelectasis, a postnatal renal ultrasound between 5-30 days of age is recommended.
- If Choroid plexus cyst (CPC) is detected, referral to Medical Genetics is recommended only if CPC is seen in combination with structural abnormalities or growth restriction. No further testing is indicated if CPC is identified in isolation and the patient's SIPS /IPS /Quad or NIPS is screen negative for trisomy 18 (for SIPS/ IPS/Quad, risk only appears on report when screen positive).
If no screening has been done and patient is less than 20 weeks and 6 days gestation, Quad screening should be offered.