Process and Implementing of Pregnancy and Newborn Screening Within Nhs Greater Glasgow and Clyde

University of Glasgow
PROCESS AND IMPLEMENTING OF PREGNANCY AND NEWBORN SCREENING WITHIN NHS GREATER GLASGOW AND CLYDE
Review of the data relating to the process of screening and detection of Trisomy 21.
Linda Simpson
31.05.2013

Supervisor: Dr. James Robins

Source data obtained from Hilary Jordan of Information Services, Dr Robins, Consultant Obstetrician and Gynaecologist, Royal Alexandra Hospital, Princess Royal Maternity Hospital and Southern General Hospital.

WHY DO WE ONLY DIAGNOSE HALF OF THE BABIES WITH TRISOMY 21 BEFORE BIRTH IN THE GREATER GLASOW AND CLYDE REGION?

Introduction

Trisomy 21 is a genetic condition in which an individual has three copies of chromosome 21 instead of two (figure 1). It is caused by non-disjunction of bivalent chromosomes at the spindle of a cell during gametogenesis (95%); Robertsonian translocation in parental karyotype* (14;21) (2-3%); or non-disjunction during mitosis resulting in two cell lines (mosaicism) with either two or three copies of chromosome 21 (1-2%)1,2. The latter is often associated with a milder phenotypic expression and higher intellectual functioning2. The presence of this additional genetic material produces a characteristic phenotype in affected individuals (table 1) and is associated with mental retardation1. These effects lie within a spectrum and individuals may have varying degrees of impairment1,2. Collectively the phenotypical features and cognitive impairment associated with Trisomy 21 is recognised as Down syndrome.

Phenotypic Features of Down’s Syndrome
Bradydactyly (shortening of fingers/ toes)
Broad hands
Duodenal atresia
Epicanthal folds
Fifth finger clindodactyly
Flat nasal bridge
Hypotonia
Mental retardation
Microcephaly
Short stature
Single palmar crease
Widening of gap between 1st and 2nd toes

DS is the commonest cause of congenital mental retardation with incidence rate increasing with maternal age (table 2). Risk is calculated as 1:940 live births at maternal age 30, increasing to 1:85 live births by age 401,3.

Figure 1. Trisomy 21 karyotype. Table 1. A tabulated list of the characteristic features seen in DS. W Varying phenotypic expression can occur.

* Where the long arm of chromosome 21 attaches to chromosome 14 and although phenotypically normal production of genetically abnormal gametes ensues.

Calculating the Risk of Down’s Syndrome in Relation to Maternal Age
Age / Risk
20 / 1:1450
25 / 1:1350
30 / 1:940
35 / 1:350
40 / 1:85

Table 2. A table adapted from Morris et al 2003 displaying the relationship between increased risk of Down’s syndrome with increasing maternal age.

Screening

Prenatal screening has been developed so that identification of affected fetuses can occur before birth. Screening tests are not diagnostic; rather they identify pregnancies in which there is a higher risk of the child having trisomy 21 (T21). Higher risk patients will be offered a diagnostic test. DS is likely to significantly impact upon the family and career2. As there is no cure or treatment for Down syndrome, prenatal diagnosis ensures that parents receive the correct information to enable adequate preparation for birth or decide whether to terminate the pregnancy3. Within Scotland, two types of screening are available in either the first trimester or second trimester. Screening is a voluntary aspect of antenatal care. A risk assessment is provided to parents; however it is important to note that a low risk result does not exclude having a child with DS2. According to the Quality indicator Standards (QIS), all women in Scotland should be offered prenatal screening either in the first trimester or second trimester where first trimester screening is unavailable4.

First trimester screening is now available to all women in the Greater Glasgow and Clyde (GGC) area since November 2012. Depending on gestation at presentation the current screening methods include:

First (1st) Trimester Screening

• Combined Ultrasound and Biochemical Screening (CUBS).

Ultrasound scan (USS) is preformed between 11+0 weeks and 13+6 days. The nuchal transluceny of aneuploidy fetuses is usually increased3,4.

Biochemical screening - Fβ-hCG and PAPP-A.

Results are combined with maternal age to provide a risk assessment. It will be either High Risk (HR) or Low Risk (LR). Those with HR result will be offered an amniocentesis or chorionic villi sampling (CVS) 4.

Note: if 1st trimester screening is accepted then no further screening will occur. A 20 week fetal anomaly scan will be offered to detect NTD.

Second (2nd) Trimester Screening

A blood sample is obtained between 15 weeks + 0 days and 20 weeks + 6 days and levels of maternal serum markers are detected. Concentration is converted to multiples of the median (MoM) 4. Markers include – AFP, hCG, UE3 and inhibin A.

Values are adjusted for co-variables i.e. smoking status, maternal weight, previous affected pregnancies and assisted conception4.

Aims and Objectives

The purpose of this project is to determine why less than half (48.8%) of the children born with DS within GGC region between the 31st March 2011 to the 1st April 2012 were not detected antenatally.

 Review case notes to determine what type of pre-natal screening was offered/ declined

 Understand the screening process to determine if adequate opportunities were utilized to screen/ diagnose affected pregnancies.

 Ensuring all information is available electronically and as hard copy

Standards

The Quality indicators are devised to ensure that screening programs meet the highest possible standards. Interpretation of these standards by GGC has set a detection rate of 95%. This audit will use these standards to assess why this region is not achieving detection potential and the reasons behind this.

Information obtained from The Regional Genetic Service:

 1st Trimester screening (1st April 2011 -31st March 2012)*

Screen positive rate: 3.6%

Detection rate: 92.3%

Specificity: 96.5%

False positive rate: 3.5%

 2nd Trimester Screening (1st April 2011 – 31st March 2012)*

Screen positive rate: 5.1%

Detection rate: 71.4%

Specificity: 95%

False positive rate: 5.1%

* April 2011 – September 2011 used cut off rates of ≥ 1 in 250, September 2011-March 2012 used cut off ≥ 1 in 150

Results

A total of 43 cases of Trisomy 21 were reported in Greater Glasgow and Clyde in 2011-2012. Sixty percent of cases were live born (n=26), thirty percent were terminated (n=13), seven percent spontaneously aborted (n=3) and two percent were stillborn (n=1) (Figure 2).

Figure 2. Pregnancy outcome for the forty-three confirmed cases of Trisomy 21 in the Greater Glasgow and Clyde region between 1st April 2011 – 31st March 2012.

Diagnosis of twenty-one cases of T21 (48.8%) occurred prenatally. Thirteen pregnancies who received a T21 diagnosis were terminated (61.9%), six proceeded to birth (28.6%) and two spontaneously aborted (9.5%) (Figure 3). Twenty-one cases were diagnosed at birth (48.8%) and one case diagnosed at post-mortem (2.3%) (Figure 4).

Figure 3. Pregnancy outcome following diagnosis of Trisomy 21.

Figure 4. Point at which Trisomy 21 was detected diagnosed.

From the live born infants with a T21 diagnosis it was possible to determine whether diagnosis occurred prenatally via screening (1st or 2nd trimester), diagnostic testing (amniocentesis, chorionic villi sampling) or after birth.

Total Screening Outcome

All women who had a subsequent affected child were offered screening if they were eligible i.e. within the gestational time limits. This was thirty-eight (88.4%) of the forty-three cases. Three (7.0%) women were offered a diagnostic test in the first instance and two (4.7%) pregnancies spontaneously aborted before screening was offered (Table 3.1).

Total Trisomy 21 Cases
Offered Screening / 38
Straight to Diagnostic / 3
Spontaneous Abortions / 2
TOTAL / 43

Table 3.1. Total number of pregnancies offered screening or diagnostic test

Of those that were offered screening, twenty-six (68.4%) accepted screening, ten (26.3%) declined, one (2.6%) was greater than 22 weeks gestation at booking thus out with screening parameters; and one (2.6%) underwent a termination of pregnancy based on USS findings. No diagnostic test was performed in this instance (Table 3.2).

Pregnancy Screening Process Outcome
Accepted Screening / 26
Declined Screening / 10
Late Gestation at Booking / 1
Termination after Screening: No Diagnostic / 1
TOTAL / 38

Table 3.2. Screening process outcome for all affected pregnancies in Greater Glasgow and Clyde from 1st April 2011-31st March 2012

From the 38 women offered pregnancy screening, ten (26.3%) declined any form of screening and nine women (23.6%) declined a diagnostic test after a HR result. Together this equates to 50% of women refusing screening or a diagnostic test (Table 3.3).

Point of Declining Screening/ Diagnostic Test
At Booking / 10
After screening (high risk result) / 9
TOTAL / 19

Table 3.3. Point during pregnancy that screening and diagnostic tests were declined

Results by Pregnancy Outcome

Live Births

With forty-three cases diagnosed, twenty-six were live born (60.5%). From this subset (n=26) nine (34.6%) received a HR screening result but declined a diagnostic test. Five (19.2%) received a prenatal diagnosis/ aroused clinical suspicion and eight (30.8%) declined any form of screening or diagnostic testing. Four patients (15.4%) received a LR result yet had an affected child (Table 4) (Figure 5.1).

Total Live Births / Number
(n = 26) / Percentage (60.5%)
Declined diagnostic test after ‘high risk’ result / 9 / 34.6%
Prenatal diagnosis or raised clinical suspicion / 5 / 19.2%
Declined all Screening/ Diagnostic Tests / 8 / 30.8%
‘Low risk’ result with subsequent T21 diagnosis / 4 / 15.4%

Table 4. Data obtained from patient files to determine screening uptake and outcome for the 26 live infants with a T21 diagnosis in the Greater Glasgow and Clyde region between 1st April 2011 – 31st March 2012.

Figure 5.1.  Screening outcome from the twenty-six cases of T21 live born infants in the Greater Glasgow and Clyde 1st April 2011 – 31st March 2012.

Termination of Pregnancy

Thirteen (30.2%) of the total diagnosed cases of T21 (n =43) resulted in termination (Figure 5.2).

Figure 5.2. Diagnostic procedure undertaken for T21 diagnosis in thirteen confirmed cases in the Greater Glasgow and Clyde region. Eleven had amniocentesis and one patient had a CVS. Note: One case proceeded straight to termination based on ultrasound alone without a confirmed diagnosis. Trisomy 21 was confirmed at post-mortem.

Pregnancy Loss

There were three spontaneous abortions (75%) and one still birth (25%). One of the pregnancy losses received a prenatal diagnosis via amniocentesis, one at post mortem and one declined diagnosis. Clinical suspicion was raised in this instance even without a definitive diagnosis (Figure 5.3).

Figure 5.3. Diagnostic procedure for the four fetal losses with confirmed trisomy 21 diagnosis.

Results by Region

Clyde Region

The region of Clyde was covered by the Royal Alexandra Hospital and had nine (20.9%) patients receive a T21 diagnosis from the 43 cases. From these nine, four declined screening (44.4%); two proceeded straight to amniocentesis (22.2%) and three accepted screening (33.3%). Two of those that accepted screening received an HR result and declined a diagnostic test. One patient received a LR result yet had a subsequent affected child (Figure 6.1). Six children were diagnosed at birth, two prenatally and one at post mortem (Figure 6.2) (Table 5).

Figure 6.1. Point of diagnosis for pregnancies within the Greater Glasgow and Clyde region.

Figure 6.2.
Number of patients that opted for prenatal screening, diagnostic testing and results obtained in the Greater Clyde region.

CHI Number / Screening Offered / Accept/ Declined / 1st/ 2nd Trimester Screening / Result / Amniocentesis/ Chorionic Villi Sampling / Trisomy 21 Diagnosis / Outcome
1705763480 RAH /  / X / - / - / X / Birth / Live
1012723143 RAH /  / X / - / - / X / Birth / Live
2408823064 RAH /  / X / - / - / X / Birth / Live
2703753187 RAH 1 /  / X / - / - /  AMNIO / Prenatal / Live
1403823022 RAH /  /  / 2nd / 1:198 / X / Prenatal / Live
3103753268 RAH /  /  / 1st / 1:159 / X / Birth / Live
1310693269 RAH 2 /  /  / - / - /  AMNIO / Prenatal / Termination
2710743124 RAH * /  / X / - / - / X / Birth / Stillborn
1910763004 RAH /  /  / 2nd / 1:5524 / - / Birth / Live

Table 5. Screening and diagnostic testing process for patients in the Greater Clyde region.

* Twin pregnancy

1. Amniocentesis done on basis of cystic hygroma at fetal anomaly scan

2. Proceeded straight to amniocentesis due to maternal age

Glasgow: South and West Region

South and west Glasgow maternities were covered by the Southern General Hospital. Here a total of nineteen diagnosis of T21 were received (Table 6) (Figure 7.1). Twelve live births, two of which had a prenatal diagnosis (16.7%); four (33.3%) accepted screening and received a HR result however declined screening; four (33.3%) declined all screening and two (16.7%) had a LR screening result yet had a subsequent affected child (Figure 7.2).

Nine (47.4%) of the 19 maternities were diagnosed prenatally, seven of these proceeded to termination and two were live births. There were no spontaneous abortions or stillbirths (Figure 7.1).

Figure 7.1. Point of diagnosis for affected pregnancies in South and West Glasgow region.

Figure 7.2. Screening and diagnostic process for maternities in South and West Glasgow.

CHI Number / Screening Offered / Accept/ Declined / 1st/ 2nd Trimester Screening / Result / Amniocentesis/ Chorionic Villi Sampling / Trisomy 21 Diagnosis / Outcome
0103736204 SGH /  /  / 2nd / 1:34 /  AMNIO / Prenatal / Termination
0302685804 SGH /  /  / 2nd / 1:38 / X / Birth / Live
0303746084 SGH /  /  / 2nd / 1:15 /  AMNIO / Prenatal / Termination
2412740860 SGH /  /  / 2nd / 1:5 / X / Birth / Live
1212686209 SGH /  /  / 2nd / 1:8 / X / Birth / Live
0307716082 SGH /  /  / 1st / NT 6.5 /  CVS / Prenatal / Termination
1704805228 SGH * /  /  / 1st / NT 5.8 /  AMNIO / Prenatal / Termination
1107946069 SGH > /  / X / - / - / X / Prenatal / Live
2710776243 SGH > /  / - / - / - / X / Prenatal / Termination
1502786168 SGH /  /  / 2nd / 1:7254 / X / Birth / Live
1510853529 SGH * 1 /  /  / - / - /  AMNIO / Prenatal / Termination
2407736184 SGH 2 > / X / - / - / - / X / Prenatal / Live
2003746226 SGH * 3 /  / X / - / - / X / Birth / Live
2705805222 SGH /  /  / 1st / NT 4.5 /  CVS / Prenatal / Termination
3107745782 SGH 4 /  /  / 1st / 1:49 / X / Birth / Live
1304716023 SGH /  / X / - / - / X / Birth / Live
1709796103 SGH /  / X / - / - / X / Birth / Live
0303666005 SGH /  / X / - / - / X / Birth / Live
0809722488 SGH /  /  / 2nd / 1:385 / X / Birth / Live

Table 6. Screening and diagnostic testing process for patients in the South and West Glasgow region.

* Twin pregnancy

> Clinical suspicion due to ultrasound scan findings

1. Selective reduction and miscarriage

2. Anomaly detected at fetal anomaly scan (22 weeks gestation at booking)

3. 18+5 weeks gestation at booking. NT 5mm

4. Private screening

Glasgow : North and East Region

Maternities in this region were covered by the Princess Royal Maternity Hospital. A total of 15 cases of T21 were diagnosed. Seven live births were recorded (46.7%) and six (40%) received a HR result; one (6.7%) received a LR result yet had an affected child. Three (20%) opted for prenatal diagnosis and three declined a diagnostic test (8.2). Five (33.3%) pregnancies were diagnosed prenatally and terminated. There were three (20%) spontaneous abortions (Table 7) (Figure 8.1).

Figure 8.1. Point of diagnosis for pregnancies in the North and East region. The point of diagnosis in each of the early pregnancy losses was different. One opted for amniocentesis, one declined all screening/ diagnostic tests (clinical suspicion evident from case notes) and one was diagnosed at post mortem

Figure 8.2. Screening and diagnostic process outcome for maternities in the North and East Region of Glasgow. Note: three of the patients who accepted screening subsequently declined a diagnostic test.

CHI Number / Screening Offered / Accept/ Declined / 1st/ 2nd Trimester Screening / Result / Amniocentesis/ Chorionic Villi Sampling / Trisomy 21 Diagnosis / Outcome
1101886269 PRMH /  /  / 2nd / 1:75 /  CVS / Prenatal / Live
2011703247 PRMH 1 / X / - / - / - /  AMNIO / Prenatal / Live
3105710825 PRMH /  /  / 2nd / 1:5 /  AMNIO / Prenatal / Live
2101696789 PRMH 2 /  /  / 1st / 1:138 / X / Birth / Live
1206746505 PRMH /  /  / 1st / 1:60 / X / Birth / Live
0808706004 PRMH /  /  / 2nd / 1:5 / X / Birth / Live
0907706541 PRMH /  /  / 2nd / 1:5 /  AMNIO / Prenatal / Termination
2502856426 PRMH /  /  / 2nd / 1:23 /  AMNIO / Prenatal / Termination
2212810946 PRMH /  /  / 2nd / 1:5 / X / Prenatal / Termination
2312896346 PRMH 3 / X / - / - / - /  CVS / Prenatal / Termination
1208696025 PRMH / X / - / - / - /  AMNIO / Prenatal / Termination
2511755149 PRMH /  /  / 2nd / 1:5 /  AMNIO / Prenatal / Spontaneous Abortion
0308716205 PRMH 4 /  / - / - / - / X / Prenatal / Spontaneous Abortion
1310775885 PRMH / X / - / - / - / - / Post Mortem / Spontaneous Abortion
0101828047 PRMH /  /  / 2nd / 1:1053 / X / Birth / Live

Table 7. Screening and diagnostic testing process for patients in the North and East Glasgow region.

1. Cystic hygroma identified at booking scan – 5.8mm.

2. Amniocentesis was originally accepted but failed. A second attempt was declined.

3. Cystic hygroma identified at booking scan. Previous placental abruption.

4. Strong prenatal suspicion of T21. Atrioventricular canal defect. IUD at 22 weeks gestation.

Additional Results:

From the forty-three cases of T21 recorded in GGC. twenty pregnancies (46.5%) had an additional malformation (Table 8). Seven (35%) of these were atrioventricular canal defects.

CHI Number / Point of Diagnosis / Outcome / Additional Malformations / Consent to FAS / Detectable at Scan / Detected
1012723143 RAH / Birth / Live / Q202, Q 212 /  / Q 212 / X
2703753187 RAH / Prenatal / Live / Q211, D1810 /  / D1810 / 
0303666005 SGH / Birth / Live / Q212 /  / Q212 / X
0307716082 SGH / Prenatal / Termination / D1810 /  / D1810 / 
2703753187 SGH / Birth / Live / Q211, D1810 /  / D1810 / 
1704805228 SGH / Prenatal / Termination / D1810 /  / D1810 / 
1107946069 SGH / Prenatal / Live / Q431, Q212 /  / Q212 / X
2710776243 SGH / Prenatal / Termination / D1810, Q701 /  / D1810 / 
2407736184 SGH / Prenatal / Live / Q410 /  / Q410 / 
1304716023 SGH / Birth / Live / Q256 /  / X / X
0809722488 SGH / Birth / Live / Q212 /  / Q212 / X
2705805222 SGH / Prenatal / Termination / D1810 /  / D1810 / 
1709796103 SGH / Birth / Live / Q2310 /  / X / X
2212810946 PRMH / Prenatal / Termination / Q210, Q430 /  / X / -
1208696025 PRMH / Prenatal / Termination / Q030 /  / Q030 / X
2511755149 PRMH / Prenatal / Spontaneous Abortion / Q210 /  / Q210 / X
0308716205 PRMH / Prenatal / Spontaneous Abortion / Q212 /  / Q212 / 
2101696789 PRMH / Birth / Live / Q212, Q250 /  / Q212 / X
2312896346 PRMH / Prenatal / Termination / D1810 /  / D1810 / 
0808706004 PRMH / Birth / Live / Q211 /  / Q211 / X
2011703247 PRMH / Prenatal / Live / Q212 /  / Q212
D1810 / X


Table 8. Addition malformations detected in affected cases and whether they were detected at USS

Congenital anomalies are classified according to ICD10 codes. A list of those that were detected (Table 9).

ICD10 CODE / Condition
D1810 / Cystic Hygroma
Q212 / Av Canal Defect
Q256 / Pulmonary Artery Stenosis
Q211 / Atria septal defect (ASD)
Q210 / Ventricular septal defect (VSD)
Q430 / Meckel’s Diverticulum
Q701 / Webbed Fingers
Q431 / Hirschsprung Disease
Q202 / Double Outlet at Left Ventricle
Q030 / Obstructive Aqueduct of Sylvius
Q410 / Duodenal Atresia
Q250 / Patent Ductus Arterosis
Q2310 / Bicuspid Aortic Valve

Table 9. ICD10 codes for congenital malformations detected in children that were diagnosed with T21.

Conclusions

 All women eligible for pregnancy screening were offered it.

 Gestation at booking determined type

 60.5% (n =26) of the cohort were offered screening (n=38) accepted.

 23.3% (n= 10) of the cohort were offered screening (n=38) declined.

 20.9% (n = 9) of women who initially accepted screening declined a diagnostic test after a HR result.

 Combination of those that declined screening and those that declined a diagnostic test (n=19) results in 50% of women. This identifies why only half of the children affected with T21 during 1st April 2011 – 31st March 2012 were diagnosed antenatally.

 Main reasons for declining the test were: belief they were not at risk, miscarriage risk from diagnostic test, and termination not an option.

 The most likely outcome after T21 diagnosis was termination – 61.9% (n=13).

 26 live births occurred: five (11.6%) were diagnosed prenatally, seventeen (65.4%) declined any form of screening or diagnosis and four (15.4%) were given a LR result.

 All women who received a LR result and had an affected child underwent 2nd trimester Quadruple screening.

 Cut off for increased result was decreased from 1 in 250 to 1 in 150 in September 2011. Two of the HR results would have received a ‘low risk’ result had this been implemented at that time thus increasing the false negative rate of this test.

 Four of the pregnancies were twin pregnancies therefore unless a diagnostic test was performed then screening is unreliable

 All women consented to the fetal anomaly scan.

 46.5% (n=20) had an additional anomaly, 17 of which were potentially detectable at scan.