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International Journal of Gynecology and Obstetrics Research IJGOR

Vol. 4(1), pp. 031-037, October, 2018. © www.premierpublishers.org ISSN: 1407-8019


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Study Profile

Neonatal and Obstetric Risk Assessment (NORA) Pregnancy


Cohort Study in Singapore
Qiu Ju Ng1, Jun Zhang2, Fei Dai3, Mor Jack Ng4, Nurul Syaza Razali5, Nyo Mie Win6, Bernard
Chern7, George SH Yeo8,10, *Kok Hian Tan9,10
Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah
1,2,3,4,5,6,7,8,9

Road, 229899, Singapore


10
Department of Maternal and Fetal Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, 229899,
Singapore

The Neonatal and Obstetric Risk Assessment (NORA) pregnancy cohort study was set up to
assess clinical, biochemical and biophysical markers for risk assessment and prediction of the
outcomes early in pregnancy. A total of 3271 patients who were in KK Women’s and Children’s
Hospital between September 2010 and October 2014 were screened and 1013 patients consented
to participate in the study. Women were followed at 18 to 22 weeks, 28 to 32 weeks and 34 weeks
and above, till their postnatal discharge from the hospital. Finally, 926 patients remained for
studying the outcome. In NORA study, we established locally derived and gestational age-specific
reference intervals for the five thyroid hormone parameters. Higher serum progesterone levels at
28–32 weeks of pregnancy were observed in women who had preterm deliveries compared with
women with term deliveries in the cohort. We also found that extracellular vesicle (EV) biomarkers
enhanced the predictive robustness of an existing pre-eclampsia (PE) biomarker sufficiently to
justify PE screening in a low-risk general obstetric population. We plan to further conduct a range
of serial assessments from the biosamples which will provide a comprehensive and valuable
information of the dynamics of maternal conditions and fetal development during pregnancy.
Keywords: Cohort profile, neonatal and obstetric risks, adverse pregnancy outcomes

INTRODUCTION
The vast majority of pregnancies result in a smooth the rise (Goldenberg et al., 2008; Tribe, 2007). In our
delivery with both healthy mother and baby. However, this hospital, the combined incidence ranges from 12 % to 18%
is not always the case, and about 15-20% of pregnancies for adverse pregnancy outcomes (9% attributed by
are high-risk pregnancies which may suffer from adverse preterm births, 3 – 4.5 % attributed by intra-uterine growth
maternal and/or fetal outcomes. These high-risk restriction and about 3 – 5% pre-eclampsia) based on our
pregnancies require multidisciplinary care and close 2008 delivery statistics (KKH Data Warehouse, 2008). It is
monitoring and hence, the management of such patients estimated that these conditions in combination may
is often resource intensive and has a significant impact on account for over 70% of adverse pregnancy outcomes.
the economics of healthcare delivery. In addition, as the Unfortunately, the causes of the pregnancy complications
median age of first-time mother rises in many parts of the remain largely unknown. And clinical outcomes associated
world including Singapore, due to delayed childbearing, with these conditions have not improved much, particularly
this would increase the proportion of high-risk pregnancies due to the poor understanding of the pathophysiology and
as advanced maternal age has been associated with inability to prevent or intervene early in the course of the
adverse pregnancy outcomes (Mills and Lavender, 2011). pregnancy.

Preterm birth is the single largest and most commonly *Corresponding author: Prof Kok Hian Tan, Perinatal
cited adverse outcome in pregnancy, followed by intra- Epidemiology and Audit Unit, Department of Maternal and
uterine growth retardation and pre-eclampsia (Lams et al., Fetal Medicine, KK Women’s and Children’s Hospital, 100
2008; Lamont, 2003; Gagnon and Wilson, 2008). Reported Bukit Timah Road, Singapore 229899.
incidence for preterm births (less than 37 weeks of Email: tan.kok.hian@singhealth.com.sg
gestation) ranges from 5 – 13%, and it is believed to be on Tel: (65) 6394 1319; Fax: (65) 6394 2241

Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Tan et al. 032

Angiogenic biomarkers, considered to be the markers of criteria. A total of 3271 patients were screened and 1013
placental function, have the potential to identify the patients consented to participate in the study. Out of 1013
subsequent risk of these adverse outcomes early in participants, 934 (92.2%) patients completed all 4
pregnancy. The pre-symptomatic levels of angiogenic antenatal visits. As 8 participants did not deliver in our
biomarkers appear to be linked to the severity and timing institution, we studied the outcome of the remaining 926
of onset of preeclampsia (Grill et al., 2009). Some studies (99.1%) patients (Figure 1).
have suggested that placental growth factor (PlGF) levels
are already significantly lower in the first trimester in
women who develop preeclampsia (Romero et al., 2008).
There has been intensive research into the use of
biochemical markers such as soluble fms-like tyrosine
kinase-1 (sFlt-1) and PlGF for early identification of pre-
eclampsia to reduce adverse outcomes and unnecessary
hospitalisations (Allen et al., 2014; Hund etal., 2014).

KK Women’s and Children’s Hospital (KKH) is the largest


maternity hospital in Singapore and is the main tertiary
referral centre for Paediatrics and Obstetrics and
Gynaecology. The Neonatal and Obstetric Risk
Assessment (NORA) cohort study was set up to target
pregnancy-related causes of adverse outcomes, with a
focus on evaluating the use of clinical, biochemical and
biophysical markers to predict the risks early enough in
pregnancy that some intervention may be implemented to Figure 1: Progress of the NORA study
improve the chance of a healthy pregnancy outcome. The
primary objectives of the NORA study are: (1) to screen Cohort follow-up
factors that are associated with adverse pregnancy
outcomes; and (2) to develop a multi-factorial prediction After consent, the participants were followed up till their
model to identify women in high risk for adverse outcomes postnatal discharge from the hospital. At recruitment,
early in pregnancy. detailed interviews, a dating ultrasound scan and routine
antenatal blood collection were done. Subsequently, the
women were seen at 18 to 22 weeks, 28 to 32 weeks and
COHORT DESCRIPTION 34 weeks and above (Table 1). The women were closely
followed up through their pregnancies and clinical and
Participants laboratory data were collected prospectively. Following
delivery, detailed information on pregnancy complications,
The study was conducted at KKH, which has an annual labour and delivery and neonatal outcomes was collected
delivery rate of about 12000 births, comprising through medical chart review.
approximately 30 – 35% of national births. It is also the
main referral hospital for complicated pregnancies and
neonatal support, as it provides a full range of tertiary level DATA COLLECTION
support. The study received an approval from the
Institutional Review Board before commencing recruitment Table 1 describes the data collected at each visit for the
of participants and data collection. entire cohort. A detailed questionnaire was administered
to participants at recruitment (less than 14 weeks) to obtain
The NORA study recruited pregnant women who had their demographics, personal medical and obstetric
viable, singleton pregnancies and were attending their first history, socio-economic status and lifestyle. Follow-up
antenatal visit, at less than 14 weeks of amenorrhoea in questionnaires were then administered at each
KKH between September 2010 and October 2014. The subsequent visit. Neonatal anthropometric assessments,
exclusion criteria were multiple gestation, chronic medical Apgar scores at 1 and 5 minutes were obtained. Quality of
conditions such as renal disease or systemic lupus sleep was assessed using the Pittsburgh Sleep Quality
erythematosus and pregnancies complicated by Index (Buysse et al,. 1989). Maternal mental health was
aneuploidy or fetal anomaly. Once potential participants gauged by the State_Trait Anxiety Inventory (Spielberger,
were identified, screening was done by the research 1983), Original Perceived Stress Scale (Cohen et al.,1983)
nurses to determine eligibility according to the study’s Roesch Questionnaire (Roesch et al., 2004) and
inclusion. A written informed consent was obtained once Edinburgh Postnatal Depression Scale (Cox et al.,1987) at
the participant has met all the inclusion and exclusion each visit.
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Int. J. Gynecol. Obstet. Res. 033

Demographic and laboratory measurement the cohort was 30.6 years; Chinese (31.1 years) and other
ethnicities (31.0 years) were a little older. Malays were
At each visit, maternal blood pressure, central aortic much less likely to attend university than other ethnicities
systolic pressure (by non-invasive arterial pulse waveform while Chinese had the lowest unemployment rate. Chinese
analysis), height and weight were measured. Ultrasound also had a substantially higher rate of unmarried status.
and Doppler studies included fetal biometry, cervical Overall, Malays had the lowest total monthly household
length, amniotic fluid, placental localization, uterine artery income while Chinese had the highest.
and fetal Doppler studies.
More than half of the study participants were nulliparous.
A total of 15 ml blood sample was collected at each visit. Chinese had the lowest body mass index (BMI) in early
Serum, plasma and buffy coat samples were separated pregnancy while Malays and Indians had a similar BMI.
and stored at -80° for subsequent analysis. A number of The prevalence of chronic hypertension and preexisting
hormones were measured, including thyroid hormones, diabetes mellitus was 1.1% and 1.4%, respectively. Very
human chorionic gonadotrophin beta unit (βHCG), few women smoked (2.6%) or drank alcohol (1.2%) during
pregnancy-associated plasma protein A (PAPP-A), sFlt-1, pregnancy. 8.4% of women reported exercise in
PlGF, progesterone, prolactin, and cortisol at all visits. pregnancy.
Markers for preterm labour included speculum
examination for placental growth factor binding protein-1 The mean gestational age at birth was 38.7±1.5 weeks
(PIGFBP-1) assessment and high vaginal swab for with a preterm birth rate of 7.1%. The mean birthweight
infection or colonization were done at 11 to 14 weeks and was 3105±458 g with little variation among ethnic groups.
at more than 34 weeks. The rates of low birthweight (<2500 g) and macrosomia (
≥4000 g) were 7.3% and 1.8%, respectively. Incidence of
Patient and public involvement intrauterine growth restriction, defined as estimated fetal
weight or abdominal circumference < the 5 th percentile
The NORA pregnancy cohort study was developed based adjusting for gender and ethnicity, or birthweight < the 3rd
to a significant extent on patients’ priorities and percentile, was 4.0%. Gestational hypertension and
experiences. Besides aiming to develop better risk preeclampsia occurred in 2.0% and 2.3% of women,
assessments to benefit patients, there has been strong respectively. Glucose tolerance test was prescribed only
considerations for outcome measures based on patient to high risk women. Approximately 40% of women had the
satisfaction and their experiences in pregnancy. Thus test, among whom 20.9% were diagnosed as gestational
sleep satisfaction and mental wellness outcome measures diabetes. Malay appeared to have the lowest incidence
were given priority and included in the study with the use (12.3%) among the ethnic groups.
of various survey scales e.g. Pittsburgh Sleep Quality
Index, State_Trait Anxiety Inventory, Original Perceived The NORA Cohort has established locally derived and
Stress Scale, Roesch Questionnaire on stress in gestational age-specific reference intervals for the five
pregnancy and Edinburgh Postnatal Depression Scale at thyroid hormone parameters (Ho et al., 2017). Another
each visit. study tested if circulating extracellular vesicles (EVs) such
as cholera toxin B chain (CTB)- or annexin V (AV)-binding
In the design of study schedule, patients’ feedbacks on EVs could enhance the predictability of existing
making it convenient for them to participate in the study biomarkers (e.g. PlGF) for preeclampsia. We found that
were taken into account. The study investigations were EV biomarkers enhanced the predictive robustness of an
arranged and performed at the specific 4 time-points when existing PE biomarker sufficiently to justify PE screening in
they visited the hospital for clinical consultations. In a low-risk general obstetric population (Tan et al., 2017).
addition, in previous studies, the issue of adequate and fair In NORA study, higher serum proesterone levels at 28–32
reimbursement for their transport fares was noted. In weeks of pregnancy were observed in women who had
NORA appropriate transport reimbursement were preterm deliveries compared with women with term
undertaken. NORA results have been presented at public deliveries (Feng et al., 2018).
forums in the hospital and also in community centers in
Singapore. It is expected there will be more sharing of the
results with the patients and public in the near future. STRENGTHS AND LIMITATIONS

This is a prospective cohort study. Over 92% of women


FINDINGS TO DATE completed all four follow-up visits. Although the
participation rate among the eligible women was less than
The cohort consisted of 470 (50.7%) Chinese, 250 (27.0%) 50%, the baseline characteristics of the participants were
Malay, 100 (10.8%) Indian and the remaining 106 (11.4%) similar to those of general obstetric population at the KK
were of other ethnicity. Table 2 describes the baseline Hospital (Roesch et al., 2004). Thus, our study population
characteristics of the study population. The average age of is a good representation of the hospital population. We
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Tan et al. 034

also conducted a wide range of assessments, repeated REFERENCES


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AUTHORS INFORMATION
1. Qiu Ju Ng , Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899. Tel. (65) 96361842, Email: qiuju.ng@mohh.com.sg
2. Jun Zhang, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899. Tel. (65) 86479759, Email: zhang.jun.jim@kkh.com.sg
3. Fei Dai, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899. Tel. (65) 98911568, Email: dai.fei@kkh.com.sg
4. Mor Jack Ng, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899. Tel. (65) 93866284, Email: ng.mor.jack@kkh.com.sg
5. Nurul Syaza Razali, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah
Road, Singapore 229899. Tel. (65) 96914593, Email: Nurul.Syaza@kkh.com.sg
6. Nyo Mie Win, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road,
Singapore 229899. Tel. (65) 91068022, Email: nyo.mie.win@kkh.com.sg
7. Bernard Chern, Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, 100 Bukit Timah
Road, Singapore 229899. Tel. (65) 92732233, Email: bernard.chern.s.m@singhealth.com.sg
8. George SH Yeo, Department of Obstetrics and Gynaecology/Maternal and Fetal Medicine, KK Women’s and Children’s
Hospital, 100 Bukit Timah Road, Singapore 229899. Tel. (65) 96774386 Email: dr.george.sh.yeo@gmail.com
9. Kok Hian Tan, Department of Obstetrics and Gynaecology/Maternal and Fetal Medicine, KK Women’s and Children’s
Hospital, 100 Bukit Timah Road, Singapore 229899. Tel. (65) 98375120, Email: tan.kok.hian@singhealth.com.sg
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Tan et al. 036

APPENDIX

Table 1: NORA study data collection


NORA study visit
11-14 18-22 28-32 ≥34 Delivery
weeks weeks weeks weeks
Mother
Demographics and social
Age ●
Ethnic group ●
Marital status ●
Education and employment status ●
Lifestyle
Smoking status ● ● ● ●
Alcohol and drug use ● ● ● ●
Caffeinated drinks ● ● ● ●
Physical activity ● ● ● ●
Use of supplements ● ● ● ●
Height ● ● ● ●
Weight ● ● ● ●
Sleep quality ● ● ● ●
Health
Medical and Surgical history ●
Stress / anxiety / depression ● ● ● ●
Obstetrics history
Gravida, Parity ●
Personal history of preterm delivery/PIH1/ pre- ●
eclampsia/gestational diabetes mellitus
Family history of hypertension/preterm ●
delivery/diabetes
Type of pregnancy (spontaneous or assisted ●
reproductive techniques)
Maternity Data Set
Blood Pressure ● ● ● ● ●
Urine dipstick ● ● ● ●
Pulsewave analysis (BPro2 reading) ● ● ● ●
Haematological and clinical chemistry ● ● ● ●
Serum biomarkers ● ● ● ●
Ultrasound and Doppler studies ● ● ● ●
High vaginal swab for culture ● ●
Gestational age at delivery ●
Mode of delivery ●
Birth weight ●
Apgar scores ●
Placenta weight ●
Complications during delivery ●
1 PIH- Pregnancy-induced hypertension
2The BPro device analyses the radial pulse wave to generate a central aortic pressure, which acts as a measure of

arterial stiffness.

Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Int. J. Gynecol. Obstet. Res. 037

Table 2: Maternal characteristics and perinatal outcome by races


Total Chinese Malay Indian Others P
N=926 N=470 N=250 N=100 N=106
Maternal Characteristics
Age (years, mean±SD) 30.6±5.0 31.1±5.0 29.8±4.8 29.7±5.0 31.0±4.8 0.001
Education (%)
Secondary school or under 9.5 11.3 10.8 3.0 4.7 0.000
High school 25.5 17.9 38.4 32.3 22.6
Junior college 28.4 26.2 36.4 21.2 26.4
University or above 36.5 44.7 14.4 43.1 46.2
Occupation (%)
White-collar worker 67.6 71.9 65.6 66.0 55.2 0.017
Blue-collar worker 10.3 10.2 10.8 7.0 12.4
Unemployment 22.1 17.9 23.6 27.0 32.4
Marital status
Married 94.1 90.9 98.0 98.0 95.3 0.001
Single/Divorced/Widowed 5.9 9.1 2.0 2.0 4.7
Total monthly household income (S$, %)
< 3500 34.5 29.1 43.6 36.0 35.8 0.000
3500-5500 30.3 26.3 35.9 35.0 31.1
5501-8500 22.0 25.9 16.0 19.0 21.7
>8500 13.2 18.8 4.8 10.0 11.3
Parity
0 previous birth 54.1 57.4 50.8 50.0 50.9 0.229
1+ previous birth 45.9 42.6 49.2 50.0 49.1
1st trimester BMI (kg/m2, mean±SD) 24.2±4.7 23.0±4.1 25.7±5.0 25.6±4.7 24.3±4.7 0.000
Disease history
Chronic Hypertension (%) 1.1 1.3 0.0 2.0 1.9 0.078
Diabetes mellitus (%) 1.4 1.6 0.9 3.2 0.0 0.181
Smoking in pregnancy (%) 2.6 3.2 2.4 0.0 2.8 0.115
Drinking in pregnancy (%) 1.2 2.1 0.0 0.0 0.9 0.01
Exercise in pregnancy (%) 8.4 9.1 8.0 7.0 7.5 0.862
Perinatal outcome
Gestational age (weeks, mean±SD) 38.7±1.5 38.7±1.4 38.7±1.7 39.0±1.1 38.7±1.9 0.386
Preterm birth (<37 weeks, %) 7.1 7.5 7.2 6.1 5.7 0.899
Birth weight (g, mean±SD) 3105±458 3099±444 3091±487 3124±399 3146±499 0.723
Birth weight (g, %)
<2500 7.3 7.7 8.0 6.0 5.7 0.886
2500-3999 90.8 90.2 90.0 93.0 93.4
≥4000 1.8 2.1 2.0 1.0 0.9
Intrauterine growth restriction (%) 4.0 4.0 3.6 5.0 3.8 0.920
Gestational hypertension (%) 2.0 2.8 1.6 1.0 0.0 0.096
Pre-eclampsia (%) 2.3 2.2 3.2 2.0 1.0 0.609
Gestational diabetes (%)1 20.9 24.6 12.3 21.7 25.6 0.076
1Glucose tolerance test was only prescribed to high risk women, which accounted for approximaTely 40% of all pregnant
women.

Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore