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Study Profile
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).
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
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Int. J. Gynecol. Obstet. Res. 035
Romero R, Nien JK, Espinoza J, Todem D, Fu WJ, Chung Accepted 8 August 2018
H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S,
Gomez R, Edwin S, Chaiworapongsa T, Levine RJ Citation: Ng QJ, Zhang J, Dai F, Ng MJ, Razali NS, Win
Karumanchi SA.(2008) A longitudinal study of NM, Chern B, Yeo GSH, Tan KH (2018). Neonatal and
angiogenic (placental growth factor) and anti- Obstetric Risk Assessment (NORA) Pregnancy Cohort
angiogenic (soluble endoglin and soluble vascular Study in Singapore. International Journal of Gynecology
endothelial growth factor receptor-1) factors in normal and Obstetrics Research, 4(1): 031-037.
pregnancy and patients destined to develop
preeclampsia and deliver a small for gestational age
neonate. J Maternal Fetal Neonat Med. 21:9–23.
Spielberger CD. (1983). State-trait anxiety inventory: a
Copyright: © 2018 Tan et al. This is an open-access
comprehensive bibliography. 2nd edn. CA: Consulting
Psychologists Press. article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted
Tan KH, Tan SS, Ng MJ, Tey WS, Sim WK, Allen JC, Lim
use, distribution, and reproduction in any medium,
SK. (2017). Extracellular vesicles yield predictive pre-
provided the original author and source are cited.
eclampsia biomarkers. J Extracell Vesicles. 6:1, DOI:
10.1080/20013078.2017.1408390
Tribe RM. (2007). A translational approach to studying
preterm labour. BMC Pregnancy Childbirth 7(Suppl
1):S8.
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
arterial stiffness.
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore
Int. J. Gynecol. Obstet. Res. 037
Neonatal and Obstetric Risk Assessment (NORA) Pregnancy Cohort Study in Singapore