POPS - Pregnancy Outcome Prediction Study

Being able to accurately identify which babies are at the highest risk of stillbirth or neonatal death means that treatments can be better targeted and families whose pregnancies are healthy can be reassured.

How well a baby is growing gives an idea of how healthy they are. Some babies are not able to grow as expected during pregnancy due to problems with the placenta. Unfortunately, for these babies it can mean they are more likely to die during pregnancy or around the time of birth or may experience complications. The POPS study set out to see if having additional ultrasound scans in the final part of pregnancy could help identify babies who are smaller than expected and to see if there are any scan or Doppler measurements that are more common in babies or are stillborn or born unwell. Researchers found that ultrasound scans can help identify babies who are small, but some still died after a reassuring scan.

Sands is currently supporting the POPS2 follow-on study to see if combining blood tests with ultrasound scans can give clearer, more accurate information.

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What is the aim of this study?

The study was designed to see whether having additional ultrasound scans in the third trimester of pregnancy helps to identify babies who are smaller than expected. It also looked at whether any scan or Doppler measurements are more common in babies in babies who are stillborn or very poorly at birth.

 

Why is this important?

Some babies are not able to grow as they should during pregnancy because the placenta isn’t working properly. This slow growth is called ‘fetal growth restriction’, and babies who have this are more likely to have problems at birth and also, sadly, are more likely to die before or around the time of birth compared with babies who have grown as expected.

Unfortunately, it isn’t easy to identify babies who have fetal growth restriction during pregnancy. In most pregnancies, the baby’s growth is estimated from the increase in size of the mother’s bump during pregnancy. There is a real need to improve the identification of babies who would benefit from extra monitoring and perhaps early delivery, and there is much debate around whether additional ultrasound scans in the third trimester would be helpful.

 

Healthy small baby or growth restriction?

Babies with fetal growth restriction fall into a larger group of babies who are said to be ‘small for gestational age’ or SGA. Most babies who are small for gestational age are healthy, but because the growth-restricted babies are also small for their gestational age, researchers sometimes look at these babies rather than growth-restricted babies because there are more of them so it is easier to study this group and get useful results.

 

What happened in the study?

A total of 4,444 first-time pregnant women took part in the POPS study, which was carried out at the Rosie Hospital in Cambridge. All the women had the usual pregnancy care they would expect in the NHS, with some women having additional ultrasound scans in the third trimester if there were concerns about the baby. The results of these scans were made known to the woman and her maternity team and were used to make decisions about the rest of the pregnancy, as would usually happen.

But as well as this ‘selective’ screening, all women in the study had ultrasound scans at 28 and 36 weeks of pregnancy. The results of these scans were not made known to the women or their maternity team. (This was because knowing the result of the scans may have influenced the rest of the measurements in pregnancy, which could make the study results less reliable.)

Once the babies were born, the research team looked at the birthweight and the scan results to see how often the scans correctly identified an SGA baby. The team also looked at whether any differences in scan measurements or Doppler results were more commonly found in the babies who were very poorly at birth or stillborn.

 

What did the study find?

The research team were able to analyse data for 3,977 babies. They were able to compare the ability of the selective scans (current care) and research scans (scanning all women) to detect the live-born babies who were SGA or severely SGA.

In this study, the selective scans (so only scanning a woman if there was a clinical reason to) correctly identified 20% of SGA babies and 32% of severely SGA babies. In comparison, scanning all women correctly identified 57% of SGA babies and 77% of severely SGA babies.

Very roughly speaking, this means the selective scans picked up 2 in 10 SGA babies and 3 in 10 severely SGA babies, whereas the universal screening picked up around 6 in 10 SGA and 8 in 10 severely SGA babies.

 

Identifying babies who were stillborn or poorly

Seven babies were stillborn in this study, 26 babies either died shortly after birth or were seriously ill at birth, and 275 babies were poorly at birth. The research team looked at the scans of these babies and also the results of Doppler tests to see if there were any patterns in the results. The aim was to find something that could pick out those babies who were SGA and poorly from those who were small and healthy.

Only one of the measurement gave this additional information. The researchers found that estimating the growth rate of the abdomen from the difference in its size at the 20 week scan and at the last scan before birth gave a measurement that was markedly lower in the babies who were SGA and poorly, very poorly or stillborn at birth.

Babies who were identified as SGA by the scans but whose abdominal growth rate was normal were healthy. But SGA babies whose abdominal growth rate was very low were much more likely to be poorly, very poorly or stillborn: 18 times more likely to be SGA and poorly at birth and about 40 times more likely to be SGA and stillborn or seriously ill.

 

What do the researchers say about these results?

The team acknowledge that scans can sometimes mis-identify a normal-sized baby as SGA, causing the parents to worry unnecessarily. They also say that another study in pregnant women who aren’t in their first pregnancy should be carried out to see if the results are the same. But on the basis of the results published, the team conclude that “a programme of screening that includes universal ultrasonography and intervention following a care bundle based on the latest RCOG (Royal College of Obstetricians and Gynaecologists) guideline has the potential to reduce the number of adverse perinatal outcomes caused by FGR (fetal growth restriction).”

 

What’s next?

While the POPS Study has shown that ultrasound can improve the detection of small babies, some babies still die after a reassuring scan. And while research to develop blood tests (looking at ‘biomarkers’ in blood) to highlight a risk of stillbirth has been promising, the tests don’t give clear enough information on their own to be helpful.

So the next question that the POPS study is asking is whether ultrasound can be combined with blood tests to identify more of the babies who are becoming ill towards the end of pregnancy. The research team in Cambridge are looking at the results of their POPS ultrasound scans and blood tests and matching these with the medical information on the babies born to mothers in the study to see if there’s a pattern. Find out more about POPS2.

The research data collected during the POPS study has also formed the basis of analysis for a wide range of research projects investigating different aspects of fetal growth restriction and exploring other possible causes and predictors of complications, preterm birth and stillbirth including changes in the placenta and the mother's metabolism during pregnancy. Some of this work is still ongoing and the POPS2 study plans to add to it further.  

Research Papers

Al Ghadban, Yasmina, Yuheng Du, D. Stephen Charnock-Jones, Lana X. Garmire, Gordon C. S. Smith, and Ulla Sovio. ‘Prediction of Spontaneous Preterm Birth Using Supervised Machine Learning on Metabolomic Data: A Case-Cohort Study’. BJOG: An International Journal of Obstetrics and Gynaecology, 20 November 2023. https://doi.org/10.1111/1471-0528.17723.
 
Burden, Christy A., Gordon C. Smith, Ulla Sovio, Gemma L. Clayton, and Abigail Fraser. ‘Maternal Hemoglobin Levels and Adverse Pregnancy Outcomes: Individual Patient Data Analysis from 2 Prospective UK Pregnancy Cohorts’. The American Journal of Clinical Nutrition 117, no. 3 (1 March 2023): 616–24. https://doi.org/10.1016/j.ajcnut.2022.10.011.
 
Cleaton, Mary A. M., Claire L. Dent, Mark Howard, Jennifer A. Corish, Isabelle Gutteridge, Ulla Sovio, Francesca Gaccioli, et al. ‘Fetus-Derived DLK1 Is Required for Maternal Metabolic Adaptations to Pregnancy and Is Associated with Fetal Growth Restriction’. Nature Genetics 48, no. 12 (December 2016): 1473–80. https://doi.org/10.1038/ng.3699.
 
Gaccioli, Francesca, Ulla Sovio, Emma Cook, Martin Hund, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Screening for Fetal Growth Restriction Using Ultrasound and the sFLT1/PlGF Ratio in Nulliparous Women: A Prospective Cohort Study’. The Lancet. Child & Adolescent Health 2, no. 8 (August 2018): 569–81. https://doi.org/10.1016/S2352-4642(18)30129-9.
 
Gaccioli, Francesca, Ulla Sovio, Sungsam Gong, Emma Cook, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Increased Placental sFLT1 (Soluble Fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction’. Hypertension (Dallas, Tex.: 1979) 80, no. 2 (February 2023): 325–34. https://doi.org/10.1161/HYPERTENSIONAHA.122.19482.
 
Goffau, Marcus C. de, Susanne Lager, Ulla Sovio, Francesca Gaccioli, Emma Cook, Sharon J. Peacock, Julian Parkhill, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Human Placenta Has No Microbiome but Can Contain Potential Pathogens’. Nature 572, no. 7769 (August 2019): 329–34. https://doi.org/10.1038/s41586-019-1451-5.
 
Gong, Sungsam, Michelle D Johnson, Justyna Dopierala, Francesca Gaccioli, Ulla Sovio, Miguel Constância, Gordon CS Smith, and D Stephen Charnock-Jones. ‘Genome-Wide Oxidative Bisulfite Sequencing Identifies Sex-Specific Methylation Differences in the Human Placenta’. Epigenetics 13, no. 3 (21 February 2018): 228–39. https://doi.org/10.1080/15592294.2018.1429857.
 
Gong, Sungsam, Ulla Sovio, Irving Lmh Aye, Francesca Gaccioli, Justyna Dopierala, Michelle D. Johnson, Angela M. Wood, et al. ‘Placental Polyamine Metabolism Differs by Fetal Sex, Fetal Growth Restriction, and Preeclampsia’. JCI Insight 3, no. 13 (12 July 2018): e120723, 120723. https://doi.org/10.1172/jci.insight.120723.
 
Jayasuriya, Nimesh A., Alice E. Hughes, Ulla Sovio, Emma Cook, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘A Lower Maternal Cortisol-to-Cortisone Ratio Precedes Clinical Diagnosis of Preterm and Term Preeclampsia by Many Weeks’. The Journal of Clinical Endocrinology and Metabolism 104, no. 6 (1 June 2019): 2355–66. https://doi.org/10.1210/jc.2018-02312.
Lager, Susanne, Ulla Sovio, Elizabeth Eddershaw, Margaretha W. van der Linden, Cansu Yazar, Emma Cook, Lisa Happerfield, et al. ‘Abnormal Placental CD8+ T-Cell Infiltration Is a Feature of Fetal Growth Restriction and Pre-Eclampsia’. The Journal of Physiology 598, no. 23 (2020): 5555–71. https://doi.org/10.1113/JP279532.
 
McBride, Nancy, Paul Yousefi, Ulla Sovio, Kurt Taylor, Yassaman Vafai, Tiffany Yang, Bo Hou, et al. ‘Do Mass Spectrometry-Derived Metabolomics Improve the Prediction of Pregnancy-Related Disorders? Findings from a UK Birth Cohort with Independent Validation’. Metabolites 11, no. 8 (10 August 2021): 530. https://doi.org/10.3390/metabo11080530.
 
Moraitis, Alexandros A., Thomas Bainton, Ulla Sovio, Peter Brocklehurst, Alexander EP. Heazell, Jim G. Thornton, Stephen C. Robson, Aris Papageorghiou, and Gordon CS. Smith. ‘Fetal Umbilical Artery Doppler as a Tool for Universal Third Trimester Screening: A Systematic Review and Meta-Analysis of Diagnostic Test Accuracy’. Placenta 108 (1 May 2021): 47–54. https://doi.org/10.1016/j.placenta.2021.03.011.
 
Olga, Laurentya, Ulla Sovio, Hilary Wong, Gordon Smith, and Catherine Aiken. ‘Association between Antenatal Diagnosis of Late Fetal Growth Restriction and Educational Outcomes in Mid-Childhood: A UK Prospective Cohort Study with Long-Term Data Linkage Study’. PLOS Medicine 20, no. 4 (24 April 2023): e1004225. https://doi.org/10.1371/journal.pmed.1004225.
 
Olga, Laurentya, Ulla Sovio, Hilary Wong, Gordon C. S. Smith, and Catherine E. M. Aiken. ‘Maternal High Body Mass Index, but Not Gestational Diabetes, Is Associated with Poorer Educational Attainment in Mid-Childhood’. American Journal of Obstetrics and Gynecology, 21 November 2023, S0002-9378(23)02029-X. https://doi.org/10.1016/j.ajog.2023.11.1227.
 
Partap, Uttara, Ulla Sovio, and Gordon C. S. Smith. ‘Fetal Growth and the Risk of Spontaneous Preterm Birth in a Prospective Cohort Study of Nulliparous Women’. American Journal of Epidemiology 184, no. 2 (15 July 2016): 110–19. https://doi.org/10.1093/aje/kwv345.
 
Pritchard, Natasha, Tu’uhevaha J. Kaitu’u-Lino, Sungsam Gong, Justyna Dopierala, Gordon C.S. Smith, D. Stephen Charnock-Jones, and Stephen Tong. ‘ELABELA/APELA Levels Are Not Decreased in the Maternal Circulation or Placenta among Women with Preeclampsia’. The American Journal of Pathology 188, no. 8 (August 2018): 1749–53. https://doi.org/10.1016/j.ajpath.2018.04.008.
 
Salavati, N., U. Sovio, R. Plitman Mayo, D. S. Charnock-Jones, and G. C. S. Smith. ‘The Relationship between Human Placental Morphometry and Ultrasonic Measurements of Utero-Placental Blood Flow and Fetal Growth’. Placenta 38 (February 2016): 41–48. https://doi.org/10.1016/j.placenta.2015.12.003.
 
Selvaratnam, Roshan J., Ulla Sovio, Emma Cook, Francesca Gaccioli, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Objective Measures of Smoking and Caffeine Intake and the Risk of Adverse Pregnancy Outcomes’. International Journal of Epidemiology 52, no. 6 (25 December 2023): 1756–65. https://doi.org/10.1093/ije/dyad123.
 
Sovio, Ulla, Gemma L Clayton, Emma Cook, Francesca Gaccioli, D Stephen Charnock-Jones, Deborah A Lawlor, and Gordon C S Smith. ‘Metabolomic Identification of a Novel, Externally Validated Predictive Test for Gestational Diabetes Mellitus’. The Journal of Clinical Endocrinology and Metabolism 107, no. 8 (18 April 2022): e3479–86. https://doi.org/10.1210/clinem/dgac240.
 
Sovio, Ulla, Francesca Gaccioli, Emma Cook, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Association between Adverse Pregnancy Outcome and Placental Biomarkers in the First Trimester: A Prospective Cohort Study’. BJOG: An International Journal of Obstetrics & Gynaecology n/a, no. n/a (2023). https://doi.org/10.1111/1471-0528.17691.
 
Sovio, Ulla, Francesca Gaccioli, Emma Cook, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Maternal Serum Levels of Soluble Fms-like Tyrosine Kinase-1 and Placental Growth Factor at 20 and 28 Weeks of Gestational Age and the Risk of Spontaneous Preterm Birth’. American Journal of Obstetrics and Gynecology 229, no. 2 (August 2023): 164.e1-164.e18. https://doi.org/10.1016/j.ajog.2023.02.001.
 
Sovio, Ulla, Francesca Gaccioli, Emma Cook, D. Stephen Charnock-Jones, and Gordon C.S. Smith. ‘Slowing of Fetal Growth and Elevated Maternal Serum sFLT1:PlGF Are Associated with Early Term Spontaneous Labor’. American Journal of Obstetrics and Gynecology 225, no. 5 (November 2021): 520.e1-520.e10. https://doi.org/10.1016/j.ajog.2021.04.232.
 
Sovio, Ulla, Francesca Gaccioli, Emma Cook, Martin Hund, D. Stephen Charnock-Jones, and Gordon C. S. Smith. ‘Prediction of Preeclampsia Using the Soluble Fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: A Prospective Cohort Study of Unselected Nulliparous Women’. Hypertension (Dallas, Tex.: 1979) 69, no. 4 (April 2017): 731–38. https://doi.org/10.1161/HYPERTENSIONAHA.116.08620.
 
Sovio, Ulla, Neil Goulding, Nancy McBride, Emma Cook, Francesca Gaccioli, D. Stephen Charnock-Jones, Debbie A. Lawlor, and Gordon C. S. Smith. ‘A Maternal Serum Metabolite Ratio Predicts Fetal Growth Restriction at Term’. Nature Medicine 26, no. 3 (March 2020): 348–53. https://doi.org/10.1038/s41591-020-0804-9.
 
Sovio, Ulla, Neil Goulding, Nancy McBride, Emma Cook, Francesca Gaccioli, D. Stephen Charnock-Jones, Deborah A. Lawlor, and Gordon C. S. Smith. ‘A Maternal Serum Metabolite Ratio Predicts Large for Gestational Age Infants at Term: A Prospective Cohort Study’. The Journal of Clinical Endocrinology and Metabolism 107, no. 4 (24 March 2022): e1588–97. https://doi.org/10.1210/clinem/dgab842.
 
Sovio, Ulla, Nancy McBride, Angela M Wood, Katya L Masconi, Emma Cook, Francesca Gaccioli, D Stephen Charnock-Jones, Debbie A Lawlor, and Gordon C S Smith. ‘4-Hydroxyglutamate Is a Novel Predictor of Pre-Eclampsia’. International Journal of Epidemiology 49, no. 1 (February 2020): 301–11. https://doi.org/10.1093/ije/dyz098.
 
Sovio, Ulla, Helen R. Murphy, and Gordon C. S. Smith. ‘Accelerated Fetal Growth Prior to Diagnosis of Gestational Diabetes Mellitus: A Prospective Cohort Study of Nulliparous Women’. Diabetes Care 39, no. 6 (June 2016): 982–87. https://doi.org/10.2337/dc16-0160.
 
Sovio, Ulla, and Gordon C. S. Smith. ‘Comparison of Estimated Fetal Weight Percentiles near Term for Predicting Extremes of Birthweight Percentile’. American Journal of Obstetrics and Gynecology 224, no. 3 (March 2021): 292.e1-292.e19. https://doi.org/10.1016/j.ajog.2020.08.054.
 
Sovio, Ulla, and Gordon C. S. Smith. ‘The Effect of Customization and Use of a Fetal Growth Standard on the Association between Birthweight Percentile and Adverse Perinatal Outcome’. American Journal of Obstetrics and Gynecology 218, no. 2S (February 2018): S738–44. https://doi.org/10.1016/j.ajog.2017.11.563.
 
Sovio, Ulla, Ian R. White, Alison Dacey, Dharmintra Pasupathy, and Gordon C. S. Smith. ‘Screening for Fetal Growth Restriction with Universal Third Trimester Ultrasonography in Nulliparous Women in the Pregnancy Outcome Prediction (POP) Study: A Prospective Cohort Study’. Lancet (London, England) 386, no. 10008 (21 November 2015): 2089–97. https://doi.org/10.1016/S0140-6736(15)00131-2.
 
Teulings, Noor E. W. D., Angela M. Wood, Ulla Sovio, Susan E. Ozanne, Gordon C. S. Smith, and Catherine E. Aiken. ‘Independent Influences of Maternal Obesity and Fetal Sex on Maternal Cardiovascular Adaptation to Pregnancy: A Prospective Cohort Study’. International Journal of Obesity (2005) 44, no. 11 (2020): 2246–55. https://doi.org/10.1038/s41366-020-0627-2.

 

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