Health and Social Care Delivery Research

Planning for a cohort study to investigate the impact and management of influenza in pregnancy in a future pandemic

  • Type:
    Extended Research Article
  • Headline:
    The study found that the UK Obstetric Surveillance System was useful in the investigation of pregnant women who were hospitalised with 2009 A/H1N1 influenza and for the subsequent development of a study to examine the impact and management of influenza in pregnancy, ready for activation in the event of a future pandemic.
  • Authors:
    Marian Knight,
    Peter Brocklehurst,
    Pat O’Brien,
    Maria A Quigley,
    Jennifer J Kurinczuk
    Detailed Author information

    Marian Knight1,*, Peter Brocklehurst2, Pat O’Brien2, Maria A Quigley1, Jennifer J Kurinczuk1

    • 1 National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK
    • 2 Institute for Women’s Health, University College London, London, UK
  • Funding:
    National Institute for Health Research (NIHR)
  • Journal:
    Health and Social Care Delivery Research
  • Issue:
    Volume: 3, Issue: 6
  • Published:
  • Citation:
    Primary Research Project. Knight M, Brocklehurst P, O’Brien P, Quigley MA, Kurinczuk JJ. Planning for a cohort study to investigate the impact and management of influenza in pregnancy in a future pandemic. Health Soc Care Deliv Res 2015;3(6). https://doi.org/10.3310/hsdr03060
  • DOI:
    https://doi.org/10.3310/hsdr03060
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Background

Evidence from the 2009 A/H1N1 influenza pandemic demonstrated that pregnant women are particularly vulnerable to infection and at an increased risk of death. Active data collection through the UK Obstetric Surveillance System (UKOSS) about women admitted to hospital during the 2009 A/H1N1 pandemic was used to inform ongoing clinical guidance regarding the use of antiviral treatment for pregnant women and demonstrated that, in addition to an increased risk of maternal morbidity, influenza infection in pregnancy is associated with poor perinatal outcomes, including an increased risk of stillbirth and preterm birth. This evidence influenced the decision to offer routine influenza immunisation to pregnant women. Even in a non-epidemic period, pregnant women continue to die from influenza.

Objective

To establish, and then to put into hibernation, the study mechanisms needed to mount a rapid investigation of the impact of pandemic influenza in pregnancy in the event of a newly emerging pandemic strain.

Design

A new UKOSS cohort study was designed, based on the 2009–10 study, and following consultation with the Pandemic Flu Planning Group at the Royal College of Obstetricians and Gynaecologists and the UKOSS Steering Committee, to identify potential previously unanswered questions.

Setting

UK maternity units.

Participants

All pregnant women admitted to hospital with influenza in a future pandemic.

Main outcome measures

Management of pregnant women with influenza infection, intervention rates, treatment and pregnancy outcome for both the mother and fetus.

Results

The study was designed and approved by the UKOSS Steering Committee and then placed into hibernation for activation in the event of an influenza pandemic.

Conclusions

Pregnant women, as a result of their changed immunological status, appear to be particularly susceptible to infection, including from influenza. The existence of the UKOSS enabled us to rapidly mount a study of pregnant women who were hospitalised with 2009 A/H1N1 influenza. Minor modifications to incorporate previously unanswered questions and our previous study enabled us to design, and then put into hibernation, a new study ready to investigate the impact and management of influenza in pregnancy, which is poised for activation in the event of a newly emerging pandemic strain. This will enable real-time data to be available on which to base rapid changes in clinical management as the as-yet-unforeseen pandemic unfolds. In the event of an influenza pandemic the study will be available to be immediately activated following expedited regulatory approvals.

Trial registration

Current Controlled Trials ISRCTN44137563.

Funding

The National Institute for Health Research Health Services and Delivery Research programme.

Notes

Article history

The research reported in this issue of the journal was funded by the Health Services and Delivery Research programme as project number 11/46/12. The contractual start date was in June 2012. The report detailing the set up phase and initial outcomes began editorial review in December 2014 and was accepted for publication in February 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The Health Services and Delivery Research editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report. Should the study progress further, the full report will be published in the Health Services and Delivery Research journal.

Declared competing interests of authors

Peter Brocklehurst reports personal fees from Oxford Analytica; grants from the National Institute for Health and Care Excellence outside the submitted work; and that he is chairperson of the National Institute for Health Research Health Technology Assessment Maternal, Neonatal and Child Health Panel (MNCH).

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Copyright statement

© Queen’s Printer and Controller of HMSO 2015. This work was produced by Knight et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

Chapter 1 Background

Evidence from the last influenza pandemic (2009 A/H1N1) showed that pregnant women were particularly vulnerable to severe complications of infection,1–5 resulting in increases in both maternal and perinatal mortality. 5–7 Further investigations, including in the UK,5 highlighted specific groups of women who were at higher risk of morbidity after 2009 A/H1N1 infection in pregnancy. Factors associated with admission to hospital with 2009 A/H1N1 in pregnancy included maternal obesity, asthma, multiparity, multiple pregnancy, black or other minority group ethnicity, and smoking among women aged < 25 years. 1,3,5 Women have continued to die from influenza associated with pregnancy seasonally since the pandemic. 8

Active data collection on pregnant women at the time of admission to hospital with confirmed 2009 A/H1N1 influenza, as well as identifying particular subgroups who were at risk of the severest disease and hence a particular target for preventative interventions, also pinpointed aspects of management that resulted in improved outcomes for women, including the importance of early antiviral treatment. 5 In the 2009 pandemic, monthly analysis of emerging data was used to inform ongoing clinical guidance. Admission to an intensive care unit, taken as a proxy for severe morbidity, was also associated with delay in starting treatment with antiviral medication (> 2 days after the onset of symptoms) in other population studies. 1,3,4,9 This has been confirmed in more recent meta-analyses of observational data. 10

Many studies of 2009 A/H1N1 in pregnancy reported very incomplete outcomes or outcomes for only a subset of severely affected women. 1,3,4,9,11,12 Half of the initial published outcome rates were calculated using subsamples of < 50% of the study cohort. The majority of studies did not follow up women to the end of their pregnancy3,4,9,11 or, in some cases, the follow-up time was too short to collect outcome information on women infected at all gestations. 3,6 This approach will have biased any results towards reporting preterm births and is likely to have led to overly pessimistic results.

The UK study13 followed up 94% of the original study cohort (n = 256) and demonstrated that poor perinatal outcomes, in addition to poor maternal outcomes, were associated with 2009 A/H1N1 influenza infection in pregnancy. The risks of poor outcomes persisted after adjustment for maternal and pregnancy characteristics that were known to be associated with poor perinatal outcomes. The study13 suggested an increased risk of perinatal mortality in women infected with 2009 A/H1N1 compared with the general population {perinatal mortality rate 39 per 1000 total births [95% confidence interval (CI) 19 to 71 per 1000 total births] compared with 7 per 1000 total births (95% CI 3 to 13 per 1000 total births), adjusted odds ratio (aOR) = 5.7; 95% CI 2.2 to 15.1}. This was explained largely by an increased risk of stillbirth, although the neonatal death rate was also significantly higher than the national rate (odds ratio 3.8, 95% CI 1.2 to 11.8). The study strengthened the evidence for offering routine immunisation to pregnant women and informed subsequent guidance in Europe. 14 More recent cohort studies using routinely collected data have identified similar findings. 15

In addition to the mortality risk, infants were at greater risk of preterm birth (aOR 4.0, 95% CI 2.7 to 5.9);13 this was a mixture of both iatrogenic and spontaneous preterm delivery. The data suggest that women with 2009 A/H1N1 infection who gave birth preterm were more likely to have been infected in their third trimester. Secondary infection with bacterial pneumonia played an important role in preterm delivery in this 2009–10 cohort; secondary pneumonia was also associated with preterm birth in women with pandemic influenza in 1919. 16 In the UK data, the risk of preterm birth associated with 2009 A/H1N1 infection persisted even after accounting for the role of secondary pneumonia, which suggested that the excess risk could not be explained by this factor alone. 13

Almost half of the infants delivered preterm were delivered early because of maternal compromise. Women are typically delivered during the third trimester in order to aid mechanical ventilation. However, emerging evidence suggests that when women are referred for management with extracorporeal membrane oxygenation (ECMO), in the absence of fetal compromise there may not be an indication to deliver the fetus early. 17 This is noted particularly at gestations of < 30–32 weeks, when the size of the uterus is unlikely to affect mechanical ventilation. Increased availability and use of ECMO may therefore have the potential to impact positively on infant outcomes, even in the presence of maternal critical illness, including not only mortality, but also long-term morbidity, care costs and emotional stress for parents.

Overall, these studies show a clear increase in risk of poor maternal and pregnancy outcomes in women infected with 2009 A/H1N1 influenza. Importantly, immunisation against 2009 A/H1N1 influenza for pregnant women was shown to have a significant impact on health outcomes for both mother and baby. 14 Almost half of the preterm births were due to early delivery for maternal compromise, indicating that the health of pregnant women, which is improved with rapid treatment with antiviral agents, is an important public health priority in future waves of this and other influenza pandemics.

In a future pandemic, however, these observed patterns may differ, and a rapid study of this susceptible group will be important to inform both ongoing preventative and management policies. In the early period of the 2009 A/H1N1 pandemic, agencies took time to co-ordinate and agree guidance. There was thus a delay before any guidance on the care of pregnant or postpartum women with A/H1N1 was issued, and delays in updating this guidance. A rapid study would minimise these delays, and allow prompt dissemination of new learning. In particular, a number of clinical questions remain unresolved, which would be informed by a future study. Of note, it is important to establish whether or not pregnancy can be successfully continued in women managed with ECMO. Limited evidence currently exists as to whether or not pregnancy can be continued during and after ECMO treatment,17 but further data are needed to fully inform management guidance and also service planning. Additionally, it will be important to investigate whether or not the seasonal influenza immunisation current at the time of the pandemic protects women against pandemic influenza. Immunisation policy changed subsequent to the most recent pandemic, such that pregnant women are now offered seasonal influenza immunisation as part of a routine programme. 18 However, uptake in pregnancy remains relatively low; at the time of writing, vaccine coverage is about 25% in pregnant women with no other complications. 19 In a new pandemic situation, establishing whether or not pregnant women have any protection from existing vaccines, as well as establishing reasons for non-immunisation, will inform immediate public health actions.

Chapter 2 Study objective

The objective of the project reported here was to establish, and then to put into hibernation, the study mechanisms and materials needed to mount a rapid investigation of the impact of pandemic influenza in pregnancy in the event of a newly emerging pandemic strain. This report thus describes the study planning and set-up phase but, as a further pandemic has not yet occurred, the study does not include any new data on influenza in pregnancy.

Chapter 3 Methods and results

The UK Obstetric Surveillance System (UKOSS) is a research platform to enable the study of rare or severe complications in pregnancy. 20 Reporting clinicians, who include midwives, anaesthetists and obstetricians, are located in all 211 consultant-led maternity units in the UK. The conditions studied using the system change over time; cases that are currently under study are reported monthly on a report card, which is returned to the central UKOSS administration team in Oxford. The monthly card is also used to update contact details when reporting staff change, so that the list of reporters is kept continually up to date. When the reporting clinician indicates on the monthly card that they have a new case to report, the UKOSS administration team will then mail out a specific data collection form. The data collection forms, which are individually designed for each condition-specific study, contain information about a woman’s sociodemographic, medical and pregnancy characteristics, together with information about the management of her condition and the outcomes of pregnancy for both her and her baby. All of the information collected is anonymous and thus can be collected without requiring women’s consent.

The UKOSS was used to conduct the UK study of pregnant women who were hospitalised with 2009 A/H1N1 influenza in the second wave of the pandemic in late 2009. 13 The normal processes of UKOSS were adapted to allow online reporting of cases and rapid return of electronic data collection forms. Data were analysed monthly and used to inform ongoing clinical guidance.

In order to prepare a new study for a potential future pandemic of influenza, the data from the previous study were examined, and the lead for the Pandemic Flu Planning Group at the Royal College of Obstetricians and Gynaecologists, together with the UKOSS Steering Committee, which includes both public and professional members, was consulted about potential unanswered questions or issues that might be pertinent to pregnant women in future pandemics. On the basis of this consultation, the data collection form that had been used to collect information in the 2009 pandemic was modified. New questions were added, particularly on the use of respiratory support, including ECMO and the timing of delivery in relation to the use of respiratory support. The data collection forms for the Influenza A/H1N1 Pandemic Study and the new study are included in Appendix 1.

The relevant regulatory approvals were obtained, a database was programmed together with a web portal for reporting cases, and the study was hibernated pending activation in the event of a pandemic. The authors were provided with a key contact at the funding body, who would advise activation in the event of a pandemic.

Chapter 4 Discussion

The UKOSS is a research platform that allows for rapid activation of studies of pregnancy complications. The set-up of this new study required very minor modifications to the data collection system that had been set up in 2009. If regulatory approvals are facilitated, the UKOSS could be mobilised rapidly to study pregnancy outcomes of any new emerging infection;13 we estimate that a study could be implemented within 2–4 weeks of approvals being obtained. Advance approval, prior to any new infection emerging, would clearly allow for even more rapid activation.

It is important to note that the UKOSS is a maternity hospital-based system; therefore, it is likely to capture only severe pregnancy complications and outcomes, or those complications and outcomes that occur during the same hospital admission as delivery. It will not, for example, necessarily identify women who have had an early pregnancy loss or termination as a result of influenza or other emerging infection, as, even if they were hospitalised, they would not necessarily be brought to the attention of maternity services. In the event of future infections, it would therefore be beneficial also to collect information in general practice. This was undertaken in the UK to a limited extent during the 2009 A/H1N1 influenza pandemic;5 however, it proved much more difficult to obtain information from the community than from hospital owing to the large number of individual reporting organisations involved. Other health systems have used routine data to identify early pregnancy complications of 2009 A/H1N1 infection; it would be beneficial in the UK if routine systems, such as the Clinical Practice Research Datalink (CPRD), could be used on a rapid basis to identify such complications in the future. Additional data to be identified from general practice data could include these early pregnancy complications, as well as hospitalisations in settings other than maternity. Although the CPRD currently covers only a small proportion of UK general practices, if coverage is expanded, a comprehensive future study could include both a UKOSS study and a linked study using the CPRD to collect additional information about complications of influenza in pregnancy presenting in other settings.

Systems such as UKOSS now exist in several specialties. UKOSS was based on the model developed by the British Paediatric Surveillance Unit (BPSU),21 and the BPSU has been successfully used to conduct studies of emerging infections in the paediatric population, an example being new variant Creutzfeldt–Jakob disease. 22 A new system has recently been set up, covering early pregnancy units – the UK Early Pregnancy Surveillance Service23 – and this would be a possible route to obtaining information about severe pregnancy complications as a result of infection in the first trimester. Other systems exist in other specialty areas, for example ophthalmology,24 paediatric surgery25 and neurology,26 all of which could be used to investigate emerging public health threats on a rapid basis.

Robust identification of rare, but extremely severe, pregnancy complications in association with emerging infections such as pandemic influenza can be a challenge even on a national basis, as studies will have limited statistical power to identify such complications. The International Network of Obstetric Survey Systems27 includes member countries across Europe and Australasia, all of whom operate systems that are similar to UKOSS. Rapid activation of a study across the entire network in a future pandemic would allow for rapid collection and collation of information on a large number of pregnancies, thus providing information to guide both prevention and management of infected pregnant women with the most efficiency.

It is important to note that information about the implications and outcomes of seasonal influenza in pregnancy is incomplete. The European Centre for Disease Prevention and Control technical report summarising the scientific advice on seasonal influenza vaccination of children and pregnant women14 identified significant gaps in the data from Europe on the burden of seasonal influenza in pregnant women, as well as data on vaccine effectiveness and safety. The majority of the limited data available comes from North America. The question therefore arises as to whether or not this study should be activated in the absence of a pandemic in order to provide those data on seasonal influenza in pregnancy for the UK. Robust UK data may further help to counsel women about the risks and benefits of influenza vaccination, as well as aiding economic evaluation.

Chapter 5 Conclusions

Pregnant women, as a result of their altered immune system and physiology, may be uniquely susceptible to not only influenza, but also other emerging infections. We were able to use the UKOSS to conduct a rapid study of pregnant women who were hospitalised with 2009 influenza A/H1N1. Only minor modifications were required to develop a study to investigate the impact and management of influenza in pregnancy ready for activation in the event of a future pandemic. The UKOSS may be used for rapid studies of any emerging infections in pregnancy; the conduct of studies across an international network may allow for even more rapid information to guide advice and management in pregnancy.

Acknowledgements

The authors would like to thank the members of the UKOSS Steering Committee for their contribution to the study.

Contribution of authors

Marian Knight (Professor of Maternal and Child Population Health) designed the study and wrote the first draft of the manuscript.

Peter Brocklehurst (Professor of Women’s Health) assisted with the design of the study and revised the manuscript.

Pat O’Brien (Consultant Obstetrician) assisted with the design of the study and revised the manuscript.

Maria A Quigley (Professor of Statistical Epidemiology) assisted with the design of the study and revised the manuscript.

Jennifer J Kurinczuk (Professor of Perinatal Epidemiology) assisted with the design of the study and revised the manuscript.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HS&DR programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HS&DR programme or the Department of Health.

References

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Appendix 1 Data collection forms

Appendix 1.1 UKOSS 2009 A/H1N1 Pandemic Influenza Study data collection form

(PDF download)

Appendix 1.2 UKOSS new planned Pandemic Influenza Study data collection form

(PDF download)

Appendix 2 Study protocol

(PDF download)

List of abbreviations

aOR
adjusted odds ratio
BPSU
British Paediatric Surveillance Unit
CI
confidence interval
CPRD
Clinical Practice Research Datalink
ECMO
extracorporeal membrane oxygenation
UKOSS
UK Obstetric Surveillance System

Pregnant women have an increased chance of developing infections and becoming seriously ill; this includes being more likely to catch influenza (flu). During the ‘swine flu’ pandemic of 2009–10 we carried out a study to investigate the effect of flu on pregnant women using a system called the UK Obstetric Surveillance System (UKOSS). We set up UKOSS in 2005 to study serious rare conditions affecting pregnant women, so, when ‘swine flu’ was declared as a pandemic, we rapidly set in place a study to look at its effects in pregnancy. We found that pregnant women had an increased risk of becoming severely ill and were also more likely to have a stillborn or premature baby. The results from the study were used to make changes to the treatment offered to pregnant women infected with ‘swine flu’ and also led to the recommendation that all pregnant women should receive vaccination against seasonal flu routinely – this is the flu that occurs every year in winter time. We know that, even though there is not a flu pandemic currently, a small number of pregnant women have nevertheless died from seasonal flu.

Using our experience from the ‘swine flu’ pandemic we have set everything in place so that if there is another flu pandemic we can rapidly activate a new UKOSS study to investigate what happens. This will provide the necessary information, once again, to enable treatment and vaccination provided during pregnancy to be tailored to the particular needs of pregnant women.

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