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Confidential: For Review Only

Associations between birth at, or after, 41 weeks gestation

and perinatal encephalopathy: A Cohort Study.

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2017-000010

Article Type: Original article

Date Submitted by the Author: 16-Mar-2017

Complete List of Authors: Odd, David; North Bristol NHS Trust, Neonatal; University of Bristol School of Social and Community Medicine, Yau, Christopher; North Bristol NHS Trust Winter, Cathy; North Bristol NHS Trust Draycott, Tim; North Bristol NHS Trust Rasmussen, Finn; Karolinska Instiutet_

Keywords: Neonatology, Epidemiology

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arch 17, 2020 by guest. Protected by copyright.

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Associations between birth at, or after, 41 weeks gestation and perinatal

encephalopathy: A Cohort Study.

David Odd (Consultant Neonatologist)1,2*

Christopher Yau1

Cathy Winter1

Timothy Draycott1

Finn Rasmussen3

1. Neonatal Unit, North Bristol NHS Trust, Bristol, United Kingdom.

2. School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.

3. Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden

* Corresponding author:

Dr David E Odd

Neonatal Unit, Southmead Hospital, Bristol, United Kingdom, BS10 5NB.

Tel: 0117 9505050

Fax: 0117 9595324

[email protected]

Key Words:

Perinatal Asphyxia;Encephalopathy;Neonatal Encephalopathy;Birth;Post-term;Prevention

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Confidential: For Review OnlyWhat is known about the subject • Preterm birth causes long term problems but

less is known about infants born after their due

date.

• Perinatal asphyxia may increase as infants

pass their due date but estimates are

conflicting and imprecise.

• A current research priority is to try to identify

babies at particularly high risk of morbidity and

mortality who will benefit from induction.

What this study adds • The risks of developing perinatal

encephalopathy increases by an estimated 3%

per day among infants that remain in utero

after their due-date.

• The association was observed in the most

recent data, in younger and older mothers and

in well grown infants.

• However this increase in risk is

disproportionately higher risk in women over

35 years old.

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ABSTRACT

Background: Preterm birth causes long term problems: even for infants born 1 or 2 weeks

early. However less is known about infants born after their due date (post-term) and over a

quarter of infants are born over one-week late, and many still remain undelivered after two

weeks. The aim of this work is to quantify the risks of infants' developing encephalopathy

when birth occurs post-term, and if other proposed risk factors modify this relationship.

Methods: The dataset contain information on 4,036,346 infants born in Sweden between

1973-2012. Exposure was defined as birth seven, or more, days after the infants' due date.

The primary outcome was the development of neonatal encephalopathy (defined as

seizures, encephalopathy, or brain injury caused by asphyxia or with unspecified cause).

Covariates were selected as presumed confounders a priori.

Results: 28.4% infants were born one or more weeks after their due date. An infants' risk of

being born with encephalopathy was higher in the post 41 weeks group in the unadjusted

(OR 1.40 (1.32-1.49)) and final model (OR 1.38 (1.29-1.47)), with the relative risk of

encephalopathy increasing by an estimated 3% per day after the due-date, and modified by

maternal age (pinteraction=0.022).

Conclusions: Singleton infants born at, or after, 41 weeks gestation have lower Apgar

scores and higher risk of developing encephalopathy in the new-born period, and the

association appeared more marked in older mothers. These data could usefully be provided

for women as part of their decision making.

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INTRODUCTION

Preterm birth causes long term problems: even for infants born 1 or 2 weeks early. However

less is known about infants born after their due date (post-term) and over a quarter of infants

are born over one-week late, and many still remain undelivered after two weeks. While there

is a plethora of work investigating the long term cognitive, educational and social functioning

of babies born prematurely[1,2] little data exist for the outcomes of those infants born after

their due date; or the mechanisms of any possible adverse outcomes [3].

Perinatal asphyxia (deprivation of oxygen during birth) is a relatively common event [4] and

while most infants tolerate it well, a small proportion of these develop immediate signs of

brain damage (hypoxic-ischemic encephalopathy (HIE)) [5]. The clinical impacts can be life-

long and devastating for them and their family; the litigation and societal costs

notwithstanding [6]. The risks of perinatal asphyxia may increase in infants born after their

due date[3] but estimates are conflicting[7]. However in contrast to preterm birth,

interventions can be used to deliver the infant if the risks of continuing the pregnancy are

higher than delivery: for either the mother or the infant. Indeed, induction of labour (IOL), has

been shown to be beneficial in high risk groups [8–11] but it’s place in post-term

management is unclear[11,12].

This dearth of data makes counselling for women difficult and consequently the management

of pregnancies beyond term varies hugely between units and countries. Current NICE

guidelines suggest that a research priority is to "identify babies at particularly high risk of

morbidity and mortality who will benefit from induction and therefore avoid induction for

babies who do not need it"[13]: the primary aim of this work. However, even small

improvements in outcomes would yield substantial health benefits for individuals and

economic benefits for health services and society.

The aim of this work is to quantify the risks of developing HIE or being born in poor condition,

when born 7 or more days after their due date (at, or after 41 completed weeks of gestation).

METHODS

Population

The dataset reviewed, contains information on 4,036,346 infants born in Sweden between

1973-2012 and registered on the nationwide birth registry of Sweden. The birth registry

provides data on 98% to 99% of births and includes Apgar scores, as well as both neonatal

and maternal diagnoses (coded using the International Classification of Diseases, 8th, 9th

and 10th revisions).

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Infants born before 37 weeks gestation (n=234,924), from multiple births (n=56,493) or with

cardiovascular, respiratory, neurological or multiple system congenital abnormalities

(n=29,535) were removed, leaving 3,715,394 infants for the study.

Infants with missing data on Apgar score or gestational age (n=7715) and those with missing

data on at least one covariate (n=280,229) were also removed, leaving 3,427,450 subjects

available for the analyses (92% of eligible subjects).

Information on birth condition and perinatal well-being was retrieved from the birth registry.

The exposure was defined as birth seven, or more, days after the infants’ due date (≥41

week gestation). A primary outcome was the development of HIE (defined as seizures,

encephalopathy, or brain injury caused by asphyxia or with unspecified cause) [14].

Secondary outcomes were Apgar scores at 1, 5 and 10 minutes, or a low Apgar score at 5

minutes (less than 7)[15].

Potential Confounders and Covariates

Covariates were selected as presumed confounders a-priori, and categorised into three

groups: i) social (maternal age, maternal occupation, maternal education), ii) antenatal (infant

gender and primiparity), and ii) intrapartum and potential causal factors (maternal or infant

infection, birth weight (g), birth by caesarean section).

Statistical Analysis

Initially, subjects with and without missing data were compared. The distribution of risk

factors and potential confounders was investigated between the infants split by their

gestation at birth. In univariable analysis the mean Apgar score at 1,5 and 10 minutes, and

the risk of developing encephalopathy was derived, split by each completed week of

gestation. Due to the non-normal distribution of the Apgar score, geometric means (with 95%

confidence intervals) were derived. Birthweight and maternal age were assumed to be

continuous variable and not grouped further beyoundb their initial units (grams and years

respectively).

In the multivariable analyses, linear (for Apgar scores) and logistic regression (for

encephalopathy and a low Apgar score at 5 minutes) models were used to assess any

association with gestational age at birth. To account for changes in coding over time, models

were multi-level to account for year of birth. Adjustment for social and antenatal confounders

was performed by adding the variables described above to the models in blocks of common

variables (defined above). Variables with potential confounding influence, but with possible

causal inference, were introduced in a final model. The impact of birth at ≥41 week gestation

on encephalopathy was calculated using the population attributable risk from this model.

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Five sensitivity analyses were performed:

1) The model was repeated using the number of weeks of birth after the due date as an

ordinal variable.

2) The model was repeated limiting the analysis to well grown (over 2500g at birth)

infants.

3) The model was repeated, testing if maternal age (greater than 35 years of age),

interacted with the association between birth ≥41 week gestation and risk of

encephalopathy.

4) The model was repeated, restricting the analysis to the most recent 10 years of data

(2003-2012).

5) The model was repeated using an imputation technique (multiple imputation using

chained equations) to impute missing values. Because of technical limitations only a

random 10% of infants without encephalopathy were included in this analysis and the

model weighted to represent the initial population.

All analyses were conducted with Stata 10 software (Stata Corp, College Station, TX), and

results are presented as number (percent), mean (SD), OR (95% confidence interval) or

median (interquartile range) as appropriate. Ethical approval was obtained from the Ethical

Review Board of Stockholm (Ref: 2015/1279-31/2). Due to using registry data, informed

consent was not obtained, and all data was provided and analysed anonymously.

RESULTS

Infants with missing data weighed less and had older mothers (Appendix). They were less

likely to be exposed to pre-eclampsia, but more likely to have been exposed to maternal or

neonatal infection. Mothers were more likely to have been nulliparous, work in manual

occupations and had less education (all comparisons p<0.001). There was no difference in

gender (p=0.726) or risk of encephalopathy (p=0.136) between those with or without

complete data.

In total, 973,430 (28.4%) infants were born one or more weeks after their due date. Infants

born ≥41 week gestation were more likely to be female, had greater birth weight and were

less likely to be exposed to maternal pre-eclampsia, or be born by caesarean section (Table

1). They were also more likely to develop maternal or neonatal infection. Mothers were

younger and more likely to be nulliparous, work in non-manual occupations and have higher

educational qualifications (all comparisons p<0.001).

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There was strong evidence that the mean Apgar score at 1,5 and 10 minutes reduced as the

infants gestational age continued beyond 39 weeks (Figure and Table 2, all p<0.001). In

addition, the risk of being born with a low Apgar score and the risk of developing

encephalopathy became greater as the infants gestational age increased (both p<0.001).

Interestingly, infants born at 37 weeks also appeared to have lower Apgar scores and higher

rates of HIE than infants born at 39 or 40 weeks gestation (post-hoc analysis; p<0.001).

Overall, infants born ≥41 weeks gestation were more likely to develop encephalopathy than

those born before 41 weeks gestation (3040 (0.12%) vs 1640 (0.17%), p<0.001). In the

unadjusted results, the mean Apgar scores at 1, 5 and 10 minutes were lower in infants born

≥41 weeks gestation and this persisted after adjustment for a-priori defined confounders, and

remained after adjusting for both confounders and other causal factors (Table 3). The risk of

encephalopathy showed a similar association, with an infants’ risk of being born with

encephalopathy higher if they were born 1 or more weeks after their due date, in the

unadjusted (OR 1.40 (1.32 to 1.49)) and adjusted analysis (OR 1.34 (1.26 to 1.42)), and also

persisted in the model controlling for potential causal factors (OR 1.38 (1.29 to 1.47)). The

risk of a low (<7) 5 minute Apgar score showed similar results (all comparisons; p<0.001).

The population attributable risk fraction of infants who developed HIE at, or after, 41 weeks

gestation was 4.6%.

Using birth after the due date as an ordinal variable (e.g. 1 week over at 41 weeks, 2 weeks

at 42 weeks etc.) demonstrated similar results to the main analysis: for each week after the

due date that the infant stayed in utero there was an associated increase in the risk of

developing neonatal encephalopathy (OR 1.22 (1.18 to 1.27)).

Repeating the model after restricting to well grown infants (OR 1.36 (1.28 to 1.46)) or to the

most recent 10 years of data (OR 1.35 (1.20 to 1.52)) provided very similar results.

There was evidence that maternal age modified the association between later birth and HIE

(p=0.022). Mothers aged 35 years and older had a higher risk that birth ≥41 weeks would

result in an infant with HIE (OR 1.67 (1.40 to 1.98)) compared to those who were younger

than 35 (OR 1.34 (1.25 to 1.43)). A multiple imputation model including all infants with

exposure and outcome date (n= 717,801, Adjusted OR 1.41 (1.31 to 1.51)) also produced

similar results to the main analysis. A final, post-hoc analysis was performed due to the

possible non-linear association of gestational age and HIE. Infants were split by gestation

age into 3 exposure groups; early (37/38 weeks), within 7 days of the due date (39/40

weeks), and late (≥41 weeks). Infants born at 37/38 weeks (OR 1.30 (1.20 to 1.40) and ≥41

weeks (OR 1.50 (1.40 to 1.60)) both demonstrated higher risks of HIE than those born within

7 days of their due date in the unadjusted analysis, but the effect was only seen in those ≥41

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weeks after correction for potential confounders (OR 1.01 (0.93 to 1.10) and OR 1.38 (1.29

to 1.48) respectively).

DISCUSSION

We have demonstrated, in a large population based data-set, that the risks of developing

perinatal encephalopathy increases significantly for each week that pregnancies continue

after their due date. Assuming that gestational age is accurately assessed and intrapartum

care of pregnancies is similar for the gestational age at birth, then this effect may be readily

preventable if this association is causal. Indeed, sensitivity analysis suggests that the relative

risk of HIE increases by an estimated 20% per week (or 3% per day) among infants that

remain in utero after their due-date (compared to infants born at, or before it). The

association appeared robust, as it was observed in the most recent data, in younger and

older mothers and in well grown infants.

Limitations of this work include the use of routine data, and the number of infants excluded

from the analysis due to missing data points. The use of routine data is likely to weaken any

association seen due to misclassification. However, the birth registry is considered a robust

source of information, thus minimising any effect seen rather than introducing false positive

findings. In particular, the measurement of gestational age in this cohort may be less

accurate than modern measures available to clinicians. However, results from the most

recent years showed similar results to those from the whole cohort. We saw little evidence

for confounding in this work although residual and uncontrolled confounding remain a

limitation of any non-randomized study. With respect to missing data, we have attempted to

investigate the impact using a multiple imputation technique, which produced almost identical

results to the main analysis, although again, any interpretation of the results should consider

this limitation.

This work suggests an increase in significant morbidity in infants born after more than 41

weeks gestation, and it seems plausible that the presumed deterioration in the in utero

environment for the foetuses also contributes to the known risk of late stillbirth. Therefore

induction of labour or caesarean section at 40 weeks gestation is likely to improve morbidity

and mortality, although we were unable to investigate perinatal deaths in this work. However,

early birth particularly by caesarean section is not without risk; in addition to respiratory

morbidity, recent work suggests poorer long term cognitive outcomes may occur for infants

born just 2 weeks early [8], although we were unable to demonstrate a higher risk of HIE in

infants born before 38 weeks (after adjustment for confounders).

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There is particular concern with regard to the risks associated with pregnancies continuing in

older women [16], and this work demonstrates a disproportionately higher risk in women over

35 years old. Furthermore, a recent interventional study for women aged over 35 years

concluded that induction of labour at 39 weeks of gestation, as compared with expectant

management, had no significant effect on the rate of caesarean section and no adverse

short-term effects on maternal outcomes. However, that study was under-powered for

neonatal outcomes [17]. A recent systematic review demonstrating reductions in caesarean

rates for women induced at term also showed that there was a reduced risk of fetal death

and admission to neonatal intensive care units with induction of labour [10].

Despite these findings, there is no general consensus on whether induction of labour should

be offered to all women at 40 weeks gestation [11,12]. Factors that should be considered

before advocating such a recommendation would include the accuracy of the gestational age

measurements, and impact of the induction process on a woman’s birth experience [13].

Indeed, midwives or obstetricians may be reticent to recommend an earlier intervention for

risk of over medicalising normal pregnancies. There may also be implications on workload

and capacity if women were to accept earlier induction of labour.

The results from this study provide further evidence to support elective induction of labour

during the 39th or 40th week of gestation. However, more randomised trials of induction of

labour at 40 weeks gestation versus expectant management need to be conducted to obtain

prospective data on long term neonatal and maternal outcomes. Whilst more research is

done in this area, if circumstances are such that gestational age can be reliably measured,

then membrane sweeping, which is not considered part of the formal induction process,

could be introduced routinely from 38-39 weeks gestation to encourage spontaneous labour

before 40 weeks gestation.

Conclusion

Singleton infants born at, or after, 41 weeks gestation have lower Apgar scores and higher

risk of developing encephalopathy in the new-born period. Expediting birth at 40 weeks

gestation, including induction of labour, could prevent a substantial proportion (up to 5%) of

all neonatal encephalopathy. These poor outcomes are more common the longer the

pregnancy continues after the infants’ due date and they do not appear to be restricted to

older mothers or low birth weight infants. These data could usefully be provided to women as

part of their decision making with regard to induction of labour. Finally, further research is

therefore needed to identify the pathways through which this effect is mediated, to ascertain

appropriate intervention points, and also establish the impact and risk/benefit ratio of pre-

emptive birth.

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Funding

This work was supported by North Bristol NHS Trust Springboard Fund (Round 9, Ref:13).

Competing interests

All authors have completed the ICMJE uniform disclosure form at

www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the

submitted work; no financial relationships with any organisations that might have an interest

in the submitted work in the previous three years; no other relationships or activities that

could appear to have influenced the submitted work.

Author’s contribution

DO, CY, CQ, TD and FR concieved the idea and developed the methodology.

DO performed the statsitical analysis and wrote the first draft of the paper.

DO, CY, CQ, TD and FR developed and approved the final manuscrupt.

Data sharing statement

Data was obtained from Statistics Sweden (http://www.scb.se/en_/) and access is not

avaliable from the authors.

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REFERENCES

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eCollection

3. Moster D1, Wilcox AJ, Vollset SE, Markestad T LR. Cerebral palsy among term and

postterm Births. JAMA. 2010;304: 976–82.

4. Odd D, Lewis G, Whitelaw A, Gunnell DJ. Resuscitation at birth and cognition at 8

years of age: a cohort study. Lancet. 2009;9: 1615–1622.

5. Azzopardi D V, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al.

Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med.

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on Social and Economic Outcomes in Early Adulthood. Pediatrics. 2011;May 9; eFi:

e1498–504. doi:10.1542/peds.2010-3604

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8. Chiossim G. Timing of Delivery and Adverse Outcomes in Term Singleton Repeat

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9. Martinez-Biarge M, Madero R, González A, Quero A, García-Alix A. Perinatal

morbidity and risk of hypoxic-ischemic encephalopathy associated with intrapartum

sentinel events. Am J Obs Gynecol2. 2012;206: 148.e1–7.

10. Mishanina E, Rogozinska E, Thatthi T, Uddin-Khan R, Khan K, Meads C. Use of

labour induction and risk of caesarean delivery: a systematic review and meta-

analysis. Can Med Assoc J. 2014;189: 665–673.

11. Smith G. Labour should be induced at term: FOR: The balance of risks versus benefits

favours offering term induction to all women. BJOG. 2015;122: 982.

12. Jacquemyn Y. Labour should be induced at term: AGAINST: No proof of benefit.

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BJOG. 2015;122: 982.

13. National Institute for Health and Clinical Excellence (NICE). Inducing labour (CG70).

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14. Odd DE, Lewis G, Whitelaw A, Gunnell D. Resuscitation at birth and cognition at 8

years of age: a cohort study. Lancet. 2009;373: 1615–22. doi:10.1016/S0140-

6736(09)60244-0

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on&list_uids=16648434

16. Walker K, Bugg G, Macpherson M, Thornton J. Induction of labour at term for women

over 35 years old: a survey of the view of women and obstetricians. Eur J Obs

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17. Walker KF, Bugg GJ, Macpherson M, McCormick C, Grace N, Wildsmith C, et al.

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Table 1.Characteristics of the study population according to gestational age at birth

(n=3,427,450)

Measure 37+0 to 40

+6 weeks 41

+0 and above

Antenatal Factors

Male 1,244,878 (50.7%) 511,567 (52.6%) <0.001

Birthweight (g) 3511 (473) 3798 (474) <0.001

Maternal pre-eclampsia 115,578 (4.7%) 38,693 (4.0%) <0.001

Intrapartum Factors

Maternal Infection 16,092 (0.66%) 7240 (0.74%) <0.001

Neonatal Infection 10,334 (0.4%) 6125 (0.6%) <0.001

Caesarean Section 294,707 (12.1%) 85,400 (8.8%) <0.001

Demographic factors

Maternal Age 28.1 (5.2) 27.8 ( 5.1) <0.001

Primiparae 995,171 (40.6%) 450,385 (46.3%) <0.001

Maternal Occupation <0.001

Manual 793,546 (32.3%) 314,211 (32.3%)

Non-manual 868,071 (35.4%) 371,740 (38.2%)

Other 792,403 (32.3%) 287,479 (29.5%)

Maternal Education Status <0.001

<9 Years 71,148 (2.9%) 28,652 (2.9%)

9-10 Years 919,214 (37.5%) 364,418 (37.4%)

Full Secondary 465,920 (19.0%) 177,561 (18.2%)

Higher Education 997,738 (40.7%) 402,799 (41.4%)

Values are number (%) or mean (±SD) as appropriate.

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Table 2. Outcome measures split by gestational age at birth

Measure Gestation at birth

37 38 39 40 41 42 43 44 45

Apgar Score

1 minutes 8.66 (8.64-8.66) 8.79 (8.79-8.80) 8.78 (8.80-8.80) 8.75 ( 8.75-8.76) 8.66 (8.65-8.66) 8.53 (8.53-8.54) 8.53 (8.51- 8.56) 8.69 (8.64-8.75) 8.75 (8.63-8.86)

5 minute 9.59 (9.59-9.60) 9.68 (9.68-9.69) 9.69 (9.69-9.69) 9.67 (9.67- 9.67) 9.62 (9.62-9.62) 9.54 (9.53-9.54) 9.43 ( 9.42-9.45) 9.40 (9.36-9.44) 9.44 (9.38-9.52)

10 minute 9.82 (9.82-9.83) 9.87 (9.87-9.88) 9.88 (9.88-9.88) 9.87 (9.87-9.87) 9.84 (9.84-9.84) 9.79 (9.79-9.80) 9.70 (9.68-9.72) 9.59 (9.51- 9.67) 9.53 (9.37- 9.70)

Low (<7) Apgar

score at 5 minutes 2,243 (1.4%) 3,755 (0.9%) 6,082 (0.8%) 8,153 (0.9%) 6,826 (1.1%) 3,616 (1.5%) 549 (1.9%) 81 (1.9%) 18 (1.6%)

Encephalopathy 324 (0.19%) 624 (0.14%) 902 (0.11%) 1,119 (0.12%) 1,019 (0.15%) 551 (0.21%) 60 (0.18%) 9 (0.17%) 1 (0.07%)

All p values for trend are <0.001

Values are number (%) or geometric mean (95% confidence interval) as appropriate.

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Table 3. Regression models for the association between birth after 40+6 weeks gestation with measures of birth condition

Measure

Unadjusted Adjusted† Fully Adjusted‡

OR (95% CI) OR (95% CI) OR (95% CI)

Apgar Score

1 minutes -0.13 (-0.13 to -0.13) -0.12 (-0.12 to -0.11) -0.12 (-0.12 to -0.11)

5 minute -0.05 (-0.06 to -0.05) -0.05 (-0.05 to -0.05) -0.05 (-0.05 to -0.05)

10 minute -0.03 (-0.03 to -0.02) -0.02 (-0.02 to -0.02) -0.03 (-0.03 to -0.02)

Low (<7) Apgar score at 5 minutes 1.36 (1.33 to 1.40) 1.31 (1.28 to 1.34) 1.45 (1.41 to 1.48)

Encephalopathy 1.40 (1.32 to 1.49) 1.34 (1.26 to 1.42) 1.38 (1.29 to 1.47)

Data are mean difference (95% confidence interval) or odds ratio (OR) (95% confidence interval) for each increasing week of gestational age at birth

All p values are <0.001

† Adjusted for sex, parity, maternal age, maternal education and maternal occupation

‡ Adjusted for maternal pre-eclampsia, multiple birth, caesarean section, birth weight, maternal infection and infant infection

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Figure. Mean Apgar scores, split by gestational age at birth.

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Appendix. Characteristics of the study population according to missing data (n=3,715,394)

Measure Study cohort Infants with missing data Difference

Antenatal Factors

Male 1,671,005 (48.8%) 140,285 (48.7%) -0.03% (-0.02% to 0.02)

Birthweight (g) 3592 (±491) 3491 (±485)- -102 (-104 to 100)

Maternal pre-eclampsia 154,271 (4.5%) 7,186 (2.5%) -2.0% (-2.1 to -1.9%)

Intrapartum Factors

Maternal Infection 23,332 (0.7%) 2,446 (0.9%) 1.7% (1.4% to 2.0%)

Neonatal Infection 16,459 (0.5%) 1,758 (0.6%) 0.12% (0.10% to 1.5%)

Caesarean Section 380,107 (11.1%) 37,722 (13.1%) 2.0% (1.9% to 2.1%)

Demographic factors

Maternal Age 28.0 (±5.2) 28.2 (±5.5) 0.11 (0.10 to 0.13)

Primiparae 1,445,556 (42.2%) 124,058 (43.1%) 0.9% (0.7% to 1.1%)

Maternal Occupation

Manual 1,107,757 (32.3%) 12,014 (39.1%) 6.8% (6.3% to 7.3%)

Non-manual 1,239,811 (36.2%) 7,446 (24.3%) -13.0% (-12.5% to -11.4%)

Other 1,079,882 (31.5%) 11,249 (36.6%) 5.1% (4.6% to 5.6%)

Maternal Education Status

<9 Years 99,800 (2.9%) 33,916 (13.4%) 10.5% (10.4% to 10.5%)

9-10 Years 303,741 (8.9%) 23,625 (9.3%) 0.5% (0.3% to 0.6%)

Full Secondary 1,623,372 (47.4%) 89,140 (35.2%) -12.2% (-12.4% to -12.0%)

Higher Education 1,400,537 (40.9%) 106,850 (42.1%) 1.3% (1.1% to 1.5%)

Values are number (%), mean (±SD) or mean difference (CI) as appropriate.

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Date Submitted by the Author: 21-Jul-2017







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Associations between birth at, or after, 41 weeks gestation and perinatal encephalopathy: A

Cohort Study.


Christopher Yau1

Cathy Winter1

Timothy Draycott1

Finn Rasmussen3





Dr David E Odd


Tel: 0117 9505050

Fax: 0117 9595324

[email protected]

Key Words:


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Confidential: For Review OnlyWhat is known about the subject • Preterm birth causes long term problems but


date.








encephalopathy increases by an estimated

20% per week among infants that remain in

utero after their due-date.




• However this increase in risk is higher in

women over 35 years old.

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ABSTRACT


early. However, less is known about infants born after their due date and over a quarter of

infants are born over one-week late, and many still remain undelivered after two weeks. The

aim of this work is to quantify the risks of infants developing encephalopathy when birth

occurs after the due date, and if other proposed risk factors modify this relationship.






Results: 28.4% infants were born one or more weeks after their due date. An infant’s risk of



encephalopathy increasing by an estimated 20% per week after the due-date, and modified

by maternal age (p=0.022).



association appeared more marked in older mothers. These data could usefully be provided

for women as part of their decision making.

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INTRODUCTION


less is known about infants born after their due date and over a quarter of infants are born

over one-week late, and many still remain undelivered after two weeks. While there is a

plethora of work investigating the long term cognitive, educational and social functioning of

babies born prematurely[1,2] little data exist for the outcomes of those infants born after their

due date; or the mechanisms of any possible adverse outcomes [3].

Perinatal asphyxia (deprivation of oxygen during birth) is a relatively common event [4] and

while most infants tolerate it well, a small proportion of these develop immediate signs of

brain damage (hypoxic-ischemic encephalopathy (HIE)) [5]. The clinical impacts can be life-

long and devastating for them and their family; the litigation and societal costs

notwithstanding [6]. The risks of perinatal asphyxia may increase in infants born after their

due date[3] but estimates are conflicting[7]. However in contrast to preterm birth,

interventions can be used to deliver the infant if the risks of continuing the pregnancy are

higher than delivery: for either the mother or the infant. Indeed, induction of labour (IOL), has

been shown to be beneficial in high risk groups [8–11] but it’s place in the management of

infants past their due date is unclear[11,12].


of pregnancies beyond term varies hugely between units and countries. Current NICE

guidelines suggest that a research priority is to "identify babies at particularly high risk of

morbidity and mortality who will benefit from induction and therefore avoid induction for

babies who do not need it"[13]: the primary aim of this work. However, even small

improvements in outcomes would yield substantial health benefits for individuals and

economic benefits for health services and society.

The aim of this work is to quantify the risks of developing perinatal encephalopathy or being

born with low Apgar scores , when born 7 or more days after their due date (at, or after 41

completed weeks of gestation).

METHODS

Population





and 10th revisions). Details of the clinical signs that led to the diagnoses are not recorded.

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(n=29,535) were removed, leaving 3,715,394 infants for the study. Infants with missing data

on Apgar score or gestational age (n=7715) and those with missing data on at least one

covariate (n=280,229) were also removed, leaving 3,427,450 subjects available for the

analyses (92% of eligible subjects) (Appendix 1)



weeks gestation). A primary outcome was the development of likely perinatal

encephalopathy (defined as an ICD coding for either ‘seizures’, ‘encephalopathy, or brain

injury caused by ‘asphyxia’ or with ‘unspecified cause’ immediately after birth) [14].

Secondary outcomes were Apgar scores at 1, 5 and 10 minutes, or a low Apgar score at 5

minutes (less than 7)[15].


Covariates were selected as presumed confounders a-priori, and categorised into three


gender and primiparity), and ii) intrapartum and potential causal factors (maternal or infant









continuous variable and not grouped further beyond their initial units (grams and years

respectively).







causal inference, were introduced in a final model. The impact of birth at ≥41 weeks

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gestation on encephalopathy was calculated using the population attributable risk from this

model.



ordinal variable.


infants.



encephalopathy.


(2003-2012).










RESULTS

Infants with missing data weighed less and had older mothers (Appendix 2). They were less





complete data.

In total, 973,430 (28.4%) infants were born one or more weeks after their due date. Over the

40 years period, there was a slight reduction in the (geometric) mean of gestational age at

birth from 40.1 (40.0-40.1) in 1973 to 39.6 (39.6-39.6) (p<0.001). Infants born ≥41 weeks

gestation were more likely to be male, had greater birth weight and were less likely to be

exposed to maternal pre-eclampsia, or be born by caesarean section (Table 1). They were

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also more likely to develop maternal or neonatal infection. Mothers were younger and more

likely to be nulliparous, work in non-manual occupations and have higher educational

qualifications (all comparisons p<0.001).






rates of encephalopathy than infants born at 39 or 40 weeks gestation (post-hoc analysis;

p<0.001). Infants born at 45 weeks gestation appeared to have the lowest rate of

encephalopathy, however, this is based on only 1 infants developing encephalopathy and

hence the confidence intervals are wide around the point estimate (0.07% (95% CI -0.07% to

0.20%)) and this observation needs to be interpreted with caution.






encephalopathy showed a similar association, with an infant’s risk of being born with





The population attributable risk fraction of infants who developed encephalopathy at, or after,

41 weeks gestation was 4.6%.







There was evidence that maternal age modified the association between later birth and

encephalopathy (p=0.022). Mothers aged 35 years and older had a higher risk that birth ≥41

weeks would result in an infant with encephalopathy (OR 1.67 (1.40 to 1.98)) compared to

those who were younger than 35 (OR 1.34 (1.25 to 1.43)). A multiple imputation model

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including all infants with exposure and outcome date (n= 717,801, Adjusted OR 1.41 (1.31 to

1.51)) also produced similar results to the main analysis. A final, post-hoc analysis was

performed due to the possible non-linear association of gestational age and encephalopathy.

Infants were split by gestation age into 3 exposure groups; early (37/38 weeks), within 7 days

of the due date (39/40 weeks), and late (≥41 weeks). Infants born at 37/38 weeks (OR 1.30

(1.20 to 1.40) and ≥41 weeks (OR 1.50 (1.40 to 1.60)) both demonstrated higher risks of

encephalopathy than those born within 7 days of their due date in the unadjusted analysis,

but the effect was only seen in those ≥41 weeks after correction for potential confounders

(OR 1.01 (0.93 to 1.10) and OR 1.38 (1.29 to 1.48) respectively).

DISCUSSION






risk of encephalopathy increases by an estimated 20% per week among infants that remain

in utero after their due-date (compared to infants born at, or before it). The association

appeared robust, as it was observed in the most recent data, in younger and older mothers

and in well grown infants.


from the analysis due to missing data points. Encephalopathy was defined using available

neonatal ICD codes consistent with our previous work [6], but may also include infants with

other neurological disease. Equally we did not have information on the indication for

operative deliveries or induction of labour; although this is likely to cause us to underestimate

any impact of post-due date delivery and this use of routine data is likely to weaken any




accurate than modern measures available to clinicians and the methods used to derive it

(initially clinical measure of last menstrual period, followed by ultrasound dating) have

changed over the study period. However, while diagnostic criteria may have changed over

the study period the models used random effects to account in part for this, and results from

the most recent years showed similar results to those from the whole cohort.

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We saw little evidence for confounding in this work although residual and uncontrolled

confounding remain a limitation of any non-randomized study. With respect to missing data,

we have attempted to investigate the impact using a multiple imputation technique, which

produced almost identical results to the main analysis, although again, any interpretation of

the results should consider this limitation.



environment for the foetuses also contributes to the known risk of late stillbirth; possibly

placental insufficiency. Alternatively we identified an increase in the risk of infection in the

later-born infants (0.6% vs 0.4%) which may have contributed to seizures or low Apgar

scores, although this association persisted after adjustment for it in the final model. Of note

however, while there were differences in demographics between the two groups investigated

here, many were often of minor magnitude (e.g. a 2-3 month difference in maternal age). It

seems possible therefore that induction of labour or caesarean section at 40 weeks gestation

may improve morbidity and mortality, although we were unable to investigate perinatal

deaths in this work. However, early birth particularly by caesarean section is not without risk;

in addition to respiratory morbidity, recent work suggests poorer long term cognitive

outcomes may occur for infants born just 2 weeks early [8], although we were unable to

demonstrate a higher risk of encephalopathy in infants born before 38 weeks (after

adjustment for confounders).


older women [16], and this work demonstrates a higher risk in women over 35 years old.

Furthermore, a recent interventional study for women aged over 35 years concluded that

induction of labour at 39 weeks of gestation, as compared with expectant management, had

no significant effect on the rate of caesarean section and no adverse short-term effects on

maternal outcomes. However, that study was under-powered for neonatal outcomes [17]. A

recent systematic review demonstrating reductions in caesarean rates for women induced at

term also showed that there was a reduced risk of fetal death and admission to neonatal

intensive care units with induction of labour [10].






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prospective data on long term neonatal and maternal outcomes. More research is required in

this area, including work looking at the role of membrane sweeping or more formal induction

processes, as well as quantifying any long term consequences to the infant.

Conclusion






older mothers or low birth weight infants. These data could usefully be provided to women as

part of their decision making with regard to induction of labour. Finally, further research is

therefore needed to identify the pathways through which this effect is mediated, to ascertain


emptive birth.

Funding


Competing interests







DO, CY, CW, TD and FR concieved the idea and developed the methodology.


DO, CY, CW, TD and FR developed and approved the final manuscrupt.

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REFERENCES



EPICure study. Arch Dis Child Fetal Neonatal Ed. 2009;94: F283–9.

doi:10.1136/adc.2008.152793



eCollection







2009;361: 1349–1358.



e1498–504. doi:10.1542/peds.2010-3604




239.





sentinel events. Am J Obs Gynecol2. 2012;206: 148.e1–7.







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BJOG. 2015;122: 982.





6736(09)60244-0











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(n=3,427,450)

Measure 37+0 to 40

+6 weeks 41

+0 and above

Antenatal Factors

Male 1,244,878 (50.7%) 511,567 (52.6%) <0.001

Birthweight (g) 3511 (473) 3798 (474) <0.001


Intrapartum Factors




Demographic factors

Maternal Age 28.1 (5.2) 27.8 ( 5.1) <0.001

Primiparae 995,171 (40.6%) 450,385 (46.3%) <0.001


Manual 793,546 (32.3%) 314,211 (32.3%)

Non-manual 868,071 (35.4%) 371,740 (38.2%)

Other 792,403 (32.3%) 287,479 (29.5%)


<9 Years 71,148 (2.9%) 28,652 (2.9%)

9-10 Years 919,214 (37.5%) 364,418 (37.4%)

Full Secondary 465,920 (19.0%) 177,561 (18.2%)



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37 (n=170,425) 38 (n=457,616) 39 (n=811,180) 40 (n=1,014,799) 41 (n=669,818) 42 (n=264,171) 43 (n=32,728) 44 (n=5,215) 45 (n=1,498)

Apgar Score

1 minutes 8.66 (8.64-8.66) 8.79 (8.79-8.80) 8.78 (8.80-8.80) 8.75 ( 8.75-8.76) 8.66 (8.65-8.66) 8.53 (8.53-8.54) 8.53 (8.51- 8.56) 8.69 (8.64-8.75) 8.75 (8.63-8.86)

5 minute 9.59 (9.59-9.60) 9.68 (9.68-9.69) 9.69 (9.69-9.69) 9.67 (9.67- 9.67) 9.62 (9.62-9.62) 9.54 (9.53-9.54) 9.43 ( 9.42-9.45) 9.40 (9.36-9.44) 9.44 (9.38-9.52)

10 minute 9.82 (9.82-9.83) 9.87 (9.87-9.88) 9.88 (9.88-9.88) 9.87 (9.87-9.87) 9.84 (9.84-9.84) 9.79 (9.79-9.80) 9.70 (9.68-9.72) 9.59 (9.51- 9.67) 9.53 (9.37- 9.70)

Low (<7) Apgar

score at 5 minutes 2,243 (1.4%) 3,755 (0.9%) 6,082 (0.8%) 8,153 (0.9%) 6,826 (1.1%) 3,616 (1.5%) 549 (1.9%) 81 (1.9%) 18 (1.6%)

Encephalopathy 324 (0.19%) 624 (0.14%) 902 (0.11%) 1,119 (0.12%) 1,019 (0.15%) 551 (0.21%) 60 (0.18%) 9 (0.17%) 1 (0.07%)



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Measure


OR (95% CI) OR (95% CI) OR (95% CI)

Apgar Score

1 minutes -0.13 (-0.13 to -0.13) -0.12 (-0.12 to -0.11) -0.12 (-0.12 to -0.11)

5 minute -0.05 (-0.06 to -0.05) -0.05 (-0.05 to -0.05) -0.05 (-0.05 to -0.05)

10 minute -0.03 (-0.03 to -0.02) -0.02 (-0.02 to -0.02) -0.03 (-0.03 to -0.02)







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275x190mm (96 x 96 DPI)

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Appendix 1.

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Appendix 2. Characteristics of the study population according to missing data (n=3,715,394)


Antenatal Factors

Male 1,671,005 (48.8%) 140,285 (48.7%) -0.03% (-0.02% to 0.02)

Birthweight (g) 3592 (±491) 3491 (±485)- -102 (-104 to 100)


Intrapartum Factors




Demographic factors

Maternal Age 28.0 (±5.2) 28.2 (±5.5) 0.11 (0.10 to 0.13)

Primiparae 1,445,556 (42.2%) 124,058 (43.1%) 0.9% (0.7% to 1.1%)

Maternal Occupation

Manual 1,107,757 (32.3%) 12,014 (39.1%) 6.8% (6.3% to 7.3%)

Non-manual 1,239,811 (36.2%) 7,446 (24.3%) -13.0% (-12.5% to -11.4%)

Other 1,079,882 (31.5%) 11,249 (36.6%) 5.1% (4.6% to 5.6%)


<9 Years 99,800 (2.9%) 33,916 (13.4%) 10.5% (10.4% to 10.5%)

9-10 Years 303,741 (8.9%) 23,625 (9.3%) 0.5% (0.3% to 0.6%)




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Date Submitted by the Author: 21-Sep-2017







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Cohort Study.


Christopher Yau1

Cathy Winter1

Timothy Draycott1

Finn Rasmussen3





Dr David E Odd


Tel: 0117 9505050

Fax: 0117 9595324

[email protected]

Key Words:


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What is known about the subject • Preterm birth causes long term problems but


date.








encephalopathy increases by an estimated 3%

per day among infants that remain in utero

after their due-date.






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ABSTRACT


















association appeared more marked in older mothers. These data could be useful if provided

to women as part of their decision making.

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INTRODUCTION







Perinatal asphyxia (deprivation of oxygen during birth) is a relatively common event with

around 7% of infants needing support after birth[4]. While most infants tolerate it well, a small

proportion, around 0.2%[4] of these develop immediate signs of brain damage (hypoxic-

ischemic encephalopathy (HIE))[5]. The clinical impacts can be life-long and devastating for

them and their family; the litigation and societal costs notwithstanding [6]. The risks of

perinatal asphyxia may increase in infants born after their due date[3] but estimates are

conflicting[7]. However in contrast to preterm birth, interventions can be used to deliver the

infant if the risks of continuing the pregnancy are higher than delivery: for either the mother

or the infant. Indeed, induction of labour (IOL), has been shown to be beneficial in high risk

groups [8–11] but it’s place in the management of infants past their due date is

unclear[11,12].


of pregnancies beyond term varies hugely between units and countries (e.g. 0.4% in Austria

vs 7% in Denmark)[13].Current NICE guidelines suggest that a research priority is to "identify

babies at particularly high risk of morbidity and mortality who will benefit from induction and

therefore avoid induction for babies who do not need it"[14]: the primary aim of this work.

However, even small improvements in outcomes would yield substantial health benefits for

individuals and economic benefits for health services and society.


born with low Apgar score (less than 7 at 5 minutes) , when born 7 or more days after their

due date (at, or after 41 completed weeks of gestation).

METHODS

Population



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encephalopathy (defined as an International Classification of Disease (ICD) coding for either

‘seizures’, ‘encephalopathy, or brain injury caused by ‘asphyxia’ or with ‘unspecified cause’

immediately after birth) [15]. Secondary outcomes were Apgar scores at 1, 5 and 10 minutes,

or a low Apgar score at 5 minutes (less than 7)[16].


Covariates were selected as presumed confounders a-priori[17], and categorised into three


gender and primiparity), and iii) intrapartum and potential causal factors (maternal or infant









continuous variable and not grouped further beyond their initial units (grams and years

respectively).





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model.



ordinal variable.


infants.



encephalopathy.


(2003-2012).










RESULTS

Infants with missing data weighed less and had older mothers (Appendix 2). They were less





complete data.


40 years period, there was a slight reduction in the (geometric) mean in the population from

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40.1 (40.0-40.1) in 1973 to 39.6 (39.6-39.6) (p<0.001) in 2012. Infants born ≥41 weeks

gestation were more likely to be male, had greater birth weight and were less likely to be

exposed to maternal pre-eclampsia, or be born by caesarean section (Table 1). They were

also more likely to develop maternal or neonatal infection. Mothers were younger and more

likely to be nulliparous, work in non-manual occupations and have higher educational

qualifications (all comparisons p<0.001).






rates of encephalopathy than infants born at 39 or 40 weeks gestation (post-hoc analysis;

p<0.001). Infants born at 45 weeks gestation appeared to have the lowest rate of

encephalopathy, however, this is based on only 1 infant developing encephalopathy and

hence the confidence intervals are wide around the point estimate (0.07% (95% CI -0.07% to

0.20%)) and this observation needs to be interpreted with caution.



















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including all infants with exposure and outcome date (n= 717,801, Adjusted OR 1.41 (1.31 to









DISCUSSION











from the analysis due to missing data points. Likely perinatal encephalopathy was defined

using available neonatal ICD codes consistent with our previous work [6], but may also

include infants with other neurological disease, and does not identify if the infants were

admitted to a NICU or not. As a routine data source, it is difficult to use the ICD codes to

further interrogate the individual reasons for the neurological signs and some uncertainty

about the underlying biological causes, and the assumption that it can be reversed by earlier

delivery must remain. Equally we did not have information on the indication for operative

deliveries or induction of labour; although this is likely to cause us to underestimate any

impact of post-due date delivery and this use of routine data is likely to weaken any


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The groups of infants did appear to vary on a number of clinical factors (e.g. infection risk),

although we saw little evidence for confounding in this work. It should be noted however that

residual and uncontrolled confounding remain a limitation of any non-randomized study. With

respect to missing data, we have attempted to investigate the impact using a multiple

imputation technique, which produced almost identical results to the main analysis, although

again, any interpretation of the results should consider this limitation.






scores, although this association persisted after adjustment for it in the final model. It should

be noted that infants over 43 weeks gestation appeared to have slightly higher 1 minute

Apgar scores (but not 5 or 10 minutes) than other post-term infants. Whether this was a

statistical imprecision due to the low numbers in these groups or evidence that the score may

be a less reliable measure of birth condition than the later measures is unclear. Of note

however, while there were differences in demographics between the two groups investigated

here, many were often of minor magnitude (e.g. a 2-3 month difference in maternal age). It

seems possible therefore that induction of labour or caesarean section at 40 weeks gestation

may improve morbidity and mortality, although we were unable to investigate perinatal

deaths in this work. However, early birth particularly by caesarean section is not without risk;

in addition to respiratory morbidity, recent work suggests poorer long term cognitive

outcomes may occur for infants born just 2 weeks early [8], although we were unable to

demonstrate a higher risk of encephalopathy in infants born before 38 weeks (after

adjustment for confounders).




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Conclusion






older mothers or low birth weight infants. While these results should perhaps not be viewed

in isolation, these data could usefully be provided to women as part of their decision making

with regard to induction of labour. Finally, further research is therefore needed to identify the

pathways through which this effect is mediated, to ascertain appropriate intervention points,

and also establish the impact and risk/benefit ratio of pre-emptive birth.

Funding


Competing interests

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REFERENCES



EPICure study. Arch Dis Child Fetal Neonatal Ed. 2009;94: F283-9.

doi:10.1136/adc.2008.152793



eCollection







2009;361: 1349–1358.



e1498-504. doi:10.1542/peds.2010-3604




239.





sentinel events. Am J Obs Gynecol2. 2012;206: 148.e1-7.






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BJOG. 2015;122: 982.

13. Zeitlin J, Blondel B, Alexander S, Breart G. Variation in rates of postterm birth in

Europe: reality or artefact? BJOG. England; 2007;114: 1097–1103.

doi:10.1111/j.1471-0528.2007.01328.x





6736(09)60244-0





17. McNamee R. Confounding and confounders. Occup Env Med. 2003;60: 227–234.







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(n=3,427,450)

Measure 37+0

to 40+6

weeks 41+0

and above

Antenatal Factors

Male 1,244,878 (50.7%) 511,567 (52.6%) <0.001

Birthweight (g) 3511 (473) 3798 (474) <0.001


Intrapartum Factors




Demographic factors

Maternal Age 28.1 (5.2) 27.8 ( 5.1) <0.001

Primiparae 995,171 (40.6%) 450,385 (46.3%) <0.001


Manual 793,546 (32.3%) 314,211 (32.3%)

Non-manual 868,071 (35.4%) 371,740 (38.2%)

Other 792,403 (32.3%) 287,479 (29.5%)


<9 Years 71,148 (2.9%) 28,652 (2.9%)

9-10 Years 919,214 (37.5%) 364,418 (37.4%)

Full Secondary 465,920 (19.0%) 177,561 (18.2%)



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37 (n=170,425) 38 (n=457,616) 39 (n=811,180) 40 (n=1,014,799) 41 (n=669,818) 42 (n=264,171) 43 (n=32,728) 44 (n=5,215) 45 (n=1,498)

Apgar Score

1 minutes 8.66 (8.64-8.66) 8.79 (8.79-8.80) 8.78 (8.80-8.80) 8.75 ( 8.75-8.76) 8.66 (8.65-8.66) 8.53 (8.53-8.54) 8.53 (8.51- 8.56) 8.69 (8.64-8.75) 8.75 (8.63-8.86)

5 minute 9.59 (9.59-9.60) 9.68 (9.68-9.69) 9.69 (9.69-9.69) 9.67 (9.67- 9.67) 9.62 (9.62-9.62) 9.54 (9.53-9.54) 9.43 ( 9.42-9.45) 9.40 (9.36-9.44) 9.44 (9.38-9.52)

10 minute 9.82 (9.82-9.83) 9.87 (9.87-9.88) 9.88 (9.88-9.88) 9.87 (9.87-9.87) 9.84 (9.84-9.84) 9.79 (9.79-9.80) 9.70 (9.68-9.72) 9.59 (9.51- 9.67) 9.53 (9.37- 9.70)

Low (<7) Apgar

score at 5 minutes 2,243 (1.4%) 3,755 (0.9%) 6,082 (0.8%) 8,153 (0.9%) 6,826 (1.1%) 3,616 (1.5%) 549 (1.9%) 81 (1.9%) 18 (1.6%)

Encephalopathy 324 (0.19%) 624 (0.14%) 902 (0.11%) 1,119 (0.12%) 1,019 (0.15%) 551 (0.21%) 60 (0.18%) 9 (0.17%) 1 (0.07%)



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Measure


Mean difference (95% CI) Mean difference (95% CI) Mean difference (95% CI)

Apgar Score

1 minutes -0.13 (-0.13 to -0.13) -0.12 (-0.12 to -0.11) -0.12 (-0.12 to -0.11)

5 minute -0.05 (-0.06 to -0.05) -0.05 (-0.05 to -0.05) -0.05 (-0.05 to -0.05)

10 minute -0.03 (-0.03 to -0.02) -0.02 (-0.02 to -0.02) -0.03 (-0.03 to -0.02)

OR (95% CI) OR (95% CI) OR (95% CI)







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275x190mm (96 x 96 DPI)

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Appendix 1.

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Appendix 2. Characteristics of the study population according to missing data (n=3,715,394)


Antenatal Factors

Male 1,671,005 (48.8%) 140,285 (48.7%) -0.03% (-0.02% to 0.02)

Birthweight (g) 3592 (±491) 3491 (±485)- -102 (-104 to 100)


Intrapartum Factors




Demographic factors

Maternal Age 28.0 (±5.2) 28.2 (±5.5) 0.11 (0.10 to 0.13)

Primiparae 1,445,556 (42.2%) 124,058 (43.1%) 0.9% (0.7% to 1.1%)

Maternal Occupation

Manual 1,107,757 (32.3%) 12,014 (39.1%) 6.8% (6.3% to 7.3%)

Non-manual 1,239,811 (36.2%) 7,446 (24.3%) -13.0% (-12.5% to -11.4%)

Other 1,079,882 (31.5%) 11,249 (36.6%) 5.1% (4.6% to 5.6%)


<9 Years 99,800 (2.9%) 33,916 (13.4%) 10.5% (10.4% to 10.5%)

9-10 Years 303,741 (8.9%) 23,625 (9.3%) 0.5% (0.3% to 0.6%)




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Date Submitted by the Author: 16-Nov-2017







j.com/



nloaded from




Cohort Study.


Christopher Yau1

Cathy Winter1

Timothy Draycott1

Finn Rasmussen3





Dr David E Odd


Tel: 0117 9505050

Fax: 0117 9595324

[email protected]

Key Words:


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What is known about the subject • Preterm birth causes long term problems but


date.








encephalopathy increases among infants that

remain in utero after their due-date.






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ABSTRACT













(OR 1.40 (1.32-1.49)) and final model (OR 1.38 (1.29-1.47)), with the relative odds of





association appeared more marked in older mothers. These data could be useful if provided

to women as part of their decision making.

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INTRODUCTION







Perinatal asphyxia (deprivation of oxygen during birth) is a relatively common event with

around 7% of infants needing support after birth[4]. While most infants tolerate it well, a small

proportion, around 0.2%[4] of these develop immediate signs of brain damage (hypoxic-

ischemic encephalopathy (HIE))[5]. The clinical impacts can be life-long and devastating for

them and their family; the litigation and societal costs notwithstanding [6]. The risks of

perinatal asphyxia may increase in infants born after their due date[3] but estimates are

conflicting[7]. However in contrast to preterm birth, interventions can be used to deliver the

infant if the risks of continuing the pregnancy are higher than delivery: for either the mother

or the infant. Indeed, induction of labour (IOL), has been shown to be beneficial in high risk

groups [8–11] but it’s place in the management of infants past their due date is

unclear[11,12].


of pregnancies beyond term varies hugely between units and countries (e.g. 0.4% in Austria

vs 7% in Denmark)[13].Current NICE guidelines suggest that a research priority is to "identify

babies at particularly high risk of morbidity and mortality who will benefit from induction and

therefore avoid induction for babies who do not need it"[14]: the primary aim of this work.

However, even small improvements in outcomes would yield substantial health benefits for

individuals and economic benefits for health services and society.


born with low Apgar score (less than 7 at 5 minutes) , when born 7 or more days after their

due date (at, or after 41 completed weeks of gestation).

METHODS

Population



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encephalopathy (defined as an International Classification of Disease (ICD) coding for either

‘seizures’, ‘encephalopathy, or brain injury caused by ‘asphyxia’ or with ‘unspecified cause’

immediately after birth) [15]. Secondary outcomes were Apgar scores at 1, 5 and 10 minutes,

or a low Apgar score at 5 minutes (less than 7)[16].


Covariates were selected as presumed confounders a-priori[17], and categorised into three


gender and primiparity), and iii) intrapartum and potential causal factors (maternal or infant








confidence intervals) were derived. Birthweight and maternal age were treated as continuous

variable and not grouped further beyond their initial units (grams and years respectively).






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model.



ordinal variable.


infants.



encephalopathy.


(2003-2012).


chained equations) to impute missing covariate values. Exposure and outcome data

(e.g. encephalopathy or gestational age data) was not imputed. Because of

computation limitations only a random 10% of infants without encephalopathy were

included in this analysis to maintain a practical sized dataset, and the model weighted

to represent the initial population (20 datasets with 42,102 infants in each).






RESULTS

Infants with missing data weighed less and had older mothers (Appendix 2). Infants excluded

with missing data were likely to have missing data for multiple variables. They were less


neonatal infection. Mothers were more likely to have been nulliparous, and had a different

profile of occupations and educational achievements (all comparisons p<0.001). There was

no difference in gender (p=0.726) or risk of encephalopathy (p=0.136) between those with or

without complete data.

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40 years period, there was a slight reduction in the (geometric) mean in the population from

40.1 (40.0-40.1) in 1973 to 39.6 (39.6-39.6) (p<0.001) in 2012. Populations were similar,

although infants born ≥41 weeks gestation were more likely to be male, had greater birth

weight and were less likely to be exposed to maternal pre-eclampsia, or be born by

caesarean section (Table 1). They were also more likely to develop maternal or neonatal

infection. Mothers were younger, more likely to be nulliparous, and had a different profile of

occupations and educational qualifications (all comparisons p<0.001). Due to the large

numbers in the dataset differences were often small and of questionable clinical relevance.


infants gestational age continued beyond 39 weeks (Figure and Table 2, all p<0.001),

although the magnitude of the difference in mean values was small. In addition, the risk of

being born with a low Apgar score and the risk of developing encephalopathy became

greater as the infants gestational age increased (both p<0.001). Interestingly, infants born at

37 weeks also appeared to have lower Apgar scores and higher rates of encephalopathy

than infants born at 39 or 40 weeks gestation (post-hoc analysis; p<0.001). Infants born at 45

weeks gestation appeared to have the lowest rate of encephalopathy, however, this is based

on only 1 infant developing encephalopathy and hence the confidence intervals are wide

around the point estimate (0.07% (95% CI -0.07% to 0.20%)) and this observation needs to

be interpreted with caution.















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including all infants with exposure and outcome date (n=717,801, Adjusted OR 1.41 (1.31 to









DISCUSSION











from the analysis due to missing data points. Likely perinatal encephalopathy was defined

using available neonatal ICD codes consistent with our previous work [6], but may also

include infants with other neurological disease, and does not identify if the infants were

admitted to a NICU or not. As a routine data source, it is difficult to use the ICD codes to

further interrogate the individual reasons for the neurological signs and some uncertainty

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about the underlying biological causes, and the assumption that it can be reversed by earlier

delivery must remain. Equally we did not have information on the indication for operative

deliveries or induction of labour; although this is likely to cause us to underestimate any

impact of post-due date delivery and this use of routine data is likely to weaken any









The groups of infants did appear to vary on a number of clinical factors (e.g. infection risk),

however the cohort was large, and able to show differences in clinical characteristics (e.g. a

2-3 month difference in maternal age) of minor magnitude and of questionable clinical

significance. Overall we saw little evidence for confounding in this work, but it should be

noted that residual and uncontrolled confounding remain a limitation of any non-randomized

study. With respect to missing data, we have attempted to investigate the impact using a

multiple imputation technique, which produced almost identical results to the main analysis,

although again, any interpretation of the results should consider this limitation.






scores, although this association persisted after adjustment for it in the final model. It should

be noted that infants over 43 weeks gestation appeared to have slightly higher 1 minute

Apgar scores (but not 5 or 10 minutes) than other post-term infants. Whether this was a

statistical imprecision due to the low numbers in these groups or evidence that the score may

be a less reliable measure of birth condition than the later measures is unclear.

It seems possible that induction of labour or caesarean section at 40 weeks gestation may

improve morbidity and mortality, although we were unable to investigate perinatal deaths in

this work. However, early birth particularly by caesarean section is not without risk; in

addition to respiratory morbidity, recent work suggests poorer long term cognitive outcomes

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may occur for infants born just 2 weeks early [8], although we were unable to demonstrate a

higher risk of encephalopathy in infants born before 38 weeks (after adjustment for

confounders).























Conclusion

Singleton infants born at, or after, 41 weeks gestation have a higher risk of developing

encephalopathy in the new-born period. Expediting birth at 40 weeks gestation, including

induction of labour, could prevent a substantial proportion (up to 5% (based on the estimated

population attributable risk)) of all neonatal encephalopathy. These poor outcomes are more

common the longer the pregnancy continues after the infants’ due date and they do not

appear to be restricted to older mothers or low birth weight infants. While these results

should not be viewed in isolation, these data could usefully be provided to women as part of

their decision making with regard to induction of labour. Finally, further research is therefore

needed to identify the pathways through which this effect is mediated, to ascertain

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emptive birth.

Funding

This research has been carried out through funding by the North Bristol NHS Trust

Springboard Fund (Round 9, Ref:13).

Competing interests













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REFERENCES



EPICure study. Arch Dis Child Fetal Neonatal Ed. 2009;94: F283-9.

doi:10.1136/adc.2008.152793



eCollection







2009;361: 1349–1358.



e1498-504. doi:10.1542/peds.2010-3604




239.





sentinel events. Am J Obs Gynecol2. 2012;206: 148.e1-7.






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BJOG. 2015;122: 982.

13. Zeitlin J, Blondel B, Alexander S, Breart G. Variation in rates of postterm birth in

Europe: reality or artefact? BJOG. England; 2007;114: 1097–1103.

doi:10.1111/j.1471-0528.2007.01328.x





6736(09)60244-0





17. McNamee R. Confounding and confounders. Occup Env Med. 2003;60: 227–234.







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(n=3,427,450)

Measure 37+0 to 40

+6 weeks 41

+0 and above Difference

Antenatal Factors

Male 1,244,878 (50.7%) 511,567 (52.6%) 1.82% (1.71% to 1.94%)

Birthweight (g) 3511 (473) 3798 (474) 288 (287 to 289)

Maternal pre-eclampsia 115,578 (4.7%) 38,693 (4.0%) -0.07% (-0.08% to 0.07%)

Intrapartum Factors

Maternal Infection 16,092 (0.66%) 7240 (0.74%) 0.09% (0.07% to 0.11%)

Neonatal Infection 10,334 (0.4%) 6125 (0.6%) 0.21% (0.19% to 0.22%)

Caesarean Section 294,707 (12.1%) 85,400 (8.8%) -3.24% (-3.31% to -3.16%)

Demographic factors

Maternal Age 28.1 (5.2) 27.8 ( 5.1) -0.30 (-0.31 to -0.29)

Primiparae 995,171 (40.6%) 450,385 (46.3%) 5.72% (5.60% to 5.83%)

Maternal Occupation

Manual 793,546 (32.3%) 314,211 (32.3%) -0.06% (-0.17% to 0.05%)

Non-manual 868,071 (35.4%) 371,740 (38.2%) 2.82% (2.70% to 2.93%)

Other 792,403 (32.3%) 287,479 (29.5%) -2.86% (-2.87% to -2.65%)


<9 Years 71,148 (2.9%) 28,652 (2.9%) 0.04% (0.04% to 0.08%)

9-10 Years 919,214 (37.5%) 364,418 (37.4%) -0.02% (-0.01% to 0.09%)

Full Secondary 465,920 (19.0%) 177,561 (18.2%) -0.75% (-0.84% to -0.65%)

Higher Education 997,738 (40.7%) 402,799 (41.4%) 0.72% (0.61% to 0.84%)

Values are number (%), mean (±SD) or difference (95% confidence interval) as appropriate.

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37 (n=170,425) 38 (n=457,616) 39 (n=811,180) 40 (n=1,014,799) 41 (n=669,818) 42 (n=264,171) 43 (n=32,728) 44 (n=5,215) 45 (n=1,498)

Apgar Score

1 minutes 8.66 (8.64-8.66) 8.79 (8.79-8.80) 8.78 (8.80-8.80) 8.75 ( 8.75-8.76) 8.66 (8.65-8.66) 8.53 (8.53-8.54) 8.53 (8.51- 8.56) 8.69 (8.64-8.75) 8.75 (8.63-8.86)

5 minute 9.59 (9.59-9.60) 9.68 (9.68-9.69) 9.69 (9.69-9.69) 9.67 (9.67- 9.67) 9.62 (9.62-9.62) 9.54 (9.53-9.54) 9.43 ( 9.42-9.45) 9.40 (9.36-9.44) 9.44 (9.38-9.52)

10 minute 9.82 (9.82-9.83) 9.87 (9.87-9.88) 9.88 (9.88-9.88) 9.87 (9.87-9.87) 9.84 (9.84-9.84) 9.79 (9.79-9.80) 9.70 (9.68-9.72) 9.59 (9.51- 9.67) 9.53 (9.37- 9.70)

Low (<7) Apgar

score at 5 minutes 2,243 (1.4%) 3,755 (0.9%) 6,082 (0.8%) 8,153 (0.9%) 6,826 (1.1%) 3,616 (1.5%) 549 (1.9%) 81 (1.9%) 18 (1.6%)

Encephalopathy 324 (0.19%) 624 (0.14%) 902 (0.11%) 1,119 (0.12%) 1,019 (0.15%) 551 (0.21%) 60 (0.18%) 9 (0.17%) 1 (0.07%)



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Measure


Mean difference (95% CI) Mean difference (95% CI) Mean difference (95% CI)

Apgar Score

1 minutes -0.13 (-0.13 to -0.13) -0.12 (-0.12 to -0.11) -0.12 (-0.12 to -0.11)

5 minute -0.05 (-0.06 to -0.05) -0.05 (-0.05 to -0.05) -0.05 (-0.05 to -0.05)

10 minute -0.03 (-0.03 to -0.02) -0.02 (-0.02 to -0.02) -0.03 (-0.03 to -0.02)

OR (95% CI) OR (95% CI) OR (95% CI)







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275x190mm (96 x 96 DPI)

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Appendix 1.

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Appendix 2. Characteristics of the study population according to missing data (n=3,715,394) Measure Study cohort

(n=3,427,450) Infants with missing data (n=287,944)

Difference

Antenatal Factors Male 1,671,005 (48.8%) 140,285 (48.7%) -0.03% (-0.02% to 0.02) Birthweight (g) 3592 (±491) 3491 (±485) -102 (-104 to 100) Maternal pre-eclampsia

154,271 (4.5%) 7,186 (2.5%) -2.0% (-2.1 to -1.9%)

Intrapartum Factors Maternal Infection 23,332 (0.7%) 2,446 (0.9%) 1.7% (1.4% to 2.0%) Neonatal Infection 16,459 (0.5%) 1,758 (0.6%) 0.12% (0.10% to 1.5%) Caesarean Section 380,107 (11.1%) 37,722 (13.1%) 2.0% (1.9% to 2.1%) Demographic factors

Maternal Age 28.0 (±5.2) 28.2 (±5.5) 0.11 (0.10 to 0.13) Primiparae 1,445,556 (42.2%) 124,058 (43.1%) 0.9% (0.7% to 1.1%)

Maternal Occupation

Manual 1,107,757 (32.3%) 12,014 (39.1%) 6.8% (6.3% to 7.3%)

Non-manual 1,239,811 (36.2%) 7,446 (24.3%) -13.0% (-12.5% to -11.4%) Other 1,079,882 (31.5%) 11,249 (36.6%) 5.1% (4.6% to 5.6%) Maternal Education Status

<9 Years 99,800 (2.9%) 33,916 (13.4%) 10.5% (10.4% to 10.5%)

9-10 Years 303,741 (8.9%) 23,625 (9.3%) 0.5% (0.3% to 0.6%)



Encephalopathy 4680 (0.14%) 424 (0.15%) 0.01% (-0.02% to 0.03%) Values are number (%), mean (±SD) or mean difference (CI) as appropriate.

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