With every week that a pregnancy continues past term (37 weeks) the risk of stillbirth increases

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With every week that a pregnancy continues past term (37 weeks), the risk of stillbirth increases, according to an analysis of more than 15 million pregnancies led by Queen Mary University of London.

The results, published in the journal PLOS Medicine, also included a small but significantly increased risk of stillbirth in mothers who continued their pregnancy to 41 weeks’ gestation (when women are routinely offered induction of labour), compared to those who delivered at 40 weeks.

The researchers say that women who are 41 weeks pregnant should not be alarmed, as the risk is low – equivalent to one additional stillbirth for every 1,449 pregnancies, compared to delivering at 40 weeks.

Compared to White women, Black women at term were also found to be 1.5 to 2 times more likely to suffer stillbirth at all gestational ages.

Lead researcher Professor Shakila Thangaratinam from Queen Mary University of London said:

“While there is an additional risk of stillbirth at 41 weeks, compared to 40 weeks, it is small.

Women who prefer not to have medical interventions such as induction of labour may therefore acknowledge this small additional risk, and choose to wait until 41 weeks so that they have more time to go into labour naturally.

Meanwhile, other women may prefer to have discussions with their healthcare providers on induction after 40 weeks. So this is all about helping women make informed decisions on timing of delivery.”

More than 3,000 babies are stillborn every year in the UK – a third of these are term babies (37 weeks or beyond) who were considered to be ‘healthy’ prior to their death.

Prolonged pregnancy is a known risk factor for stillbirth and women are routinely offered induction of labour after 41 weeks’ gestation.

This recommendation is based on evidence of increased stillbirth risk beyond 41 weeks.

However, one in three women with a stillbirth at term loses her baby before this period.

The magnitude of this risk is not routinely communicated due to a previous lack of robust evidence.

The researchers have now analysed data from 13 separate studies in the UK, US, Denmark and Norway, which included 15,124,027 pregnancies, 17,830 stillbirths and 2,348 newborn deaths.

Despite the stillbirth risk figures, delivery before 41 weeks did not increase the risk of newborn death (defined as a death during the first 28 days of life) – the risk was unchanged for births between 38 and 41 weeks of gestation.

The risk increased by 87 per cent for deliveries at 42 weeks’ gestation compared to 41 weeks.

Professor Thangaratinam added: “This is the largest study of its kind, and finally provides precise estimates of potential risks of stillbirth.

Now that we understand the extent to which stillbirth risks increase with each week of pregnancy, we should be incorporating this information in all discussions around delivery plans in pregnant women at term.

“We were surprised to see how much poorer pregnancy outcomes were for Black women—they were up to twice more likely to experience stillbirth than White women.

Healthcare professionals need to take these added risks into account when developing care plans for these women.”

Limitations of the study include variations in the definitions of low risk pregnancy, the wide time-span of the studies, loss of data due to exclusion of studies that did not provide stillbirth estimates in weekly intervals, and potential confounders affecting the outcome.


The risk of stillbirth after 32 weeks of gestation increases with gestational age, and half of these late fetal deaths occur at term.1 

Term stillbirth theoretically can be avoided through the judicious use of labor induction, and stillbirth prevention lies at the heart of many of the accepted indications for labor induction. However, once the child is born, he or she faces new mortality risks, often risks that may be determined partially by gestational age at birth.

Determining the optimal time of delivery to minimize the risk of stillbirth necessarily must include considering the mortality risk faced by the child after birth.

For nonanomalous infants born at term, the most common causes of death are asphyxia, infection, and sudden infant death syndrome (SIDS). Rates of infection and SIDS decrease with increasing gestational age at term, with the highest rates at 37 weeks.2 

The risk of both neonatal and infant death has been shown in multiple studies to decrease with gestational age at term but then increase again at 41 weeks of gestation.25 

Part of the relationship between gestational age and infant death is driven by the fact that SIDS deaths decrease with gestational age until 40–41 weeks, after which they begin to increase again; SIDS is the leading cause of postneonatal death in nonanomalous infants.4,6,7

This study attempts to use epidemiologic information to describe the multiple dimensions of risk faced by pregnant women and their health care providers when comparing the risks of stillbirth at term with the risk of infant death after birth, considering that gestational age is one of the many shared risk factors for both stillbirth and infant death.8 

Previous studies have attempted to examine the optimal time for delivery by comparing stillbirth risk with a composite of infant morbidity and mortality; in this study, we attempted to develop a risk estimate of mortality alone.9Go to:

MATERIALS AND METHODS

We conducted a retrospective cohort study of term births that occurred in California from 1997 to 2006. We obtained institutional review board approval from the Committee on Human Research at the University of California, San Francisco, the institutional review board at Oregon Health and Science University, and the California Office of Statewide Health Planning and Development and the Committee for the Protection of Human Subjects. Because the data are deidentified and part of the public record of vital statistics, informed consent was not required.

The data for these calculations come from the California Vital Statistics Birth Certificate Data, California Patient Discharge Data, Vital Statistics Death Certificate Data, and Vital Statistics Fetal Death File.10 

The State of California maintains linked data sets that include maternal antepartum and postpartum hospital records for the 9 months before delivery and 1 year after delivery as well as birth records and all infant admissions occurring within the first year of life.

Linkage is performed by the California Office of Statewide Health Planning and Development Healthcare Information Resource Center under the State of California Health and Human Services Agency using a unique “record linkage number” specific to the mother–infant pair.

The birth certificate data use last menstrual period as the basis for gestational age dating in days.

This gestational age is converted to weeks and treated as an ordered categorical variable. If the last menstrual period was missing or nonsensical, the mother– infant pair was excluded for analysis.

This study includes all births from 37 to 42 weeks of gestation; 37 weeks of gestational age included births ranging from 37 0/7 weeks to 37 6/7 weeks, and 42 weeks of gestational age included births from 42 0/7 weeks to 42 6/7 weeks. We excluded multiple gestations, pregnancies complicated by diabetes mellitus (pre-existing or gestational) and chronic hypertension, and infants with congenital anomalies or genetic causes of death based on the International Classification of Diseases (ICD), 9th and 10th Revision codes. Causes of infant death were taken from the ICD, 9th Revision (years 1997–1998) or ICD, 10th Revision (years 1999–2007) codes on death certificates and were grouped into large thematic categories.

The incidence of stillbirth at a given gestational age was calculated as the number of stillbirths (whether antepartum or intrapartum) at that gestational age per 10,000 ongoing pregnancies.

Infant mortality at each gestational age was calculated as the number of infants born at this gestational age who die within 1 year of life per 10,000 live births at that same gestational age.

For reference, a neonatal death is defined as death within the first 30 days of life, whereas early neonatal death, the metric included in estimates of perinatal mortality, is defined as death within 7 days of life.

The goal of this project was to compare the mortality risks between delivery at a certain gestational age with that of expectant management (ie, continuing the pregnancy for another week and then delivering 1 week later). More specifically, the mortality risk of delivery at a given week was defined as the rate among those infants born at that week of gestation.

The mortality risk of 1 week of expectant management was defined as the risk of stillbirth over that week plus the mortality risk experienced by infants born in the subsequent week of gestation.

Infant death, rather than neonatal death, was chosen as the preferred metric to examine because of its greater magnitude and persistent correlation with gestational age at delivery. As mentioned previously, infant mortality has been shown to vary with gestational age at term and shares many of the same risk factors as stillbirth.4,6 

Although only early neonatal death rates have classically been included in estimates of perinatal risk, as neonatal intensive care improves, a larger proportion of children with complications resulting from gestational age or intrapartum events may be surviving beyond the neonatal period, contributing to the decrease in neonatal mortality rates over time.4,11 

Also, recent data demonstrate that term infants who die within the first year of life are more likely to do so within the postneonatal period (age 29–365 days of life) than in the neonatal period.12 Any gestational age-related mortality effect in these children will be better captured by examining infant death rates.

Our calculations rely on the following assumptions:

1) the risks of stillbirth and infant death have a uniform distribution throughout a particular week of gestation;

2) when estimating the risk of delivering at a particular gestational age, the fetus is not at risk for stillbirth beyond that gestational age; therefore, their mortality risk in that week is equal only to the risk of infant death; and

3) all probabilities are conditional rather than cumulative; that is, the risk of stillbirth at 41 weeks of gestation includes the assumption that the pregnancy is viable at that gestational age and has not had a stillbirth in the weeks prior.

The composite risk of expectant management for 1 week represents the sum of the probability of stillbirth during a given week of gestation plus the probability of infant death when birth occurs the subsequent week.

This composite risk of expectant management beyond each given week of gestation then was compared with the risk of infant death for children born in the given week of gestation.

The “number needed to deliver” was calculated as an analogous measure to the “number needed to treat” by taking the reciprocal of the absolute risk difference between delivery and expectant management.

Statistical calculations were performed with Excel and Stata 12, including proportions, relative risks, and 95% confidence intervals (CIs).

Exponential modeling was performed and goodness of fit was reported with the coefficient of determination, R2.

Chi square tests were performed to compare proportions of independent variables and analysis of variance was performed to compare means. Statistical significance was reached with a P value of<.05 or if 95% CIs did not overlap. We assumed that the binomial probability distributions of both mortality risks approximated the normal distribution and derived the CI of the composite risk using the sum of the variances plus twice the covariance of the estimates of infant death and stillbirth.

RESULTS

The sample included 3,820,826 nonanomalous term and postterm singleton births delivered in California between 1997 and 2006. Baseline demographic data are displayed in Table 1. The highest risk of stillbirth was seen at 42 weeks with 10.8 per 10,000 ongoing pregnancies (95% CI 9.2–12.4 per 10,000) (Table 2). The risk of stillbirth increased in an exponential fashion with increasing gestational age (R2=0.956) (Fig. 1).

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Fig. 1
This graph compares the risk of delivery (represented by infant death) with the risk of expectant management for 1 week (represented by the stillbirth rate plus the infant death risk at the subsequent gestational age) at each gestational age at
term. The stillbirth rate also is displayed graphically to demonstrate its exponential rate of change.

Table 1

Demographic Characteristics of Women With Singleton, Nonanomalous Gestations Between 37 and 42 Weeks of Gestation in California Between 1997 and 2006

CharacteristicStillbirth
(n=3,999)
Infant Death
(n=3,879)
Alive
(n=3,812,948)
P
Maternal age (y)28.2±6.525.7±6.227.6±6.2<.001
Race or ethnicity
  White1,356 (34.0)1,567 (40.5)1,438,897 (37.8)<.001
  Black (non-Hispanic)365 (9.2)500 (12.9)203,057 (5.3)
  Hispanic1,847 (46.3)1,373 (35.5)1,685,985 (44.3)
  Asian or Pacific Islander407 (10.2)336 (8.7)423,646 (11.1)
  Other12 (0.3)94 (2.4)56,773 (1.5)
More than 12 y of education1,444 (37.7)1,069 (30.1)1,431,712 (42.7)<.001
Private payer1,414 (45.8)1,046 (37.8)1,581,738 (53.2)<.001
Nulliparous862 (38.4)1,403 (36.3)1,525,096 (40.0)<.001
Gestational age (wk)38.9±1.439.2±1.439.3±1.3<.001
Birthweight (g)2,911±8523,232±6583,431±464<.001
Male sex1,992 (50)2,198 (56.7)1,929,958 (51)<.001

Data are mean±standard deviation or n (%) unless otherwise specified.

Table 2

Risk of Stillbirth, Infant Death, and Expectant Management by Gestational Age

Gestational
Age (wk)
DeliveriesStillbirth
Total
Stillbirth/10,000
Ongoing Pregnancies
(95% CI)
Infant Death/10,000
Live Births (95% CI)
Composite Risk of
Expectant Management for
1 wk*/10,000 (95% CI)
37336,6408072.1 (2.0–2.3)14.4 (13.1–15.7)12.6 (11.8–13.3)
38730,9089572.7 (2.6–2.9)10.5 (9.7–11.2)11.6 (11.0–12.1)
391,099,4699513.5 (3.2–3.7)8.8 (8.3–9.4)12.9 (12.3–13.6)
40977,1016914.2 (3.9–4.5)9.5 (8.9–10.1)14.9 (14.0–15.9)
41508,4384116.1 (5.5–6.7)10.8 (9.9–11.7)17.6 (15.8–19.3)
42168,27018210.8 (9.2–12.4)11.5 (9.9–13.1)

CI, confidence interval.*Composite risk=risk of stillbirth at this gestational age+risk of infant death at the next gestational age week.

Infant death risk by gestational age at birth had a U-shaped curve, greatest at 37 weeks of gestation with a nadir at 39 weeks (Fig. 1).

The highest infant mortality rate was 14.4 per 10,000 (95% CI 13.1–15.7 per 10,000 live births) at 37 weeks of gestation, 1.6 times higher than the rate at 39 weeks of gestation (8.8 per 10,000 live births, 95% CI 8.3–9.4 per 10,000, relative risk 1.63, 95% CI 1.47–1.82) (Tables 2 and ​and3).3)

The most common cause of infant death was SIDS, comprising 27.7% of all infant deaths among children born between 37 and 42 weeks, followed by accidents (13.6%), complications of labor and delivery (11.7%), and infections (11.0%) (Table 4).

Table 3

Comparative Risks of Stillbirth, Infant Death, and Expectant Management by Gestational Age

Gestational
Age (wk)
Stillbirth
Risk
Infant
Death
Risk
Expectant
Management
Risk*
37Referent1.6 (1.5–1.8)Referent
381.3 (1.2–1.4)1.2 (1.1–1.3)0.9 (0.8–1.0)
391.6 (1.5–1.8)Referent1.0 (0.9–1.1)
402.0 (1.8–2.2)1.1 (0.9–1.2)1.2 (1.1–1.3)
412.9 (2.6–3.2)1.2 (1.1–1.4)1.4 (1.2–1.6)
425.1 (4.4–6.0)1.3 (1.1–1.5)

Data are relative risk (95% confidence interval).*Expectant management risk=risk of stillbirth at this gestational age+risk of infant death at the next gestational age week.

Table 4

Causes of Infant Death by Gestational Age, 37–42 Weeks

Infant Death
Category
Gestational Age (wk)
373839404142Total
SIDS133 (27.5)210 (27.5)274 (28.3)254 (27.5)151 (27.6)51 (26.4)1,073 (27.7)
Accident64 (13.2)114 (14.9)129 (13.3)125 (13.5)70 (12.8)26 (13.5)528 (13.6)
Related to labor and delivery73 (15.1)79 (10.4)96 (9.9)109 (11.8)63 (11.5)35 (18.1)455 (11.7)
Infection40 (8.3)108 (14.2)107 (11.1)92 (10.0)60 (11.0)20 (10.4)427 (11.0)
Pulmonary24 (5.0)34 (4.5)42 (4.3)42 (4.6)30 (5.5)6 (3.1)178 (4.6)
Cardiac22 (4.6)22 (2.9)20 (2.1)24 (2.6)17 (3.1)7 (3.6)112 (2.9)
Neoplasm13 (2.7)20 (2.6)18 (1.9)26 (2.8)13 (2.4)5 (2.6)95 (2.5)
Other85 (17.6)141 (18.5)222 (22.9)190 (20.6)100 (18.3)31 (16.1)769 (19.8)
Missing30 (6.2)35 (4.6)60 (6.2)62 (6.7)43 (7.9)12 (6.2)242 (6.2)
Total4847639689245471933,879

SIDS, sudden infant death syndrome.

Data are n (%) or n.

A composite death rate was calculated to express the mortality risk associated with expectant management at any given gestational age. This risk is calculated as a sum of the stillbirth probability at a given week of gestation and the probability of infant death at the subsequent week of gestational age. This risk was highest at 41 weeks of gestation (17.6 per 10,000, 95% CI 15.8 –19.3) and lowest at 38 weeks of gestation (11.6 per 10,000, 95% CI 11.0 –12.1).

To determine whether the mortality risk is higher with delivery or with expectant management, the composite death rate related to expectant management was compared with the risk of infant death at each week of term pregnancy.

At 37 weeks of gestation, the risk of expectant management is lower than the risk of delivery (12.6 compared with 14.4 per 10,000, relative risk 0.87, 95% CI 0.77– 0.99) (Table 5).

At 38 weeks of gestation, the risk of expectant management is higher than the risk of delivery, although the CIs overlap: 11.6 (95% CI, 11.0 –12.1) compared to 10.5 (95% CI, 9.7–11.2 per 10,000).

Thereafter, the risk of expectant management is statistically significantly higher than the risk of delivery; at 39 weeks of gestation, the risk of expectant management is 12.9 per 10,000, whereas the risk of delivery is 8.8 per 10,000 (relative risk 1.47, 95% CI 1.35–1.59).

These risks continue to diverge substantially at 40 and 41 weeks of gestation, favoring delivery over expectant management when considering the overall risk for either fetal or infant death (Fig. 1).

The absolute risk differences, although statistically significant at 39 weeks of gestation and beyond, are small, ranging from 4.1 per 10,000 (95% CI 3.23– 4.97 per 10,000) at 39 weeks of gestation to 6.8 per 10,000 at 41 weeks of gestation (95% CI 5.32– 8.24 per 10,000).

To better understand the magnitude of this difference, we can calculate the “number needed to deliver,” which is analogous to the “number needed to treat.”

This should be interpreted as the number of women who would need to be delivered at a given gestational age to prevent one excess death.

From these data, the number needed to deliver ranged from 2,442 (95% CI 2,014 –3,101) at 39 weeks of gestation to 1,476 (95% CI 1,214 –1,881) at 41 weeks of gestation.

Table 5

Relative and Absolute Risks of Expectant Management Compared With Delivery at 37–41 Weeks of Gestation

Gestational
Age (wk)
Relative Risk of Expectant
Management Compared
With Delivery (95% CI)
Absolute Risk Difference
Between Expectant Management
and Delivery/10,000 (95% CI)
No. Needed to Deliver at This
Gestational Age to Prevent a
Single Excess Death (95% CI)
370.87 (0.77–0.99)−1.84 (−3.59 to −0.09)
381.11 (1.00–1.22)1.11 (0.03–2.18)9,042 (4,587–316,456)
391.47 (1.35–1.59)4.10 (3.23–4.97)2,442 (2,014–3,101)
401.58 (1.45–1.71)5.47 (4.49–6.44)1,829 (1,552–2,228)
411.63 (1.47–1.81)6.78 (5.32–8.24)1,476 (1,214–1,881)

CI, confidence interval.


More information: ‘Risks of stillbirths and neonatal deaths with advancing gestation at term: a systematic review and meta-analysis of cohort studies of 15 million pregnancies’. Muglu et al. PLOS MedicineDOI: 10.1371/journal.pmed.1002838

Journal information: PLoS Medicine
Provided by Queen Mary, University of London

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