The authors have declared that no competing interests exist.
Conceived and designed the experiments: RB NIH MW UMR CBP HP RMS DJD BJS GRS MAK CH MDV DLC DC RLG. Analyzed the data: NIH CBP MAK. Wrote the first draft of the manuscript: RB. Contributed to the writing of the manuscript: RB NIH MW UMR CBP HP RMS DJD BJS GRS MAK CH MDV DLC DC RLG.
¶ Membership of the Stillbirth Collaborative Research Network is provided in the Acknowledgments.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Please access these websites via the online version of this summary at
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on
The UK National Health Service Choices website provides information about
MedlinePlus provides links to other resources about
Information about the
One in 160 births at ≥20 wk gestation in the United States is stillborn, resulting in over 25,000 stillbirths each year
First, birth weight percentile is a function of birth weight and age of the fetus. Thus, studies using gestational age (GA) at delivery rather than GA at death, as an estimate of the age of the fetus, systematically overestimate the GA of stillbirths. This leads to overestimation of the proportion of birth weights considered SGA and underestimation of birth weights considered large for GA (LGA) among stillbirths.
Second, a number of maternal characteristics such as weight, height, age, race/ethnicity, parity, exposures during pregnancy, smoking, and measures of placental function (such as maternal blood concentrations of placental hormones) have been observed to influence the magnitude of both fetal growth and risk of stillbirth
Therefore, we hypothesized that accounting for time of death in determining fetal age and birth weight percentile, and determining percentiles of birth weight based on norms that account for factors affecting birth weight in normal pregnancies, will more accurately identify the proportion of stillbirths associated with abnormal growth than using traditional methods.
This study was approved by the institutional review boards at each of the clinical recruiting sites and at the data coordinating center. All mothers participating in the study gave written informed consent.
The Stillbirth Collaborative Research Network (SCRN) conducted a population-based case–control study of stillbirths in the United States. The study design has been previously described
A stillbirth was defined by Apgar scores of 0 at 1 and 5 min, and no signs of life by direct observation. The protocol included an in-hospital maternal interview, medical record abstraction, placental pathology examination, and biospecimen collection for stillbirths and live births. For stillbirths, a standardized postmortem examination was also performed.
Fetal age was based on an estimated due date and the date of delivery for live births and an estimated due date and estimated date of death for stillbirths, using an algorithm developed by the SCRN investigators
The SCRN algorithm for estimating time of death and fetal age at death in stillbirths considered the following: the reliability of the estimated due date; the length of the interval between the time the fetus was last documented alive and the time fetal demise was first recorded based on information from prenatal care visits, hospitalizations, and ultrasound examinations (the time-of-death interval); and information available from postmortem examination, including degree of fetal maceration and foot length measurement. The estimated due date was considered reliable if estimated by ultrasound or by certain menstrual dating that agreed with ultrasound (within specified constraints). Briefly, (1) if the estimated due date was reliable, the fetal age at death was estimated using the due date and the date fetal demise was diagnosed (if the interval during which death occurred was ≤1 d) or the date at the midpoint of the time-of-death interval (if the interval was >1 and ≤7 d); (2) if the estimated due date was unreliable, or the time-of-death interval was >7 d, GA at death was estimated using foot length, or using GA reported by the study site at screening based on clinical criteria when foot length information was not available. Precise estimates of GA at death, defined as meeting reliable dating criteria and having an interval of 1 wk or less during which the demise could have occurred, were possible for 47% of stillbirths.
The fetal age at death estimated by the SCRN algorithm was used for all stillbirths in the primary analysis. For comparison, GA at stillbirth delivery, calculated using the estimated due date and the delivery date, and GA at delivery minus 2 d were also used as estimates of fetal age at death to examine the impact on birth weight percentiles. For live births, fetal age at delivery was estimated using the estimated due date if reliable and the delivery date, or if the estimated due date was unreliable, the GA reported by the study site at screening was used.
Fetal weight percentiles were determined based on birth weight and the fetal age estimate for stillbirths and live births. Birth weight was obtained from medical records or postmortem examination and was compared to expected weight for GA based on three types of norms: population, ultrasound, and individualized norms
GASCRN is the fetal age at death (for stillbirths) or delivery (for live births) estimated by the SCRN algorithm
The estimated GA at death (for stillbirths) or delivery (for live births) using the SCRN algorithm (GASCRN) was recorded in weeks, with days retained as a fractional component. Alexander et al. reported 5th, 10th, 50th, 90th, and 95th percentiles of birth weight for completed weeks of GA derived using data from over 3 million US 1991 single live births
The observed birth weight of each infant was compared to the interpolated 5th, 10th, 50th, 90th, and 95th percentiles of birth weight for GASCRN and assigned to a percentile category (e.g., <10th percentile). Three infants with GASCRN>44.5 wk were assigned to the 10th–90th percentile category based on birth weight between the 10th and 90th percentiles reported for 44 wk.
Hadlock et al. used in utero fetal weight, estimated with ultrasound measurements, from 392 uncomplicated pregnancies progressing to term among predominantly middle-class white women to develop a best-fitting equation for fetal weight as a function of GA
Bukowski et al. developed a regression model for birth weight in a normal population using singleton births from 9,818 women with uncomplicated pregnancies
Variable | ||
Maternal weight | 2,293 | 55 |
Maternal height | 2,334 | 14 |
Race/ethnicity | 2,347 | 1 |
Maternal education | 2,230 | 118 |
Marital status | 2,238 | 110 |
Number of prior term pregnancies | 2,345 | 3 |
Number of prior abortions | 2,347 | 1 |
Altitude of residence | 2,348 | 0 |
Cigarettes/day first trimester | 2,236 | 112 |
Ovulation induction | 2,346 | 2 |
Nuchal translucency size | 76 | 2,272 |
Pregnancy-associated plasma protein A | 103 | 2,245 |
Free beta human chorionic gonadotropin | 42 | 2,306 |
Alpha-fetoprotein | 870 | 1,478 |
Inhibin A | 576 | 1,772 |
Total human chorionic gonadotropin | 838 | 1,510 |
Unconjugated estriol | 831 | 1,517 |
First trimester size (DeltaGA) | 621 | 1,727 |
Male fetus | 2,341 | 7 |
After computing an individualized expected birth weight at 280 d (BWINDIV280) for each SCRN infant, an individualized expected birth weight for GASCRN (eBW) was calculated using a proportion derived using Hadlock et al.'s equation
Finally, an individualized birth weight percentile was estimated as the normal probability of an individualized
In sensitivity analyses, individualized norm percentiles were recalculated based on three different reduced prediction equations that included subsets of variables largely non-missing in the SCRN cohort, instead of the original 19 variables. First, percentiles were estimated based on a prediction equation that included the 11 variables with largely non-missing values in the SCRN cohort (maternal weight, height, race/ethnicity, education, marital status, number of prior term pregnancies, number of prior abortions, altitude of residence, use of ovulation induction to become pregnant, cigarettes smoked per day during the first trimester, and male fetus), with coefficients derived using data from the original Bukowski et al. population. Second, percentiles were estimated based on a prediction equation that included the six variables suggested previously
Data were weighted for the analysis. The analysis weights were constructed in steps. First, weights were constructed that took into account the sampling design, including staggered enrollment starts across the 59 site hospitals, and different sampling probabilities associated with the oversampling of live births <32 wk gestation and live births at ≥32 wk gestation to women of African descent. Some women screened and determined eligible for the study were not approached, and others were approached but did not consent. Additional weight adjustments were constructed to account for this nonresponse and utilized information collected at screening to determine characteristics associated with the likelihood of participating. The final analysis weights were constructed as the product of these weighting factors. Details of the live birth sample selection procedure and construction of the analysis weights have been reported previously
The analysis was restricted to singleton stillbirths and live births with non-missing birth weight and GA≥20 wk at death or delivery. Statistical significance for comparisons of characteristics between stillbirths and live births was determined by the median or chi-square test, and for comparisons between proportions among stillbirths by the McNemar test. Crude and adjusted odds ratios (ORs) and 95% confidence intervals were calculated from logistic regression models. Primary results used all stillbirths and all live births. Term stillbirth and live birth were defined as GA of 37 wk 0 d or more. To assess the association of SGA and LGA with preterm stillbirth, the logistic model was restricted to preterm stillbirth versus all live births. Multivariable models used to estimate adjusted ORs included study site (five geographic areas) and stillbirth risk factors known at the beginning of pregnancy
The SCRN identified 953 women with stillbirths and 3,088 women with live births eligible for participation in the study. Of these, 663 (70%) women with stillbirths and 1,932 (63%) women with live births consented to participate. Women with stillbirths enrolled in the study did not differ from those not enrolled on maternal age, maternal race/ethnicity, insurance/method of payment, or GA at delivery
Women who delivered stillbirths were more likely than women who delivered live births to be non-Hispanic black (23% versus 11%,
Category | Characteristic |
Stillbirth | Live Birth | |
528 | 1,382 | |||
0.50 | ||||
Median | 26 | 26 | ||
Interquartile range | 21 to 32 | 22 to 31 | ||
0.02 | ||||
Median | 28 | 29 | ||
Interquartile range | 23 to 34 | 24 to 34 | ||
<0.001 | ||||
Non-Hispanic white | 34 | 46 | ||
Non-Hispanic black | 23 | 11 | ||
Hispanic | 38 | 36 | ||
Other | 6 | 8 | ||
0.003 | ||||
<18.5 | 4 | 3 | ||
18.5–24.9 | 40 | 50 | ||
25–29.9 | 26 | 23 | ||
30–34 | 15 | 12 | ||
≥35 | 16 | 11 | ||
<0.001 | ||||
0–11 | 24 | 19 | ||
12 | 31 | 26 | ||
≥13 | 45 | 55 | ||
<0.001 | ||||
Not married | 26 | 15 | ||
Cohabiting | 26 | 24 | ||
Married | 48 | 60 | ||
0.02 | ||||
No insurance | 5 | 4 | ||
Any public/private assistance | 55 | 49 | ||
VA/commercial health insurance/HMO | 40 | 47 | ||
0.13 | ||||
Only public/private assistance | 9 | 6 | ||
Assistance and personal income | 38 | 38 | ||
Only personal income | 53 | 56 | ||
0.31 | ||||
A | 31 | 34 | ||
B | 14 | 11 | ||
O | 51 | 51 | ||
AB | 4 | 3 | ||
9 | 11 | 0.20 | ||
0.003 | ||||
Did not smoke | 79 | 86 | ||
<10 cigarettes/day | 11 | 7 | ||
≥10 cigarettes/day | 10 | 7 | ||
0.60 | ||||
Did not drink | 58 | 58 | ||
Drank, no bingeing | 21 | 23 | ||
Binged | 21 | 19 | ||
0.03 | ||||
Never | 66 | 69 | ||
Ever, without addiction | 29 | 28 | ||
Ever, with addiction | 5 | 2 | ||
Hypertension | 11 | 5 | <0.001 | |
Diabetes | 5 | 2 | <0.001 | |
Seizure disorder | 3 | 2 | 0.23 | |
<0.001 | ||||
Nulliparous; never pregnant or only elective terminations | 36 | 30 | ||
Nulliparous with previous losses | 11 | 5 | ||
Multiparous with no previous losses at <20 wk or stillbirths | 31 | 46 | ||
Multiparous with no stillbirth but previous losses at <20 wk | 14 | 17 | ||
Multiparous with stillbirth | 7 | 2 | ||
<0.001 | ||||
Median | 28 | 39 | ||
Interquartile range | 23 to 36 | 38 to 40 | ||
<0.001 | ||||
20–23 wk | 33 | <1 | ||
24–27 wk | 17 | <1 | ||
28–31 wk | 11 | 1 | ||
32–36 wk | 21 | 9 | ||
37+ wk | 18 | 89 | ||
<0.001 | ||||
Median | 992 | 3,317 | ||
Interquartile range | 454 to 2,468 | 2,978 to 3,628 | ||
52 | 50 | 0.55 | ||
13 | 3 | <0.001 |
Information was missing as follows (unweighted missing
Percentages may not sum to 100 because of rounding.
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
Unweighted sample sizes were 527 stillbirths and 1,821 live births.
Average number of cigarettes smoked per day during the 3 mo prior to pregnancy or alcohol consumption during the 3 mo prior to pregnancy.
Drank without bingeing was defined as 0–6 drinks in a typical week and no occasion where four or more drinks were consumed in a single time period (“binge”). Bingeing was defined as at least one binge and/or seven or more drinks in a typical week.
GA at death (stillbirths) or delivery (live births) by the SCRN algorithm
HMO, health maintenance organization; VA, Veterans Affairs.
Some variables used to compute individualized norms were missing in a proportion of pregnancies and were set to mean, median, or weighted average (
Birth Weight Norms and Percentiles | SB | LB | Crude OR for SB (95% CI) |
Adjusted OR for SB (95% CI) |
528 | 1,382 | |||
<5th percentile | 33 | 9 | 6.47 (4.91–8.53) | 6.01 (4.41–8.20) |
5th–<10th | 8 | 6 | 2.05 (1.35–3.12) | 1.84 (1.13–2.98) |
10th–90th | 42 | 72 | Reference | Reference |
>90th–95th | 4 | 5 | 1.39 (0.85–2.26) | 1.48 (0.87–2.52) |
>95th | 13 | 7 | 3.04 (2.14–4.30) | 2.57 (1.73–3.81) |
<5th percentile | 33 | 10 | 5.82 (4.38–7.71) | 5.33 (3.92–7.26) |
5th–<10th | 8 | 6 | 2.33 (1.55–3.50) | 2.07 (1.29–3.32) |
10th–90th | 43 | 73 | Reference | Reference |
>90th–95th | 3 | 4 | 1.33 (0.78–2.25) | 1.27 (0.69–2.31) |
>95th | 12 | 7 | 2.67 (1.88–3.80) | 2.21 (1.49–3.28) |
<5th percentile | 30 | 7 | 6.80 (5.08–9.12) | 6.24 (4.49–8.67) |
5th–<10th | 8 | 5 | 2.33 (1.48–3.65) | 2.06 (1.26–3.35) |
10th–90th | 43 | 72 | Reference | Reference |
>90th–95th | 4 | 6 | 1.17 (0.73–1.89) | 1.45 (0.83–2.54) |
>95th | 15 | 9 | 2.58 (1.87–3.56) | 2.21 (1.54–3.17) |
<5th percentile | 30 | 7 | 6.64 (4.96–8.88) | 6.25 (4.51–8.67) |
5th–<10th | 7 | 6 | 2.04 (1.30–3.20) | 1.74 (1.06–2.84) |
10th–90th | 44 | 71 | Reference | Reference |
>90th–95th | 4 | 7 | 0.95 (0.58–1.57) | 1.04 (0.58–1.87) |
>95th | 14 | 9 | 2.66 (1.93–3.68) | 2.39 (1.67–3.44) |
Birth weight for GA at death (stillbirths) or delivery (live births) by the SCRN algorithm
Unadjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that included effects for percentile group only.
Adjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that in addition to the percentile group indicators included study site number; paternal age (<20, 20–34, 35–39, ≥40 y); the following maternal variables (categorized as shown in
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
Unweighted sample sizes were 527 stillbirths and 1,821 live births. Unweighted (weighted) sample sizes included in computation of adjusted ORs were 452 (451) stillbirths and 1,665 (1,261) live births.
Individualized norm percentiles were derived using the fetal weight equation from Bukowski et al.
All 19 variables were used in the fetal equation here. (Fetal heart rate was included in the original Bukowski equation but was not collected by the SCRN study. GA in days minus 280 d drops out of the equation when predicting birth weight at 280 d.)
Individualized norm percentiles were derived using the subset of 11 variables largely non-missing in the SCRN cohort in the fetal weight equation to predict term birth weight: maternal weight, height, race/ethnicity, education, marital status, number of prior term pregnancies, number of prior abortions, altitude of residence, use of ovulation induction to become pregnant, cigarettes smoked per day during the first trimester, and male fetus.
Individualized norm percentiles were derived using the subset of six variables suggested by Gardosi et al.
Individualized norm percentiles were derived using a subset of five variables (the six variables above minus number of cigarettes smoked) in the fetal weight equation to predict term birth weight: maternal weight, height, race/ethnicity, number of prior term pregnancies, and male fetus.
LB, live birth; SB, stillbirth.
SGA pregnancies were associated with a statistically significant 3- to 4-fold increased risk of stillbirth compared to AGA pregnancies using percentiles based on population, ultrasound, and individualized norms (OR [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA birth weight was associated with a significantly increased risk of stillbirth using percentiles derived from the ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not using percentiles based on the population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). Abnormal fetal growth (SGA or LGA) was identified in 25% of stillbirths using population norms and in twice as many stillbirths using ultrasound (57%,
Birth Weight Norms and Percentiles | SB | LB | Crude OR for SB (95% CI) |
Adjusted OR for SB (95% CI) |
528 | 1,382 | |||
<5th percentile | 33 | 9 | 6.47 (4.91–8.53) | 6.01 (4.41–8.20) |
5th–<10th | 8 | 6 | 2.05 (1.35–3.12) | 1.84 (1.13–2.98) |
10th–90th | 42 | 72 | Reference | Reference |
>90th–95th | 4 | 5 | 1.39 (0.85–2.26) | 1.48 (0.87–2.52) |
>95th | 13 | 7 | 3.04 (2.14–4.30) | 2.57 (1.73–3.81) |
<10th | 41 | 15 | 4.59 (3.59–5.88) | 4.39 (3.34–5.78) |
>90th | 17 | 12 | 2.33 (1.73–3.14) | 2.13 (1.52–2.97) |
<5th percentile | 36 | 10 | 6.32 (4.86–8.22) | 5.44 (4.03–7.33) |
5th–<10th | 9 | 7 | 2.30 (1.54–3.43) | 2.33 (1.50–3.62) |
10th–90th | 43 | 77 | Reference | Reference |
>90th–95th | 4 | 3 | 2.50 (1.43–4.37) | 1.99 (1.04–3.81) |
>95th | 8 | 3 | 4.39 (2.79–6.89) | 3.71 (2.23–6.16) |
<10th | 45 | 17 | 4.67 (3.69–5.92) | 4.27 (3.27–5.59) |
>90th | 12 | 6 | 3.48 (2.42–5.01) | 2.90 (1.92–4.37) |
<5th percentile | 12 | 4 | 3.49 (2.36–5.16) | 3.05 (1.99–4.67) |
5th–<10th | 9 | 4 | 2.51 (1.64–3.84) | 2.18 (1.31–3.65) |
10th–90th | 75 | 84 | Reference | 1.00 (1.00–1.00) |
>90th–95th | 2 | 4 | 0.48 (0.22–1.05) | 0.55 (0.22–1.40) |
>95th | 3 | 4 | 0.75 (0.42–1.32) | 0.70 (0.40–1.22) |
<10th | 20 | 8 | 3.00 (2.22–4.04) | 2.62 (1.86–3.68) |
>90th | 4 | 8 | 0.63 (0.40–1.01) | 0.64 (0.39–1.05) |
Birth weight for GA at death (stillbirths) or delivery (live births) by the SCRN algorithm
Unadjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that included effects for percentile group only.
Adjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that in addition to the percentile group indicators included study site number; paternal age (<20, 20–34, 35–39, ≥40 y); the following maternal variables (categorized as shown in
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
Unweighted sample sizes were 527 stillbirths and 1,821 live births. Unweighted (weighted) sample sizes included in computation of adjusted ORs were 452 (451) stillbirths and 1,665 (1,261) live births.
Individualized norm percentiles were derived using the fetal weight for GA equation from Bukowski et al.
Ultrasound norm percentiles were derived using the fetal weight for GA equation and standard error from Hadlock et al.
Alexander et al. population norm percentiles of birth weight for GA were used
Simple linear interpolation was used with the Alexander birth weight percentiles reported for completed weeks of GA in whole weeks to derive birth weight percentiles for GA in weeks and days.
LB, live birth; SB, stillbirth.
SGA and LGA defined using the ultrasound and individualized norms were also associated with significantly increased risk of stillbirth in the subsets of pregnancies without pregestational diabetes, gestational diabetes, hypertension, or preeclampsia; non-anomalous births at more than 24 wk of gestation; and pregnancies with optimal estimates of GA and time of death (
Birth Weight Norms and Percentiles | Subset without Maternal Diabetes or Hypertension/Preeclampsia | Non-Anomalous Singletons ≥24 wk Gestation | Subset with Optimal Estimates of GA |
||||||
SB | LB | Crude OR for SB (95% CI) |
SB | LB | Crude OR for SB (95% CI) |
SB | LB | Crude OR for SB (95% CI) |
|
382 | 1,079 | 310 | 1,339 | 200 | 972 | ||||
<5th percentile | 30 | 8 | 6.14 (4.40–8.56) | 36 | 8 | 7.50 (5.44–10.36) | 28 | 8 | 5.50 (3.63–8.33) |
5th–<10th | 8 | 7 | 2.08 (1.30–3.34) | 9 | 7 | 2.40 (1.47–3.92) | 10 | 6 | 2.45 (1.36–4.43) |
10th–90th | 45 | 74 | Reference | 41 | 72 | Reference | 46 | 73 | Reference |
>90th–95th | 5 | 5 | 1.46 (0.84–2.53) | 3 | 5 | 1.12 (0.58–2.15) | 4 | 6 | 1.00 (0.45–2.19) |
>95th | 13 | 7 | 3.15 (2.10–4.74) | 10 | 7 | 2.35 (1.50–3.69) | 13 | 7 | 3.00 (1.79–5.00) |
<10th | 38 | 15 | 4.32 (3.23–5.77) | 46 | 15 | 5.28 (3.95–7.06) | 37 | 14 | 4.16 (2.87–6.02) |
>90th | 17 | 12 | 2.40 (1.70–3.38) | 13 | 13 | 1.82 (1.23–2.68) | 17 | 13 | 2.07 (1.32–3.23) |
<5th percentile | 33 | 9 | 6.02 (4.41–8.23) | 38 | 10 | 6.71 (4.94–9.13) | 32 | 10 | 5.56 (3.77–8.21) |
5th–<10th | 10 | 8 | 2.16 (1.38–3.39) | 11 | 7 | 2.71 (1.71–4.31) | 9 | 7 | 2.22 (1.23–4.00) |
10th–90th | 45 | 78 | Reference | 44 | 77 | Reference | 47 | 77 | Reference |
>90th–95th | 5 | 3 | 2.88 (1.52–5.45) | 3 | 3 | 1.48 (0.67–3.28) | 5 | 3 | 2.94 (1.40–6.16) |
>95th | 7 | 3 | 4.59 (2.68–7.86) | 5 | 3 | 2.95 (1.62–5.36) | 6 | 3 | 3.31 (1.62–6.77) |
<10th | 43 | 17 | 4.31 (3.27–5.68) | 48 | 17 | 5.06 (3.83–6.69) | 42 | 17 | 4.15 (2.91–5.90) |
>90th | 12 | 5 | 3.74 (2.44–5.73) | 8 | 6 | 2.24 (1.37–3.65) | 12 | 6 | 3.13 (1.83–5.35) |
<5th percentile | 9 | 3 | 3.00 (1.83–4.92) | 11 | 4 | 3.60 (2.26–5.73) | 13 | 3 | 4.06 (2.31–7.15) |
5th–<10th | 8 | 4 | 2.14 (1.29–3.54) | 10 | 4 | 2.74 (1.69–4.46) | 5 | 4 | 1.35 (0.65–2.81) |
10th–90th | 79 | 85 | Reference | 75 | 84 | Reference | 79 | 84 | Reference |
>90th–95th | 2 | 4 | 0.62 (0.28–1.36) | <1 | 4 | 0.18 (0.04–0.75) | <1 | 4 | 0.12 (0.02–0.90) |
>95th | 2 | 4 | 0.50 (0.23–1.08) | 4 | 5 | 0.93 (0.49–1.76) | 3 | 5 | 0.73 (0.32–1.65) |
<10th | 17 | 7 | 2.53 (1.76–3.63) | 21 | 7 | 3.15 (2.22–4.47) | 18 | 7 | 2.62 (1.67–4.11) |
>90th | 4 | 8 | 0.56 (0.32–0.97) | 4 | 8 | 0.60 (0.33–1.07) | 4 | 9 | 0.46 (0.21–0.97) |
Birth weight for GA at death (stillbirths) or delivery (live births) by the SCRN algorithm
In this subset, GA was estimated using an expected due date based on an ultrasound examination at ≤20 wk 6 d or last menstrual period that agreed with that ultrasound, and for stillbirths there was an interval of 7 d or fewer between the date the fetus was last recorded alive and the date fetal demise was first reported.
Unadjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that included effects for percentile group only.
The ORs adjusted for stillbirth risk factors as defined in
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
In the subset of pregnancies without maternal diabetes or hypertension/preeclampsia, unweighted sample sizes were 384 stillbirths and 1,402 live births. In the subset of non-anomalous singletons ≥24 wk gestation, unweighted sample sizes were 315 stillbirths and 1,661 live births. In the subset with optimalestimation of GA, unweighted sample sizes were 199 stillbirths and 1,226 live births.
Individualized norm percentiles were derived using the fetal weight for GA equation from Bukowski et al.
Ultrasound norm percentiles were derived using the fetal weight for GA equation and standard error from Hadlock et al.
Alexander et al. population norm percentiles of birth weight for GA were used
Simple linear interpolation was used with the Alexander et al. birth weight percentiles reported for completed weeks of GA in whole weeks to derive birth weight percentiles for GA in weeks and days.
LB, live birth; SB, stillbirth.
Among stillbirths identified as LGA by each of the norms, only one had a GA of more than 40 wk, and LGA was observed among preterm as well as term stillbirths. Hydrops was diagnosed among 11% (10/91), 14.5% (9/62), and 12.5% (3/24) of stillbirths identified as LGA using the individualized, ultrasound, and population norms, respectively. LGA was associated with stillbirth in the subset of non-anomalous pregnancies, which excluded the pregnancies with hydrops (
Accounting for the time of death in stillbirths to determine fetal age did influence the proportion of SGA and LGA infants (
Birth Weight Norms and Percentiles | Stillbirths | Live Births | Using Percentiles Based on GA at Delivery | |||
GA at Death | GA at Delivery Minus 2 d | GA at Delivery | Crude OR for SB (95% CI) |
Adjusted OR for SB (95% CI) |
||
528 | 561 | 570 | 1,382 | |||
<5th percentile | 33 | 44 | 48 | 9 | 11.25 (8.62–14.67) | 11.27 (8.40–15.12) |
5th–<10th | 8 | 6 | 6 | 6 | 2.04 (1.33–3.14) | 2.22 (1.36–3.62) |
10th–90th | 42 | 37 | 35 | 72 | Reference | Reference |
>90th–95th | 4 | 3 | 2 | 5 | 0.87 (0.48–1.55) | 1.02 (0.55–1.87) |
>95th | 13 | 11 | 8 | 7 | 2.48 (1.69–3.64) | 2.15 (1.40–3.29) |
<10th | 41 | 50 | 54 | 15 | 7.34 (5.77–9.33) | 7.70 (5.91–10.04) |
>90th | 17 | 14 | 11 | 12 | 1.79 (1.28–2.49) | 1.68 (1.16–2.42) |
<5th percentile | 36 | 45 | 51 | 10 | 11.34 (8.79–14.63) | 10.79 (8.11–14.35) |
5th–<10th | 9 | 8 | 7 | 7 | 2.17 (1.43–3.31) | 2.24 (1.41–3.57) |
10th–90th | 43 | 38 | 34 | 77 | Reference | Reference |
>90th–95th | 4 | 2 | 2 | 3 | 1.62 (0.83–3.18) | 1.56 (0.76–3.19) |
>95th | 8 | 7 | 5 | 3 | 3.87 (2.37–6.34) | 2.98 (1.73–5.12) |
<10th | 45 | 53 | 58 | 17 | 7.58 (6.01–9.57) | 7.53 (5.80–9.78) |
>90th | 12 | 9 | 8 | 6 | 2.79 (1.86–4.19) | 2.31 (1.48–3.61) |
<5th percentile | 12 | 23 | 25 | 4 | 8.98 (6.36–12.68) | 9.20 (6.33–13.39) |
5th–<10th | 9 | 9 | 9 | 4 | 3.10 (2.06–4.66) | 2.90 (1.78–4.72) |
10th–90th | 75 | 65 | 63 | 84 | Reference | Reference |
>90th–95th | 2 | 1 | <1 | 4 | 0.34 (0.13–0.89) | 0.53 (0.19–1.45) |
>95th | 3 | 2 | 2 | 4 | 0.67 (0.36–1.25) | 0.62 (0.34–1.15) |
<10th | 20 | 31 | 34 | 8 | 6.01 (4.59–7.88) | 6.02 (4.44–8.16) |
>90th | 4 | 4 | 3 | 8 | 0.53 (0.31–0.89) | 0.58 (0.34–1.01) |
Birth weight percentiles for stillbirths ≥20 wk gestation using three GA estimates: GA at delivery, GA at delivery minus 2 d, and GA at death estimated using the SCRN algorithm
Unadjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that included effects for percentile group only.
Adjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that in addition to the percentile group indicators included study site number; paternal age (<20, 20–34, 35–39, ≥40 y); the following maternal variables (categorized as shown in
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
Unweighted sample sizes were 527, 561, and 570 stillbirths for GA at death, GA at delivery minus 2 d, and GA at delivery, respectively, and 1,821 live births. Unweighted (weighted) sample sizes included in computation of adjusted ORs were 491 (489) stillbirths and 1,665 (1,261) live births.
Individualized norm percentiles were derived using the fetal weight for GA equation from Bukowski et al.
Ultrasound norm percentiles were derived using the fetal weight for GA equation and standard error from Hadlock et al.
Alexander et al. population norm percentiles of birth weight for GA were used
Simple linear interpolation was used with the Alexander et al. birth weight percentiles reported for completed weeks of GA in whole weeks to derive birth weight percentiles for GA in weeks and days.
SGA and LGA birth weights based on ultrasound and individualized norm percentiles were significantly associated with an increased risk of preterm as well as term stillbirth. Using population norms, only SGA pregnancies were significantly associated with preterm and term stillbirth (
Birth Weight Norms and Percentiles | Preterm SB and All LB | Term SB and LB | ||||
Preterm SB | All LB | Crude OR for Preterm SB (95% CI) |
Term SB | Term LB | Crude OR for Term SB (95% CI) |
|
433 | 1,382 | 94 | 1,233 | |||
<5th percentile | 36 | 9 | 7.37 (5.52–9.84) | 19 | 8 | 3.30 (1.80–6.04) |
5th–<10th | 7 | 6 | 1.88 (1.18–2.99) | 12 | 6 | 2.83 (1.38–5.81) |
10th–90th | 41 | 72 | Reference | 49 | 73 | Reference |
>90th–95th | 4 | 5 | 1.44 (0.85–2.45) | 4 | 5 | 1.17 (0.45–3.07) |
>95th | 12 | 7 | 2.97 (2.03–4.35) | 16 | 6 | 3.67 (1.97–6.84) |
<10th | 43 | 15 | 5.04 (3.88–6.54) | 30 | 15 | 3.10 (1.86–5.15) |
>90th | 16 | 12 | 2.31 (1.67–3.21) | 20 | 12 | 2.52 (1.45–4.39) |
<5th percentile | 39 | 10 | 7.30 (5.53–9.63) | 21 | 10 | 3.08 (1.77–5.39) |
5th–<10th | 8 | 7 | 2.22 (1.44–3.45) | 13 | 6 | 2.88 (1.42–5.86) |
10th–90th | 41 | 77 | Reference | 55 | 78 | Reference |
>90th–95th | 5 | 3 | 2.96 (1.65–5.30) | 2 | 3 | 0.92 (0.21–3.95) |
>95th | 8 | 3 | 4.49 (2.76–7.31) | 9 | 3 | 4.69 (2.12–10.41) |
<10th | 47 | 17 | 5.22 (4.06–6.72) | 34 | 16 | 3.00 (1.86–4.85) |
>90th | 12 | 6 | 3.76 (2.55–5.55) | 11 | 6 | 2.74 (1.35–5.55) |
<5th percentile | 13 | 4 | 3.71 (2.47–5.55) | 7 | 4 | 2.33 (1.00–5.41) |
5th–<10th | 8 | 4 | 2.25 (1.42–3.57) | 12 | 4 | 3.68 (1.80–7.55) |
10th–90th | 76 | 84 | Reference | 69 | 84 | Reference |
>90th–95th | 2 | 4 | 0.51 (0.23–1.17) | <1 | 4 | 0.29 (0.04–2.12) |
>95th | 1 | 4 | 0.31 (0.12–0.77) | 11 | 5 | 2.81 (1.39–5.67) |
<10th | 21 | 8 | 2.97 (2.17–4.07) | 19 | 8 | 3.02 (1.70–5.36) |
>90th | 3 | 8 | 0.40 (0.21–0.74) | 12 | 9 | 1.67 (0.86–3.22) |
Birth weight for GA at death (stillbirths) or delivery (live births) by the SCRN algorithm
Unadjusted OR for stillbirth for infants with birth weight in the percentile group shown compared to infants in the reference group from a logistic regression model that included effects for percentile group only.
Analysis weights that accounted for the basic study design plus other aspects of the sampling were used.
In the subset used to assess risk of preterm stillbirth, unweighted sample sizes were 433 preterm stillbirths and 1,821 (preterm and term) live births. In the subset of term pregnancies, unweighted sample sizes were 94 stillbirths and 1,386 live births.
Individualized norm percentiles were derived using the fetal weight for GA equation from Bukowski et al.
Ultrasound norm percentiles were derived using the fetal weight for GA equation and standard error from Hadlock et al.
Alexander et al. population norm percentiles of birth weight for GA were used
Simple linear interpolation was used with the Alexander et al. birth weight percentiles reported for completed weeks of GA in whole weeks to derive birth weight percentiles for GA in weeks and days.
LB, live birth; SB, stillbirth.
This study demonstrates that stillbirth is associated with both growth restriction and excess growth. The extremes of SGA and LGA (<5th and >95th percentiles) were associated with the highest risk of stillbirth.
The strengths of this study lie in its geographically defined population-based design capturing live births and stillbirths, the large number of stillbirths evaluated, the accurate estimation of GA at death in stillbirths, the assessment of fetal growth using different fetal growth standards, and the ability to examine the contribution of factors affecting both birth weight and the risk of stillbirth. The systematic and standardized estimation of time of death and thus GA at death for stillbirths allowed for more accurate assessment of the association between birth weight and stillbirth and, consequently, of the association of stillbirth with LGA.
Prior studies have either not accounted for the interval between time of death and time of delivery of stillbirths
Studies evaluating the interval between death and delivery have shown that in 25%–50% of stillbirths the interval was longer than 7 d
Many prior studies of stillbirth have focused exclusively on the association of stillbirth with SGA
A recent case series reported a higher than expected proportion of LGA among stillbirths. However, the majority of the LGA stillbirths in this series were related to fetal hydrops or maternal diabetes
In our study, abnormal fetal growth was identified in twice as many stillbirths using ultrasound and individualized norms as when using population norms. Although SGA was associated with stillbirth based on all three norms, the association of stillbirth with LGA was observed only when using ultrasound or individualized norms. Differences in design may account for these results. The population norms by Alexander et al. are commonly used and were developed using birth weights from all pregnancies resulting in single live births, including those with complications associated with growth abnormalities, resulting in a wide range of birth weights between the 10th and 90th percentiles, classified as AGA
In a large population of uncomplicated pregnancies, population reference percentiles and, to a lesser degree, ultrasound norms were shown to overestimate the proportion of AGA and to underestimate the proportion of LGA infants
In individualized norms, the predictors of fetal growth, the sizes of their effects, and the ranges of their values were derived from a carefully selected population of almost 10,000 pregnancies without pregnancy or neonatal complications
Consistent with prior studies, the findings of this study show that population norms are inferior to norms derived from uncomplicated populations, either ultrasound or individualized norms
The strength and pattern of the association between fetal growth and risk of stillbirth was similar in term and preterm pregnancies. SGA and LGA birth weights were associated with increased risk of stillbirth in preterm as well as term pregnancies using ultrasound or individualized norms. Using population norms, only SGA pregnancies had an increased risk of stillbirth, both preterm and term. The distribution of GA at death was similar among stillbirths classified as SGA, AGA, and LGA using ultrasound norms and also when classified using individualized norms, and the association of stillbirth with SGA and with LGA was observed when using both of these norms.
The association of LGA with stillbirth in this study was not related to post-term GA or known conditions that increase fetal weight and risk of stillbirth. Among stillbirths classified as LGA, only one pregnancy was greater than 40 wk. LGA was also associated with stillbirth among the subset of pregnancies that excluded hydrops and other congenital abnormalities. Because the relationship between congenital abnormalities and birth weight is complex and depends on the type of abnormality, we conducted analyses in pregnancies with and without congenital abnormalities. Both showed similar patterns of associations. Although the effect of maceration on a stillbirth's birth weight is uncertain, if birth weight is decreased in macerated stillbirths, this would decrease the strength of the association with LGA. However, the associations between SGA and LGA and risk of stillbirth were also observed in the subset with optimal estimates of fetal age that included non-macerated stillbirth infants with a short interval of less than 7 d between the time they were last reported alive and the time they were first identified as demised.
Screening for gestational diabetes is performed in the US at 24 to 28 wk. Women at increased risk with a history of gestational diabetes, impaired glucose metabolism, or obesity are additionally screened in early pregnancy
A limitation of this study is that retrospective review of medical records was used to obtain birth weight, criteria for GA estimation, and certain maternal characteristics. However, these variables were recorded in medical records prospectively and thus were unlikely to be subject to substantial bias. Many of the characteristics used to determine individualized expected birth weight were missing and were replaced with reference values. However, individualized norms based on subsets of non-missing variables showed very similar findings (
The mechanism of stillbirth in LGA pregnancies is not known. However, it has been suggested that LGA stillbirths may have relatively insufficiently large placentae, which, although not small per se, may be inadequate to support the metabolic demands of a large fetus, rendering it vulnerable to insults during pregnancy
In summary, when accounting for time of death and using norms developed in normal pregnancies, both SGA and LGA birth weights were associated with stillbirth in our study. The association is mainly related to severe SGA and LGA pregnancies, with birth weights either below the 5th or above the 95th percentile. Thus, classifying 10% of pregnancies as abnormally grown has the potential to identify 44%–46% of future stillbirths. This would provide an opportunity for prevention of stillbirth, especially in term pregnancies, when delivery is associated with relatively low neonatal mortality and morbidity. However, the effectiveness of stillbirth prevention would be expected to be decreased by inaccuracy of the fetal growth estimates. The association between large birth weights and stillbirth cannot be captured by population norms that include pregnancies with complications associated with growth abnormalities.
Our results suggest that, contrary to current practices and recommendations, the most effective approach to identifying fetal growth abnormalities for prediction and prevention of stillbirth would focus on both severe SGA and LGA (<5th and >95th percentile) pregnancies and would use norms developed from normal pregnancies, rather than population norms, for fetal growth surveillance. This strategy would identify as at risk almost half of the pregnancies that would result in stillbirth. However, the majority of stillbirths would remain unidentified either because of inaccuracy of the fetal growth assessment or because they are not associated with growth abnormalities.
(DOC)
The Stillbirth Collaborative Research Network is solely responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The following institutions and researchers compose the Stillbirth Collaborative Research Network: University of Texas Health Science Center at San Antonio—Donald J. Dudley, Deborah L. Conway, Karen Aufdemorte, Angela Rodriguez, Monica Pina; University of Utah School of Medicine—Robert M. Silver, Michael W. Varner, Kristi Nelson; Emory University School of Medicine and the Rollins School of Public Health—Carol J. Rowland Hogue, Barbara J. Stoll, Janice Daniels Tinsley, Bahig Shehata, Carlos Abramowsky; Brown University—Donald Coustan, Halit Pinar, Marshall Carpenter, Susan Kubaska; University of Texas Medical Branch at Galveston—George R. Saade, Radek Bukowski, Jennifer Lee Rollins, Hal Hawkins, Elena Sbrana; RTI International—Corette B. Parker, Matthew A. Koch, Vanessa R. Thorsten, Holly Franklin, Pinliang Chen; Pregnancy and Perinatalogy Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health—Marian Willinger, Uma M. Reddy; Columbia University Medical Center—Robert L. Goldenberg.
appropriate for gestational age
body mass index
gestational age
large for gestational age
odds ratio
Stillbirth Collaborative Research Network
small for gestational age