Methods

We conducted a retrospective cohort study of singleton pregnancies presenting to Washington University School of Medicine perinatal ultrasound units for routine anatomic survey from 1990-2009. We used the perinatal database at Washington University. Our medical center is an academic tertiary care center that serves as a major regional and national referral center. Our perinatal database is a large, well-maintained system with dedicated research personnel for the collection of data and maintenance. Self-report questionnaires are used to collect maternal demographic information and medical and obstetric histories. The questionnaires are administered at the initial ultrasound visit. Follow-up information is obtained by trained research personnel from the medical record. In the event that the patient delivers outside of the medical system, follow-up information is obtained through telephone contact with the patient and/or referring physician. Further details of data collection and management have been published previously.

Ultrasound scans were performed by certified sonographers dedicated to performing obstetric and gynecologic examinations. Final diagnosis was made by the attending maternal fetal medicine physician. The gestational age was assigned by ultrasound dates if >5 days from last menstrual period in the first trimester or >10 days from last menstrual period in the second trimester. SGA was assigned by birthweight using the population-based chart published by Alexander et al and defined as birthweight <10th percentile for the gestational age at delivery. We excluded pregnancies that were complicated by prenatally diagnosed major fetal anomalies and aneuploidy and those that were without neonatal follow-up information or birthweight data ( Figure 1 ).

Flow diagram of study population

The flow diagram details the study population and the exclusion criteria to identify small-for-gestational-age ( SGA ) pregnancies ongoing at 24 weeks of gestation. The diagram also details the breakdown of birth outcomes that occurred from 24-33 weeks 6 days of gestation.

Trudell. Preterm SGA stillbirth and neonatal death. Am J Obstet Gynecol 2014 .

Given that our aim was to compare the risks of stillbirth with neonatal death in the early preterm period, we examined the risks of stillbirth and neonatal death from 24-33 weeks 6 days of gestation utilizing the method of life-table analysis described by Smith. First, we calculated the risk of stillbirth by week. Within our database, stillbirth is defined as intrauterine fetal death at ≥20 weeks of gestation but deliveries at <24 weeks of gestation or at ≥34 weeks of gestation were excluded from the analyses in accordance with the aim of this study. We calculated the conditional probability of stillbirth per 10,000 ongoing SGA pregnancies. To account for censoring, deliveries that may have occurred during the particular time period for which the probability was calculated, one-half of the deliveries during that time period were subtracted from the denominator. Therefore, the conditional probability (P) of stillbirth (SB) during time period n given ongoing SGA pregnancies at the beginning of that time period n is (OP n ) and the number of births B: P(SB) n = SB n /(OP n -1/2B n ).

The clinical question of timing of delivery is not limited to the conditional probability of stillbirth because, if expectant management is chosen, then the fetus remains in utero during this time period and is exposed to the risks of stillbirth in the weeks preceding delivery. Therefore, the risk of stillbirth for the fetus at 28 weeks of gestation that is currently in utero at 26 weeks of gestation is the cumulative probability of stillbirth at 26, 27, and 28 weeks of gestation. The cumulative probabilities of stillbirth were calculated from the conditional probabilities as 1 – (probability of survival), where the probability of survival is 1 – (probability of death). Therefore, the cumulative probability (CP) of stillbirth (SB) during time n : CP(SB) n = 1 – [(1 – Cn ₁ )(1 – Cn ₂ )…..(C n _x )].

To compare the risk of stillbirth with the risk of neonatal death over time, the risk of neonatal death was calculated per live births. Neonatal death was defined as death by 30 days of life. Neonatal deaths were relatively rare; therefore, gestational age strata were collapsed into 2-week intervals. The conditional probability (P) of neonatal death (D) during time period n with live births (L) was calculated as: P(D)n = Dn/L n .

To compare the risk of neonatal death to the risk of stillbirth over time, we then collapsed stillbirths into 2-week strata and calculated the conditional and cumulative probabilities of stillbirth for each stratum. To explore a lower threshold of SGA, a secondary analysis was performed to evaluate the risks of neonatal death and stillbirth with SGA defined by birthweight <5th percentile.

Finally, because the cumulative probability is a retrospective calculation used to project risk into the future and the point in time when SGA was diagnosed is not known, we also took a prospective approach to the probability of death by estimating the relative risk of expectant management for 2 weeks compared with immediate delivery, as previously described by Rosenstein et al. Using this approach, the composite risk of expectant management for a time period is the sum of the conditional probability of stillbirth during that time period and the probability of neonatal death in the following time period. This method assumes delivery in the subsequent interval of time.

Descriptive statistics were used to calculate maternal characteristics of SGA pregnancies that delivered from 24-33 weeks 6 days of gestation for stillbirths, neonatal deaths, and neonates who survived >30 days of life. The cumulative risk of stillbirth with 95% confidence interval (CI) and the risk of neonatal death with 95% CI were calculated for the 2-week gestational age strata as stated earlier, then risk ratios with 95% CI were determined. Given the 20-year study period, sensitivity analysis was performed to assess changes in clinical practice or technology over time. The risk of stillbirth among SGA pregnancies that delivered at >24 weeks of gestation was assessed and compared using χ ² for 2 time periods that were determined by days from initiation of enrollment of 50% of the study cohort. Statistical analysis was calculated with STATA software (version 12; StataCorp, College Station, TX).

Results

Of 76,453 singleton pregnancies, there were 7036 ongoing SGA pregnancies at 24  weeks of gestation that met the inclusion criteria and 290 SGA births from 24-33 weeks 6 days of gestation. Figure 1 shows the details of the study population and breakdown of the outcomes of SGA births. Table 1 demonstrates relevant maternal demographic characteristics of the ongoing SGA pregnancies that delivered from 24-33 weeks 6 days gestation that resulted in stillbirth, neonatal death, or neonatal survival at >30 days of life.

The number of ongoing SGA pregnancies, stillbirths, live births, and neonatal deaths per week is given in Table 2 along with the conditional and cumulative probabilities of stillbirth per 10,000 ongoing SGA pregnancies. With increasing gestational age, the cumulative risk of stillbirth rises from 14 in 10,000 ongoing SGA pregnancies in week 24 of gestation to 91 in 10,000 ongoing SGA pregnancies in week 33 of gestation ( Figure 2 ).

Cumulative risk of stillbirth

The rise in the cumulative risk of stillbirth per 10,000 ongoing small-for-gestational-age pregnancies from 24-33 weeks 6 days of gestation.

Trudell. Preterm SGA stillbirth and neonatal death. Am J Obstet Gynecol 2014 .

The cumulative risk of stillbirth per 10,000 ongoing SGA pregnancies and risk of neonatal death per 10,000 SGA live births by 2-week gestational age strata is shown in Table 3 . There is a steep fall in neonatal deaths with increasing gestational age from 4444 per 10,000 SGA live births during the 24-25 week 6 days of gestation strata to 89 per 10,000 SGA live births during the 32-33 week 6/7 days of gestation strata ( Figure 3 ). The cumulative risk of stillbirth over gestation, as demonstrated in Figure 2 , is displayed again in Figure 3 on a larger scale that also shows the risk of neonatal death over time. The risk of neonatal death is greater than the risk of stillbirth for all gestational age strata up to 31 weeks 6 days of gestation, at which point the ratio of the risks is 0.97 ( Table 3 ).

Risk of stillbirth and neonatal death

The rise in the cumulative risk of stillbirth per 10,000 ongoing small-for-gestational-age pregnancies from 24-33 weeks 6 days of gestation transposed over the fall in neonatal death per 10,000 small-for-gestational-age live births.

Trudell. Preterm SGA stillbirth and neonatal death. Am J Obstet Gynecol 2014 .

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