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Reprints: Darios Getahun, MD, MPH, Department of Research and Evaluation, Kaiser Permanente Southern California, 100 Los Robles Ave., 2nd Floor, Pasadena, CA 91101
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, West Los Angeles Medical Center, Kaiser Permanente Southern California, Pasadena, CA
We sought to examine the association between first-pregnancy stillbirth and subsequent adverse perinatal outcomes.
Study Design
This cohort study examined the first 2 singleton deliveries at 20-44 weeks' gestation from 1991-2008 (n = 71,315) using birth certificate, hospitalization, and outpatient encounter files. Multivariable logistic regression models were used to assess the association.
Results
Stillbirth was observed in 5.3 of 1000 first deliveries. There was an increased risk of ischemic placental disease (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2–2.1), fetal distress (OR, 2.8; 95% CI, 1.7–4.5), chorioamnionitis (OR, 2.3; 95% CI 1.5–4.3), extreme preterm birth (OR, 4.2; 95% CI, 1.8–9.9), and early neonatal mortality (OR, 8.3; 95% CI, 3.7–18.6) in pregnancies after stillbirth vs pregnancies after live birth. Interpregnancy intervals <2 and ≥4 years after stillbirth increased the risk of ischemic placental disease and spontaneous preterm birth. Risks varied by stillbirth subtype.
Conclusion
A first-pregnancy stillbirth may increase adverse perinatal outcomes in subsequent pregnancy.
Despite technological advances in obstetric and neonatal care, it remains one of the major causes of perinatal mortality in developed countries and even more so in developing countries.
In the United States, the annual incidence of stillbirth declined gradually from 18.4 per 1000 in 1950 to 6.2 per 1000 in 2003, a relative decline of 66%.
Of the 2 types of stillbirths, antepartum (prior to the onset of labor) and intrapartum (after the onset of labor), antepartum stillbirth accounts for 65-85% of all fetal deaths.
The etiology of stillbirth remains largely unknown. However, both genetic and environmental factors may contribute to the pathogenesis of the disease. Previous studies have identified numerous potential maternal risk factors for stillbirth including advanced maternal age,
However, few data exist on the relationship between stillbirth and ischemic placental diseases (IPDs) (defined as small-for-gestational age [SGA] birth/intrauterine growth restriction, preeclampsia, and placental abruption) and other adverse perinatal and neonatal outcomes such as fetal distress, chorioamnionitis, spontaneous preterm birth (SPTB), and neonatal mortality in subsequent pregnancies. It is also unclear whether the magnitudes of the association between a prior stillbirth and above-listed adverse perinatal outcomes are modified by the interval between pregnancies.
Given the patterns of recurrence of stillbirth and the evidence for clinically undiagnosed infection/inflammation, abruption, or both when placental pathology is conducted after stillbirth,
we speculate that these adverse outcomes may be mediated through a common or shared etiology that are known to cause vasculopathy, placental ischemia, and uteroplacental underperfusion, which may be central to the etiologic feature of IPD. Therefore, the purposes of this study were to: (1) examine the association between stillbirth in the first pregnancy and adverse perinatal outcomes in the second pregnancy; and (2) determine whether risks are modified by the time between the stillbirth and the subsequent pregnancy.
Materials and Methods
We conducted a retrospective cohort study of all births to Kaiser Permanente Southern California members for the years 1991-2008 (approximately 30,000 annual deliveries). The study was approved by our institutional review board. Using each member's unique medical record number, we linked 3 databases: the perinatal services system, maternal and infant hospitalization in all of our hospitals, and outpatient health care encounter files. The perinatal services system data file contains data from the infant's birth certificate, maternal sociodemographic and behavioral characteristics, complications of labor and delivery, and fetal and infant outcomes in all of our hospitals. The maternal and infant hospitalization records as well as outpatient physician encounter files include International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes from which we derived maternal medical history, obstetric history, and procedures.
Self-reported maternal race was categorized as non-Hispanic white, non-Hispanic black (African American), Hispanic, and Asian/Pacific Islander. Other independent variables considered as either potential determinants or confounders for the association between a first-pregnancy stillbirth and adverse outcome in subsequent pregnancy included: maternal age (<20, 20-29, 30-34, ≥35 years), education (<12, 12, and ≥13 years of completed schooling), timing of prenatal care initiation (early or first trimester vs second trimester or later or no prenatal care), smoking and alcohol use during pregnancy (yes/no), fetal sex (male or female), interval between the first birth and a subsequent pregnancy (interpregnancy intervals of <12, 12-17, 18-23, 24-29, 30-35, 36-41, ≥42 months), maternal medical conditions (chronic hypertension, diabetes mellitus, renal disease, and autoimmune disease), obstetric complications (premature rupture of membranes and cord complications), and congenital (chromosomal and nonchromosomal) anomaly, which were all assessed using ICD-9-CM codes.
Stillbirth was defined as the death of a fetus at ≥20 weeks' gestation and further categorized as antepartum (the death of a fetus prior to the onset of labor) and intrapartum (the death of a fetus after the spontaneous onset of labor). The outcomes that were examined included risks of IPD, fetal distress, chorioamnionitis, SPTB, and neonatal mortality. IPD was defined as the occurrence of any ≥1 of the following closely related conditions
: preeclampsia (hypertensive disorder >20 weeks of pregnancy, combined with proteinuria and/or edema; based on ICD-9-CM codes 642.4 and 642.5), SGA birth (fetuses with race-/ethnicity- and sex-specific weight ≤10th percentile for the gestational age), intrauterine growth restriction (fetal weight <10th percentile for gestational age as determined through an ultrasound), and placental abruption (a premature separation of the normally implanted placenta; based on ICD-9-CM code 762.1). Doppler studies of umbilical and uterine vessels and histologic and biochemical examination of the placenta exhibit several similarities of these conditions including uteroplacental underperfusion, chronic hypoxia, and placental ischemia.
To improve the distinction between constitutional and pathological SGA, we used previously proposed criteria requiring race-/ethnicity- and sex-specific standard.
We defined SGA as birthweight that is <10th percentile based on the 1991-2008 race-/ethnicity- and sex-specific birthweight-for-gestational age cutoffs (internal standard). Additional outcomes examined in this study include fetal distress (persistent late decelerations or other heart rate patterns consistent with fetal hypoxia), chorioamnionitis (an inflammation at the maternal-fetal interface; based on ICD-9-CM codes 762.7x and 658.4x), SPTB (a premature labor and delivery occurring at 20-36 completed weeks of gestation [extremely preterm 20-28, very preterm 29-33, and moderately preterm 34-36 weeks of gestation]), and neonatal death (the death of a live-born infant within the first 28 days.
Gestational age was estimated from the date of the last menstrual period (LMP) in most cases. When the date of LMP was missing or the observed birth weight was inconsistent with the LMP-based estimate of gestational age, the clinical estimate of gestational age reported on the infant's birth certificate was used instead.
There were 540,956 pregnancies that resulted in singleton live birth or stillbirth in our hospitals from 1991-2008. From these pregnancies, we sequentially excluded births to women with only 1 pregnancy in one of our hospitals, with nonconsecutive pregnancies, or who had their first birth <1991 (n = 465,275) and pregnancies that ended at <20 or >44 completed weeks' gestation or deliveries of infants who weighed <500 g (n = 4366). The justification for limiting the analysis to singleton pregnancies only is that multiple gestation pregnancies inherently have an increased risk of adverse pregnancy outcomes. We excluded pregnancies that ended at <20 or >44 completed weeks, and birthweights of <500 g to avoid errors in gestational age estimation.
After these exclusions, we had a final analytic sample of 71,315 women with their first 2 successive pregnancies that resulted in live birth or stillbirth.
First, we compared the maternal demographic and behavioral characteristics of the second pregnancy between women with and without stillbirth in the first pregnancy using χ2 test. Differences with P < .05 were considered statistically significant. Next, multiple logistic regression models were applied to examine the associations between stillbirth in the first pregnancy and adverse outcomes in the second pregnancy after controlling for potential confounding variables including maternal age, race/ethnicity, education, prenatal care, smoking and alcohol use during pregnancy, fetal sex, interpregnancy interval, and medical and obstetric risk factors. Women who had a live birth in their first pregnancy served as reference for each outcome studied. When we studied a specific adverse outcome, we excluded women who had a history of the outcome to avoid accounting for recurrence in the risk estimate except for preterm birth and stillbirth recurrence. We further assessed for the effect of statistical interaction between stillbirth in the first pregnancy and interpregnancy interval on the risk of adverse perinatal outcomes in the second pregnancy. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to explore the strength of the associations. The analyses were also stratified by stillbirth subtypes (antepartum and intrapartum) and by interpregnancy intervals to determine whether associations are modified by these factors. Cox proportional hazard model was used to estimate the recurrence risk of stillbirth in subsequent pregnancy. The outcome variable was time to event with the event being a stillbirth, and “survival time” being gestational age at delivery. All analyses were performed using software (SAS, Version 9.1; SAS Institute, Cary, NC).
Results
The incidence of stillbirth in the first pregnancy was 5.3 per 1000 singleton births. The incidence rates of antepartum and intrapartum stillbirth were 3.5 per 1000 and 1.2 per 1000 singleton births, respectively, while the rate of unknown stillbirth subtype was 0.6 per 1000 singleton births.
The distribution of maternal and fetal characteristics in the second pregnancy based on stillbirth and live birth status in the first pregnancy is presented in Table 1. When we examined maternal demographic and behavioral characteristics, women whose first pregnancy resulted in a stillbirth tended to be younger, be African American, have initiated prenatal care later in the pregnancy, have had a shorter interpregnancy interval, and have had a male child than women whose first pregnancy resulted in a live birth.
TABLE 1Maternal and infant characteristics at the second births by first-pregnancy live birth or stillbirth status: Kaiser Permanente Southern California, 1991-2008
Characteristics in the second pregnancy
First pregnancy
P value
Live birth (%) n = 70,942
Stillbirth (%) n = 373
Maternal age, y
.017
<20
3.0
4.3
20-24
17.1
20.9
25-29
29.9
27.4
30-34
31.4
27.9
≥35
18.7
19.6
Maternal race/ethnicity
< .001
White
32.1
23.9
African American
10.2
23.3
Hispanic
43.7
40.5
Asian/Pacific Islander
12.6
11.0
Others/unknown/multiple races
1.1
0.5
Maternal education, y
.859
<12
12.4
12.1
12
28.5
29.2
≥13
58.9
58.7
Late/no prenatal care
14.8
20.9
.004
Smoked during pregnancy
2.2
2.7
.563
Drank alcohol during pregnancy
0.8
1.3
.239
Male sex
51.9
51.7
< .001
Pregnancy interval, mo
< .001
<12
19.3
48.6
12-23
31.5
20.2
24-35
20.9
11.1
36-47
11.5
7.4
≥48
14.6
11.1
Chronic hypertension
1.8
4.6
< .001
Diabetes mellitus
1.4
2.7
.034
Renal disease
0.7
1.1
.389
Autoimmune disease
0.01
0.00
.885
pPROM
1.1
3.2
< .001
Cord complications
11.8
14.2
.147
Congenital anomalies
0.5
1.9
< .001
pPROM, preterm premature rupture of membranes.
Getahun. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009.
Table 2 shows the association between first-pregnancy stillbirth and second-pregnancy adverse perinatal outcomes. A first pregnancy resulting in stillbirth was associated with an increased risk of IPD (OR, 1.6; 95% CI, 1.2–2.1), fetal distress (OR, 2.8; 95% CI, 1.7–4.5), chorioamnionitis (OR, 2.3; 95% CI, 1.5–4.3), SPTB (OR, 2.5; 95% CI, 1.7–3.8), and early neonatal death (OR, 8.3; 95% CI, 3.7–18.6) in a second pregnancy compared to a first pregnancy that resulted in a live birth.
TABLE 2Associations between first-pregnancy stillbirth and adverse outcomes in the second pregnancy
Adjustments were made for maternal age, race/ethnicity, prenatal care, child's sex, interpregnancy intervals, chronic hypertension, diabetes, premature rupture of membranes, and congenital anomalies.
Ischemic placental disease
16.1
24.1
1.7 (1.3–2.2)
1.6 (1.2–2.1)
Preeclampsia
3.1
6.4
2.2 (1.4–3.6)
2.3 (1.4–3.8)
SGA/IUGR
13.2
17.7
1.5 (1.2–2.0)
1.3 (1.0–1.8)
Placental abruption
0.9
1.6
2.0 (0.8–4.8)
1.5 (0.6–4.0)
Fetal distress
2.3
5.1
3.1 (2.0–5.0)
2.8 (1.7–4.5)
Chorioamnionitis
1.5
3.7
2.8 (1.7–4.3)
2.3 (1.5–4.3)
SPTB (<37 wk)
7.1
20.8
3.0 (2.1–4.4)
2.5 (1.7–3.8)
Moderately preterm
5.4
10.6
2.1 (1.2–3.4)
1.9 (1.1–3.1)
Very preterm
1.5
6.6
3.9 (2.0–7.7)
3.2 (1.6–6.7)
Extremely preterm
0.6
5.5
7.3 (3.4–15.7)
4.2 (1.8–9.9)
Neonatal mortality
0.2
2.2
11.6 (5.7–23.9)
7.1 (3.2–15.7)
Early neonatal
0.2
1.9
11.9 (5.5–25.7)
8.3 (3.7–18.6)
CI, confidence interval; IUGR, intrauterine growth restriction; OR, odds ratio; SGA, small for gestational age; SPTB, spontaneous preterm birth.
We excluded women if they had a history of the outcome under study.
Women who had a live first birth in each category served as reference group.
Getahun. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009.
a Adjustments were made for maternal age, race/ethnicity, prenatal care, child's sex, interpregnancy intervals, chronic hypertension, diabetes, premature rupture of membranes, and congenital anomalies.
The Figure depicts the association between a prior stillbirth and adverse perinatal outcome in the second pregnancy based on stillbirth subtypes. A first pregnancy that resulted in an antepartum but not intrapartum stillbirth was significantly associated with IPD (OR, 1.6; 95% CI, 1.3–2.0), fetal distress (OR, 2.9; 95% CI, 1.6–5.2), and chorioamnionitis (OR, 2.9; 95% CI, 1.7–4.9) compared to a first pregnancy that resulted in live birth. However, intrapartum stillbirth did not increase the risk of fetal distress or chorioamnionitis. Risk of SPTB and early neonatal mortality were increased for women who had an intrapartum or an antepartum stillbirth during their first pregnancy.
FIGUREAssociations between first pregnancy stillbirth and subsequent adverse outcomes
aAdjustments were made for maternal age, race/ethnicity, timing of initiation of prenatal care, child's sex, interpregnancy intervals, chronic hypertension, diabetes, premature rupture of membranes, and congenital anomalies. We excluded women if they had a prior history of the outcome under study. Women who had a live first birth in each category served as reference group.
CI, confidence interval; IUGR, intrauterine growth restriction; SGA, small for gestational age.
Getahun. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009.
The rate of stillbirth in the second pregnancy was 13.4 per 1000 women (5/373) for those who had a prior stillbirth compared with 3.6 per 1000 women (257/70,942) for those who had a prior live birth. Women whose first pregnancy resulted in a stillbirth had a 3.5-fold (95% CI, 1.9–6.9) increased risk of stillbirth in their second pregnancy compared to women whose first pregnancy resulted in a live birth. When we stratified the analysis by stillbirth subtype for the second pregnancy, we found that women whose first pregnancy resulted in intrapartum stillbirth were at increased risk for both antepartum (hazard ratio, 7.1; 95% CI, 1.7–28.8) and intrapartum (hazard ratio, 7.0; 95% CI, 1.7–28.4) stillbirth in their second pregnancy. In comparison, women whose first pregnancy resulted in an antepartum stillbirth were not at increased risk of antepartum and intrapartum stillbirth in the second pregnancy.
Short (<24 months) interpregnancy interval was observed for 50.8% of women with first live birth and 69.0% of women with first stillbirth. After adjustment for maternal age, race/ethnicity, prenatal care, and medical and obstetric risk factors, compared with those conceiving at <24 months after a previous live birth, those conceiving at <24 months after a previous stillbirth had 1.6-fold (95% CI, 1.2–2.1) increased risk for IPD and 2.9-fold (95% CI, 2.1–4.1) increased risk of SPTB at <37 weeks. Compared with those conceiving at ≥48 months after a previous live birth, those conceiving at ≥48 months after a previous stillbirth had 2.3-fold (95% CI, 1.3–4.3) increased risk of IPD and 3.7-fold (95% CI, 1.9–7.1) increased risk of SPTB at <37 weeks. Compared with those conceiving at <24 months and ≥48 months, those conceiving between 24-48 months seem to have a lower risk of IPD and SPTB, however, the difference in risks among the groups categorized by interpregnancy interval is not statistically significant (P values .782 and .578, respectively). We did not detect any interaction effect between stillbirth in the first-pregnancy and interpregnancy interval on the risk of adverse perinatal outcomes in the second pregnancy (data not shown).
Comment
The findings of this study suggest that women whose first pregnancy resulted in stillbirth are at increased risk of conditions that constitute IPD (preeclampsia, SGA, intrauterine growth retardation, and abruption), fetal distress, chorioamnionitis, SPTB, and early neonatal mortality in their second pregnancy. Antepartum but not intrapartum stillbirth in the first pregnancy was associated with increased risk of IPD in the second pregnancy. This study also provides evidence that the interval between the first 2 successive pregnancies modifies the magnitude of associations with shorter and longer intervals between the first and second pregnancy resulting in an increased risk of IPD and SPTB.
We further showed that a history of stillbirth in the first pregnancy was associated with a higher incidence of stillbirth recurrence in the second pregnancy, an observation that is consistent with the findings of previous studies. Samueloff et al
showed a 5-fold increased risk of recurrence of stillbirth in subsequent pregnancies. Furthermore, consistent with our findings of the association between stillbirth in the first pregnancy and subsequent preterm birth, Black et al
recently reported a 2.4-fold (95% CI, 1.7–3.4) increased risk of preterm birth in women with a prior stillbirth. However, unlike our findings, their study did not show an association between stillbirth in the first pregnancy and stillbirth and neonatal death in the second pregnancy, perhaps due to small sample.
The pathoetiologic mechanism by which IPD, SPTB, and stillbirth occur is not well understood. However, there is strong evidence suggesting that genetic and environmental factors may contribute to the etiologic mechanism of the disease.
Although SGA babies can be classified as either constitutionally or pathologically small, intrauterine growth restriction is thought to result from compromised placental vascular development, suboptimal uterine blood flow, and impaired oxygen and nutrient transfer to the fetus that are necessary to meet the growing fetal demand.
Given the patterns of IPDs, stillbirth, SPTB, and early neonatal mortality observed in this study, and previously reported clinically undiagnosed vasculopathy, infection, and inflammation or the presence of these 3 factors, we speculate that these conditions may be mediated, perhaps, through a common or shared etiology, including vasculopathy, uteroplacental underperfusion, chronic hypoxia, and placental ischemia.
interpregnancy intervals are associated with increased risk of adverse perinatal outcomes. The current study showed that both shorter and longer interpregnancy intervals are associated with increased risk of IPD and SPTB in subsequent pregnancy. Although the mechanism(s) underlying the association of first-pregnancy stillbirth and a subsequent adverse pregnancy outcome remains speculative, findings of this study suggest that there may be a chronic inflammatory condition that may not have been resolved within the interval. There are a number of other potential explanations of the finding. The maternal depletion hypothesis
suggest a short interpregnancy interval may not ensure sufficient time between subsequent pregnancies for the mother to recover from the nutritional burden and maternal stress attributable to the pregnancy loss. Hence, the uterine lining may not support a pregnancy conceived within the first 2 years. Additionally, there may be a selective fertility whereby couples will try to replace a lost child within a short period after miscarriage.
Our results demonstrating the association between shorter and longer interpregnancy intervals and adverse perinatal outcomes are comparable to previous studies.
Future studies examining outcomes of successive pregnancies need to take into consideration the interpregnancy intervals and their association with IPD and SPTB.
The interpretation of these findings must take into account both the limitations and the strengths of the study methodology. The coding of behavioral risk factors such as smoking and alcohol use during pregnancy on birth certificates and in the perinatal database may not always be reliable and these behaviors may be underreported. Second, a strong association between maternal overweight status or obesity and stillbirth has previously been reported
but we cannot take maternal obesity into consideration in this study given the lack of information on prepregnancy weight or weight gain during pregnancy. Because female infants are smaller than male infants and black infants are smaller than white and Hispanic infants at the same gestational age, the growth curve for diagnosis of intrauterine growth abnormalities that does not account for differences by sex and race/ethnicity may lead to inaccurate diagnosis of infants as small.
To improve the distinction between constitutional and pathological smallness for gestational age, we calculated sex- and race-/ethnicity-specific birth weight-for-gestational age cutoffs (internal standard) using data on the first 2 successive singleton deliveries in all of our hospitals between 1991-2008. The strength of the current study include a large sample of women from diverse racial and ethnic backgrounds, the ability to adjust for potential confounding factors, and our ability to limit the analysis to primiparous women and examine the outcomes for their first and second pregnancies.
In conclusion, findings of this study suggest that a first-pregnancy stillbirth may increase adverse pregnancy and early neonatal outcomes in subsequent pregnancy.
Acknowledgment
The authors thank Vicki Chiu, MS, senior consulting data analyst, for her technical support.
References
Kalter H.
Five-decade international trends in the relation of perinatal mortality and congenital malformations: stillbirth and neonatal death compared.
This study was supported by Kaiser Permanente Direct Community Benefit funds.
Cite this article as: Getahun D, Lawrence JM, Fassett MJ, et al. The association between stillbirth in the first pregnancy and subsequent adverse perinatal outcomes. Am J Obstet Gynecol 2009;201:378.e1-6.
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