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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Royal Victoria Hospital and the Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada; and the Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Address reprint requests to: Robert H. Usher, MD Royal Victoria Hospital 687 Pine Avenue West Montreal, Quebec H3A 1A1 Canada E-mail: rusher{at}is.rvh.mcgill.ca
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Methods: We conducted a hospital-based cohort study of 84,294 births weighing 500 g or more from 1961–1974 and 1978–1996. Unexplained fetal deaths were defined as fetal deaths occurring before labor without evidence of significant fetal, maternal, or placental pathology.
Results: One hundred ninety-six unexplained antepartum fetal deaths accounted for 27.2% of 721 total fetal deaths. Two thirds of the unexplained fetal deaths occurred after 35 weeks’ gestation. The following factors were independently associated with unexplained fetal death: maternal prepregnancy weight greater than 68 kg (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI] 1.85, 4.68), birth weight ratio (defined as ratio of birth weight to mean weight for gestational age) between 0.75 and 0.85 (OR 2.77; 95% CI 1.48, 5.18) or over 1.15 (OR 2.36; 95% CI 1.26, 4.44), fewer than four antenatal visits in women whose fetuses died at 37 weeks or later (OR 2.21; 95% CI 1.08, 4.52), primiparity (OR 1.74; 95% CI 1.26, 2.40), parity of three or more (OR 2.01; 95% CI 1.26, 3.20), low socioeconomic status (OR 1.59; 95% CI 1.14, 2.22), cord loops (OR 1.75; 95% CI 1.04, 2.97) and, for the 1978–1996 period only, maternal age 40 years or more (OR 3.69; 95% CI 1.28, 10.58). Trimester of first antenatal visit, low maternal weight, postdate pregnancy, fetal-to-placental weight ratio, fetal sex, previous fetal death, previous abortion, cigarette smoking, and alcohol use were not significantly associated with unexplained fetal death.
Conclusion: In this study, we identified several factors associated with an increased risk of unexplained fetal death.
Many fetal deaths can be attributed to maternal disorders, such as diabetes or hypertensive disease; to fetal pathology, such as congenital anomalies or severe fetal growth restriction (FGR); to placental pathology, such as abruptio placentae; or to complications of labor or delivery. Yet many antepartum fetal deaths remain unexplained. These deaths have been difficult to prevent because determinants of unexplained fetal death have not been identified. The proportion of all fetal deaths that are unexplained has remained fairly constant over the decades.1 The objective of this study was to assess the relationship between maternal, fetal, and pregnancy characteristics and unexplained antepartum fetal death.
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All fetal deaths are reviewed at a departmental meeting of the entire obstetric staff as well as the pathologist, and the primary cause of fetal death was assigned by one of the authors (RHU) employing a standard system of classification of primary cause of death used throughout the entire period. This classification includes potentially lethal anomalies, infection, severe FGR (25% or more underweight or beneath the 2.4th percentile for gestational age based on sex-specific Royal Victoria Hospital growth curves), isoimmunization, abruptio placentae, intrapartum asphyxia, maternal hypertension, maternal diabetes, and other causes including prolapsed cord, placenta previa, nonimmune hydrops, twin-to-twin transfusion, vasa previa, maternal disease (eg, lupus, hyperthyroidism), and trauma demonstrated at autopsy or evidence of fetal-maternal transfusion. There was a 97% fetal and placental autopsy rate with complete gross and microscopic examination. All cases were included, including those without an autopsy.
Unexplained fetal deaths were defined as deaths occurring before labor with no evident fetal, maternal, or placental abnormality sufficient to be considered the cause of death. Fetal deaths associated with maternal complications (ie, hypertension, diabetes), fetal abnormalities (ie, major congenital anomalies, severe growth restriction), placental pathology (ie, abruption, placenta previa, or fetal-maternal hemorrhage), intrapartum asphyxia (asphyxia related to labor and delivery), infection, or other identifiable likely cause were classified under specific causes of fetal death. Maternal disease was excluded initially by clinical judgement and in later years by multiple tests after a fetal death that looked for occult disease such as lupus. Cord loops, including single and multiple nuchal cord loops, or cord knots, which were present in a large proportion (21%) of births, were not accepted as primary cause of otherwise unexplained fetal death, but were analyzed as potential determinants in this study.
Information about maternal, fetal, neonatal, and placental factors, including all diagnoses assigned for mother or fetus, was entered prospectively into a computerized database at time of discharge. Fetal death rates were calculated for 19 factors selected by the authors for possible importance in the current study. For factors with statistically significant associations with fetal death, a multiple logistical regression analysis was done controlling for all other significantly associated factors. To assess the strength of association of each factor with unexplained fetal death, etiologic fractions were calculated using prevalence of exposure and relative risk.
Classification of birth weight for gestational age was by the birth weight ratio, ie, the ratio of the actual birth weight to the mean birth weight for that gestational age, according to sex-specific growth curves developed at this hospital on the basis of ultrasound-confirmed menstrual dating. Although severe growth restriction (ratio less than 0.75) was considered as a primary cause of death and excluded from consideration in this study, milder growth restriction (0.75 to 0.85, equivalent to the 2.4 to 10.4 percentiles) was analyzed for a possible role in unexplained fetal death, as was excessive fetal growth (ratio greater than 1.15, ie, the 87th percentile).
Gestational age was calculated from menstrual history or from early ultrasound results (which were usually available) if they differed from the menstrual estimate by more than 7 days. The gestational age assigned was that at the time of fetal death, rather than at the time of delivery (if these differed). Timing of fetal death was estimated by last fetal movements. The fetal death rate was calculated for each 2-week gestational period, using as the denominator all fetuses surviving in utero at the start of that period. The incidence of unexplained fetal death at each gestational age was calculated per 1000 fetuses at risk. Postdate pregnancies were defined as those that progressed at least 1 week beyond the expected date of delivery (41 completed weeks).
Socioeconomic status was defined as public compared with private hospital service for the early period (1961–1974) or, when this distinction no longer existed with the introduction of universal medical care coverage, as maternal schooling less than 13 years (recorded only for the 1978–1996 period).
Adequacy of prenatal care was assessed by trimester of first antenatal visit and by total number of antenatal visits. Because women who had a fetal death that occurred earlier in gestation are expected to have fewer antenatal visits, this variable was analyzed after restriction to births after 37 weeks’ gestation.
The role of previous fetal death was analyzed by multiple logistic regression by creating a composite variable that included both parity and (for parous women only) a positive or negative history of previous fetal death.
Bivariate statistical analyses were done using 
2 tests for categoric independent variables (potential determinants). Multiple logistic regression analyses were used to assess the independent contributions of the determinants. For prepregnancy weight, schooling, and prepregnancy body mass index (BMI), there were many cases with missing values. For these variables, the following sensitivity analyses were done to assess the effects of missing values on the results: we assessed the confounding effects of these variables by comparing the results before and after variable-wise deletion and evaluated the potential for selection bias by comparing results before and after eliminating all subjects with missing values (case-wise deletion). All analyses were done with SAS-PC software (SAS Institute, Cary, NC).
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).
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). In 1978–1996, the risk of unexplained fetal death occurring per week of gestation increased from one in 21,052 between 29 and 32 weeks to one in 4080 at 39 and 40 weeks to one in 2564 pregnancies at 41 and 42 weeks. The increased risk postdate did not achieve statistical significance, however, and only 8.1% of unexplained fetal deaths occurred 7 days or more postdate. After 1978, all infants at this institution were delivered before 43 weeks. To ensure that this lack of association with postdate pregnancy was not caused by the removal of severely growth restricted infants (less than 0.75) from consideration, the risk of unexplained fetal death was recalculated including infants of all birth weights. The difference in risk at 39–40 weeks (0.51 per 1000) and 41 weeks or later (0.93 per 1000) was not significant; only 7% of all unexplained fetal deaths occurred postterm.
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). Some data were available for one period only or had different definitions in the two periods. In both study periods, there was an increased incidence of unexplained fetal death in nulliparas and in multiparas with three or more previous births, women of low socioeconomic status, those with a prepregnancy weight over 68 kg, and (among births at or after 37 weeks) those with fewer than four antenatal visits. Maternal age 40 years or older was significantly associated with unexplained fetal death in the latter period. A birth weight ratio between 0.75 (2.4th percentile) and 0.85 (10.4th percentile) or over 1.15 (87.0th percentile) and the presence of one or more cord loops were also associated with an increased risk (data on birth weight ratio and cord loops were available only for 1978–1996).
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We attempted to control for the mutually confounding effects of the many risk factors by entering factors that had a significant association with unexplained fetal death into a multivariate logistic regression analysis (Table 3). The models shown in Table 3 include a term for missing values for schooling and prepregnancy weight. From the sensitivity analyses, variable-wise deletion showed negligible confounding of the effects of other risk factors. Deletion of cases with missing variables severely restricted the number of cases for study, leading to an unstable model with wide confidence intervals, although the direction of effects remained the same. Therefore, the results are based on the model controlling for those risk factors with a separate category representing the unknown values.
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To ascertain whether the traditional concern about older nulliparous mothers was valid, a separate interaction analysis was done for that group of women. A significant association (odds ratio [OR] greater than 3.3, 95% CI 1.72, 6.31) was found.
To examine the effect of antenatal visits, a separate logistic regression analysis was done after restricting gestational age to 37 weeks or more, which included 103 unexplained antepartum fetal deaths. An increased risk of unexplained fetal death in women who had fewer than four antenatal visits was apparent in the combined data. However, trimester of onset of antenatal care was not related to unexplained fetal death rate.
Table 4 shows the etiologic fractions for the factors that had a statistically significant association with unexplained fetal death. Primiparity had the highest etiologic fraction (24%). The next most important determinant was excessive prepregnancy weight, followed by low socioeconomic status, cord loops, birth weight ratio over 1.15 and between 0.75 and 0.85, whereas multiparity of three or more and fewer than four antenatal visits were relatively minor determinants.
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Discussion |
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Yudkin et al3 reported an institutional analysis of 63 unexplained stillbirths among 40,635 consecutive deliveries in 1978–1985, which represented 43% of all fetal deaths. In that study, growth-restricted fetuses included among the unexplained stillbirths accounted for 40% of the unexplained fetal deaths. If those fetuses were excluded, the rate of unexplained deaths would have been 26%. They found the risk of an unexplained stillbirth gradually increased until term, and was fourfold higher after 41 weeks. Similar findings of increased risk with gestational age are reported for all stillbirths in a large Swedish population study.6 In our study, the findings were similar until 40 weeks. Factitious postdate pregnancies were eliminated in our study by use of early ultrasound confirmation of menstrual dating.7 Routine fetal surveillance after the due date was not done at our hospital until the past few years and could not have had a significant effect in reducing risk after the due date.
An Australian study reported a high rate (59%) of stillbirths that were unexplained, due to inclusion of fetuses with growth restriction, hypertensive and diabetic mothers, no autopsy in 30%, and the use of death certificates to assign cause of death.4
In the present study we found eight factors that had statistically significant associations with unexplained fetal death, including high prepregnancy weight (over 68 kg), mild growth restriction (birth weight ratio of 0.75–0.85), large size for gestational age (birth weight ratio over 1.15), few antenatal visits (less than four), primiparity, multiparity (three or more), low socioeconomic status, and cord loops. The factor most strongly associated with unexplained fetal death was excessive prepregnancy weight. Several studies8–10 have reported that to be associated with increased risk of overall perinatal mortality, but they did not relate it to unexplained fetal death. In our study, this association was found even after controlling for maternal age and excluding maternal diabetes and hypertensive disease. Although we did not find a significant association with maternal prepregnancy BMI, our OR of 2.30 (95% CI 0.66, 7.97) was similar to the OR of 2.6 (95% CI 1.7, 3.8) reported recently in a larger Swedish study of stillbirth risk by maternal body mass.11
The finding of an association between high birth weight ratio (greater than 1.15 or 87th percentile) and unexplained fetal death was unexpected because excessive prepregnancy weight was controlled for and maternal diabetes (diagnosed by standard glucose challenge testing) and fetal hydrops were excluded.
A significant association was observed for women who had fewer than four antenatal visits among fetuses delivered at 37 weeks or later. This latter finding might reflect the woman’s lesser personal responsibility for health care, because it persisted even after controlling for socioeconomic status and occurred in a setting of universal health insurance, where office visits and hospital care are provided without cost to the patient.
Women of low socioeconomic status, whether defined by public service status or schooling less than 13 years, had an increased risk for unexplained fetal death. This was true even after controlling for factors such as prepregnancy weight, smoking, and other factors associated with low socioeconomic status.
Studies of perinatal mortality have reported an increased rate of fetal death among nulliparas and grand-multiparas.6,12,13 In our study, nulliparous and multiparous women with three or more previous births had an increased risk of unexplained fetal death, even after controlling for deleterious factors associated with nulliparity (ie, preeclampsia) and multiparity (ie, diabetes, essential hypertension).
Several investigators reported an increase in fetal deaths among older women and had different interpretations of the role of medical complications of pregnancy.6,12–17 In our study, most of the effect we observed in the bivariate analysis diminished after controlling for parity, prepregnancy weight, socioeconomic status, and antenatal visits in the multivariate analysis, although in the latter period women 40 years old or older were still at significantly higher risk. When nulliparity was considered separately, women over 35 years old were at increased risk during the entire study period.
The association of cord loops with otherwise unexplained fetal death, which barely achieved statistical significance (OR 1.75, CI 1.04, 2.97), was no longer significant when preterm infants with their lower incidence of cord loops and fetal death were excluded. We assumed that fetal death occurring in association with cord loops was unexplained rather than caused by the cord loop.
Smoking, alcohol use, suboptimal antenatal care as defined by trimester of the first antenatal visit, fetal sex, previous abortion, rate of weight gain, and placenta to birth weight ratio were not significantly associated with unexplained fetal death. In the study by Raymond et al,6 the increased risk of fetal death associated with smoking was attributed entirely to the combination of FGR and antepartum bleeding disorders.
The lack of association found with alcohol consumption and illicit drug use should be interpreted with caution because of missing data and probable underreporting. The data regarding BMI, schooling, and prepregnancy weight should also be interpreted with caution because of the large number of missing values. Although there was no increased risk associated with previous fetal death, any inherent risk associated with a history of previous fetal death was probably nullified by the increased surveillance that those women would have received.
Certain specific causes of fetal death could, however, have been incompletely diagnosed, leading to their inclusion as unexplained in this cohort. Although maternal disease was excluded, it was done so using clinical judgment in the initial period. Therefore it is possible that undiagnosed mild lupus, antiphospholipid antibody syndrome, or fetal-to-maternal bleeding affected the outcomes. Only in later years was routine blood glucose testing and more extensive testing, such as Kleihauer-Betke test, done after fetal death.
We found that the rate of unexplained fetal death rigorously defined has declined, at least in our institution, during the past four decades concomitant with the decline in the overall rate of fetal death. The contribution to this reduction of general improvement in population health compared with improvement in health care during pregnancy is not definable. The association of several factors that we identified in this study with unexplained antepartum fetal death should form the basis for further studies to determine the potential benefit of increased fetal surveillance in such pregnancies and the costs associated with such an intervention.
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Footnotes |
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Received March 22, 1999. Received in revised form July 13, 1999. Accepted July 22, 1999.
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2. Smith LP, deLeon A, Funnell WRJ, Lalonde AB, McLean FH, Usher RH. A research-oriented system for McGill Obstetrical and Neonatal Data (MOND). Acta Obstet Gynecol Scand 1982;109 Suppl: 49–50.
3. Yudkin PL, Wood L, Redman CWG. The risk of unexplained stillbirth at different gestational ages. Lancet 1987;1:1192–4.[Medline]
4. Alessandri LM, Stanley FJ, Gardner BG, Newnham J, Walters BNJ. A case control study of unexplained antepartum stillbirths. Br J Obstet Gynaecol 1992;99:711–8.[Medline]
5. Alessandri LM, Stanley FJ, Newnham J, Walters BN. The epidemiological characteristics of unexplained antepartum stillbirths. Early Hum Dev 1992;30:147–61.[Medline]
6. Raymond EG, Cnattingius S, Kiely JL. Effects of maternal age, parity, and smoking on the risk of stillbirth. Br J Obstet Gynaecol 1994;101:301–6.[Medline]
7. Kramer MS, McLean FH, Boyd ME, Usher RH. The validity of gestational age estimation by menstrual dating in term, preterm, postterm gestations. JAMA 1988;260:3306–8.[Abstract]
8. Johnson JWC, Longmate JA, Frentzen B. Excessive maternal weight and pregnancy outcome. Am J Obstet Gynecol 1992;167: 353–72.[Medline]
9. Naeye RL. Maternal body weight and pregnancy outcome. Am J Clin Nutr 1990;52:273–9.
10. Wolfe HM, Zador IE, Gross TL, Martier SS, Sokul RJ. The clinical utility of maternal body mass index in pregnancy. Am J Obstet Gynecol 1991;164:1306–10.[Medline]
11. Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Pregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338:147–52.
12. Kiely JL, Paneth N, Susser M. An assessment of the effects of maternal age and parity in different components of perinatal mortality. Am J Epidemiol 1986;123:444–54.
13. Fretts RC, Schmittdiel J, McLean FH, Usher RH, Goldman MB. Increased maternal age and the risk of fetal death. N Engl J Med 1995;333:953–7.
14. Forman MR, Meirik O, Berendes HW. Delayed childbearing in Sweden. JAMA 1984;262:3135–9.
15. Hansen JP. Older maternal age and pregnancy outcome: A review of the literature. Obstet Gynecol Surv 1986;41:726–42.[Medline]
16. Kane SH. Advancing age and the primigravida. Obstet Gynecol 1967;29:409–14.
17. Fretts RC, Usher RH. Causes of fetal death in women of advanced maternal age. Obstet Gynecol 1997;89:40–5.[Abstract]
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