Stillbirth and neonatal outcomes in South Australia, 1991-2000

Stillbirth and neonatal outcomes in South Australia, 1991-2000 Jodie M. Dodd, FRANZCOG,a Jeffrey S. Robinson, FRANZCOG,a Caroline A. Crowther, FRANZCOG,a and Annabelle Chan, FAS PHMb North Adelaide, Australia OBJECTIVES: The purpose of this study was to determine the effect of maternal factors associated with impaired placental function on stillbirth and neonatal death rates in South Australia. STUDY DESIGN: From 1991 to 2000, the South Australian Pregnancy Outcome Unit’s population database was searched to identify stillbirths and neonatal deaths in women with maternal medical conditions during pregnancy and in twin and singleton pregnancies. RESULTS: Women with hypertension and carbohydrate intolerance and who smoked during pregnancy had an increased risk of stillbirth. Women with twin pregnancies had a significantly higher stillbirth rate than for singletons at each week of gestational age. An increase in stillbirth rate at later gestations was seen with singletons, with a similar trend in twins but rising from 36 weeks’ gestation. CONCLUSION: There is a clinical correlation between maternal factors associated with impaired placental function and increased risk of stillbirth, suggesting that intrauterine fetal death represents the mortality end point in a spectrum of intrauterine hypoxia. (Am J Obstet Gynecol 2003;189:1731-6.) Key words: Stillbirth, perinatal mortality, perinatal morbidity, multiple pregnancy Over the past decade, the stillbirth rates in South Australia have remained relatively constant, at an average of 6.6 per 1000 births.1 In South Australia, a stillbirth is defined as the death of a fetus in utero, with birth weight of at least 400 g, or of at least 20 weeks gestational age. The stillbirth rate is the number of stillbirths per 1000 total births. Yudkin et al2 emphasized that the risk of stillbirth should be calculated using the number of fetuses that remain in utero at each gestational age as the denominator. When calculated in this way, there is a large increase in the risk of stillbirth with advancing gestational age.2-4 In contrast, Cotzias et al5 calculated the total risk of stillbirth from each week of gestation. This is not a clinically useful risk because not all pregnant women will reach 42 weeks’ gestation. Fetal umbilical cord arterial and venous oxygen tension correlate with birth weight.6 Unexplained intrauterine fetal death has been suggested to occur as a result of placental insufficiency and is the mortality end point from a spectrum of degrees of intrauterine hypoxia. It would then be expected that maternal conditions known to be associated with intrauterine hypoxia and placental insufficiency could produce a similar effect on stillbirth but perhaps occur at an earlier gestational age. Similarly, From the Department of Obstetrics and Gynecology, University of Adelaide,a and the Department of Human Services, South Australian Government.b Received for publication Apr 4, 2003; revised May 26, 2003; accepted June 6, 2003. Reprints not available from the authors. Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1016/S0002-9378(03)00854-8 neonatal outcomes indicative of hypoxia would be expected to parallel the trends in stillbirth by gestational-specific age. It is well established that the risks associated with twin pregnancies compared with singleton pregnancies are greater for both women and fetuses. Retrospective studies have identified the lowest perinatal mortality and morbidity rates for twin gestations to occur from 36 weeks’ gestation.7-11 This study was conducted to determine the lowest rates of stillbirth and neonatal death by gestational age for singleton and twin pregnancies in South Australia throughout the period of 1991 to 2000 and the effect of maternal smoking, hypertension, and carbohydrate intolerance during pregnancy on stillbirth rate. For a subset of these women who gave birth at the Women’s and Children’s Hospital, neonatal outcomes suggestive of intrauterine hypoxia were sought by gestational age. Material and methods Information was sought from the South Australian Pregnancy Outcome Unit about the occurrence of stillbirth and neonatal deaths in women with both twin and singleton pregnancies by cause and gestational week, commencing at 20 weeks’ gestational age. Terminations of pregnancy were excluded from the analysis. Information was obtained about the presence or absence of maternal conditions such as hypertension, glucose intolerance, and maternal smoking during pregnancy. A stillbirth was defined as the death of a fetus, before birth, weighing at least 400 g or of at least 20 weeks’ gestational age.1 A live birth was defined as the complete expulsion or extraction from its mother of a product of 1731 1732 Dodd et al conception, irrespective of the duration of pregnancy, after which such separation breathes or shows any other evidence of life, such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles, regardless of whether the umbilical cord has been cut or the placenta is attached.12 A neonatal death was defined as the death of a live-born fetus that occurs within 28 days of birth.1 The South Australian perinatal data collection for 19912000 was used in the analyses in this article. All births were notified under legislation to the Pregnancy Outcome Statistics Unit on the Supplementary Birth Record, completed by midwives for each birth occurring in the state. Additional postmortem information was forwarded by the pathologist where an autopsy had been conducted. Each stillbirth and neonatal death was reviewed by the Perinatal Subcommittee of the Maternal, Perinatal and Infant Mortality Committee to try to determine the cause of death and possible preventable factors. This committee included health professionals involved in perinatal care (for example, obstetrics, midwifery, general practice, neonatology, and pathology). In each year, to ensure as complete as possible a record, missing information was sought by the committee from individuals who managed the pregnancy. A stillbirth rate for both singletons and twins was calculated by dividing the number of singleton or twin stillbirths by the total number of singleton or twin live births occurring at each week of gestational age or later, and multiplying the value by 1000. A stillbirth rate was therefore obtained per 1000 births for each week of gestational age. A neonatal mortality rate for both singletons and twin pregnancies was calculated by dividing the number of singleton or twin neonatal deaths by the total number of singleton or twin live births occurring at that gestation or later and multiplying the value by 1000. A neonatal mortality rate was therefore obtained per 1000 total live births for each week of gestational age. For women who gave birth at the Women’s and Children’s Hospital between 1993 and 2000, information was obtained about the occurrence of meconium-stained liquor and cardiotocograph (CTG) abnormalities in labor by week of gestational age, from the hospital’s clinical information service, where a database was maintained recording birth and neonatal outcomes. Additional outcomes sought were those indicative of intrauterine hypoxia and were obtained for both singletons and twins by week of gestational age at birth. Outcomes included Apgar score of less than 7 at 5 minutes, birth weight less than the third centile for gestational age and infant sex,13 cord pH at birth of less than 7.18 with base excess less than ÿ8, admission to the neonatal intensive care unit (NICU), use of ventilatory assistance, seizures within the first 24 hours of life, use of tube feeding, and an ultrasound diagnosis of hypoxic ischemic encephalopathy.14 These December 2003 Am J Obstet Gynecol adverse outcomes included those considered as important measures of term and postterm neonatal morbidity.15,16 The occurrence of these adverse outcomes were then summed up for each week of gestational age for both singleton and twin infants to generate a composite morbidity and mortality index per 1000 births. By use of categorical modeling and likelihood ratio tests, and assuming that the stillbirth, neonatal mortality, and perinatal mortality rates were derived from a Poisson distribution, rates were compared between singletons and twins to determine any difference in the overall shape of the curve obtained and to detect any upward shift or shift to the left in mortality rates. A value of less than .05 was taken as significant. Results Throughout the period of 1991-2000, there were a total of 191,941 births in South Australia, 5594 of which were to women with twin pregnancies. Over the same period, there were 1088 stillbirths and 585 neonatal deaths, 113 stillbirths and 104 neonatal deaths of which were to women with twin pregnancies. A total of 73.9% of women with a stillbirth consented to a perinatal autopsy. The most common causes of stillbirth at all gestational ages were those categorized as ‘‘unexplained,’’ with a rate of 1.91 per 1000 pregnancies. The contribution of unexplained stillbirths was greater for those occurring after 32 weeks’ gestation (1.23 per 1000 births), in which the effects of spontaneous preterm birth, fetal anomalies, and infection were relatively less. The stillbirth rate for twin pregnancies was found to be significantly higher than for singletons at each week of gestational age (P < .0001). An increase in stillbirth rate at later gestations was seen with singleton pregnancies, rising from 0.79 per 1000 births at 40 weeks’ gestation, to 1.04 per 1000 births at 41 weeks’ gestation, to 3.1 per 1000 births at 42 weeks’ gestation or greater. A similar trend was noted with twin pregnancies but was seen at an earlier gestational age, rising from 30 weeks and further from 36 weeks. The increase in stillbirth rate seen in singleton pregnancies from 40 weeks’ gestation did not occur at a statistically significant earlier gestational age in twin pregnancies (P = .17) (Fig 1). Cause of stillbirth by gestational age differed between singleton and twin pregnancies, with the effect of spontaneous preterm birth being greater and occurring at an earlier gestational age in twins compared with singleton pregnancies. The proportion of unexplained stillbirths overall was greater for singleton pregnancies, although the proportion of unexplained stillbirths among twin pregnancies was greater after 32 weeks’ gestation (Table). Twin pregnancies were found to have significantly higher neonatal mortality rates than singleton infants at all gestational ages of birth (P < .0001). The neonatal mortality rate for twin pregnancies peaked at 25 weeks’ Dodd et al 1733 Volume 189, Number 6 Am J Obstet Gynecol Fig 1. Stillbirth rate (per 1000) in South Australia, 1991-2000. Closed squares, Singletons; closed diamonds, twins. Fig 2. Neonatal mortality rate (per 1000) in South Australia, 1991-2000. Closed squares, Singletons; closed diamonds, twins. Table. Causes of stillbirth (%) by gestational age for singleton and twin pregnancies in South Australia, 1991-2000 Singletons Cause Spontaneous preterm IUGR Unexplained stillbirth Birth trauma Intrapartum asphyxia Hypertension Maternal disease APH Fetal abnormality Hemolytic disease Infection Twin-twin transfusion Other Twins <32 wk >32 wk Total <32 wk >32 wk Total 15.3 5.9 20.0 0 0.1 4.3 3.5 15.5 14.8 0.6 12.5 0 7.4 0.4 8.5 45.8 0.5 5.7 6.5 4.8 12.7 4.6 0.5 3.4 0 6.7 8.7 7.0 31.4 0.2 2.6 5.3 4.1 14.3 10.3 0.5 8.4 0 7.1 47.9 0.9 8.0 0 0 0 0 6.1 3.8 0 8.0 24.9 0.5 1.9 9.6 25.0 0 9.6 5.8 0 3.8 23.1 0 0 21.2 0 38.9 2.6 11.3 0 1.9 1.1 0 5.7 7.5 0 6.4 24.2 0.4 IUGR, Intrauterine growth retardation; APH, antepartum hemorrhage. gestation (3 per 1000 live births) and then decreased to an average of 0.33 per 1000 births at 29-36 weeks, increasing slightly at 37-38 weeks with a further increase with advancing gestational age, reaching a maximum level at 40 weeks’ gestation of 6.49 per 1000 live births, almost 15 times greater than that observed in singletons at the same gestational age. In contrast, singleton pregnancies had a lower neonatal mortality rate at each gestational age of birth, gradually increasing from 0.44 per 1000 live births at 40 weeks’ gestation to 0.76 per 1000 live births at 41 weeks’ gestation, and 1.38 per 1000 live births at 42 weeks’ gestation. The increase in neonatal mortality seen in singleton pregnancies from 40 weeks’ gestation did not occur at a statistically significant earlier gestational age in twin pregnancies (P = .13) (Fig 2). The overall perinatal mortality rate (including stillbirths and neonatal deaths but excluding terminations of pregnancy) for the period 1991-2000 was almost five times greater for twin pregnancies (perinatal mortality rate [PMR] 38.79 per 1000 births) than for singleton pregnancies (PMR 7.75 per 1000 births), with rates significantly higher in twin pregnancies than in singletons for each gestational age (P < .001). The increase in perinatal mortality seen in singleton pregnancies from 37 weeks’ gestation did not occur at a statistically significant earlier gestational age in twin pregnancies (P = .13). The occurrence of stillbirth among women with hypertension during pregnancy was greater than for those women without hypertension (either preexisting or pregnancy related). This effect was greater at all gestational ages after 25 weeks but approached the same level for women without hypertension after 40 weeks’ gestation (Fig 3). A similar trend was noted in women with glucose intolerance during pregnancy, with increased rates of stillbirth after 25 weeks’ gestation compared with women who did not have glucose intolerance, although the risk of stillbirth was six times greater in the presence of glucose intolerance at 41 weeks’ gestation and beyond (Fig 4). Women who smoked during their pregnancy had a greater gestational age–specific risk of stillbirth for all gestational ages, being two to three times greater from 34 weeks’ gestation (Fig 5). Between 1993 and 2000, 25,545 women with singleton pregnancies and 1642 women with twin pregnancies gave birth at the Women’s and Children’s Hospital. The gestational age–specific rise in stillbirths was paralleled by a similar increase in the risk of both meconium-stained liquor and CTG abnormalities in the subset of pregnancies 1734 Dodd et al Fig 3. Stillbirth rate (per 1000) by presence of maternal hypertension in South Australia. Closed diamonds, Normotension; closed squares, hypertension. Fig 4. Stillbirth rate (per 1000) by maternal carbohydrate tolerance in pregnancy, in South Australia, 1986-2000. Closed diamonds, Normal carbohydrate tolerance; closed squares, abnormal carbohydrate tolerance. studied (Fig 6). The risk of meconium-stained liquor increased after 36 weeks and sharply rose at 38 weeks’ gestation. The gestational age–specific risk of CTG abnormalities increased from 38 weeks’ gestation. The composite neonatal morbidity and mortality index was significantly greater at each week of gestational age for twin pregnancies than for singletons. The rate was lowest in twins at 37 weeks’ gestation and then increased. A similar trend was observed in singletons, with the increased risk occurring from 39 to 40 weeks’ gestation (Fig 7). Comment Women with twin pregnancies were shown in this study to have an increased risk of stillbirth, neonatal death, and markers of intrauterine hypoxia. However, as with any retrospective study, there are factors that limit the extent to which data can be extrapolated and generalized to a clinical population. Although the data obtained from the South Australian Pregnancy Outcome Statistics Unit is of high quality,19 there was no provision for data to be collected regarding the chorionicity of twin pregnancies. In addition, data were coded by infant outcome, rather than by the outcome for the pregnancy. Therefore, twin pregnancies in which both fetuses or infants died were December 2003 Am J Obstet Gynecol Fig 5. Stillbirth rate (per 1000) by maternal smoking status in pregnancy in South Australia, 1998-2000. Closed diamonds, Nonsmokers; closed squares, smokers. recorded as two separate mortality events. This clearly has implications because an adverse outcome affecting both infants is not an independent variable in the setting of a twin pregnancy. Although the data set reviewed birth outcomes over a 10-year period, the actual number of mortality events and number of twin pregnancies (217 stillbirths and neonatal deaths of 5594 twin pregnancies) formed a smaller proportion of the overall number of births in the state (191,933 births). This may account for the apparent earlier rise in mortality outcomes in twin pregnancies from 36-38 weeks’ gestation compared with singletons, despite a lack of statistical significance being demonstrated. Women with twin pregnancies were shown in this study to have an increase in stillbirth rate from 30 weeks’ gestation, but particularly from 36 weeks’ gestation, compared with singletons born at the same gestational age. The proportion of unexplained stillbirths in twin pregnancies increased after 32 weeks’ gestation, suggesting that with advancing gestational age the effect of placental insufficiency is greater than the effect of other pathologic conditions more specific to twin pregnancies. The findings of increased risk of stillbirth in women with twin pregnancies from 36 weeks’ gestation is earlier than the findings of other reports, which suggest an increased risk from 38 weeks’ gestation.7-11 Maternal disease states are known to affect placental function and, therefore, have the capacity to influence fetal well-being. Women with hypertension during pregnancy have an increased risk of stillbirth, particularly at earlier gestational ages compared with women who are normotensive. The effect of hypertension during pregnancy on stillbirth rates as term approaches is less dramatic, with the risk being similar to women without hypertension. This may be a reflection of disease severity, with women with severe preeclampsia presenting and giving birth earlier in gestation. It may also be a reflection of a beneficial effect from treatment of hypertension, either with medication or induction of labor as term approaches. The severity of hypertensive disease was not available from the data set because any degree of Dodd et al 1735 Volume 189, Number 6 Am J Obstet Gynecol Fig 6. Presence of meconium-stained liquor and CTG abnormalities in labor at the Women’s and Children’s Hospital, 19932000. Closed diamonds, Meconium-stained liquor; closed squares, CTG abnormality. hypertension falls within the same classification, precluding correlation between stillbirth risk and severity of disease. Similarly, women with carbohydrate intolerance during pregnancy demonstrated an increased risk of stillbirth at almost all gestational ages. This increased risk was most marked from 41 weeks’ gestation and beyond. Again, it was not possible to determine the effect of disease severity on the risk of stillbirth from the data set because women were included with preexisting diabetes, gestational diabetes, and carbohydrate intolerance of pregnancy. Women who smoked during their pregnancy had a greater gestational age–specific risk of stillbirth for almost all gestational ages, at approximately two times greater from 34 weeks’ gestation. Intrauterine exposure to tobacco smoke has been associated with a 2-fold increase in stillbirth risk and infant mortality compared with women who were nonsmokers during pregnancy. Approximately 25% of stillbirths and 20% of infant deaths may be avoidable if women ceased smoking in the first trimester of pregnancy.17 The association between meconium-stained liquor, nonreassuring fetal heart rate tracing during labor, and adverse neonatal outcome has been recognized and used as an indirect indicator of intrauterine hypoxia.18 The occurrence of these events by week of gestational age was found to parallel and precede the gestational age–specific rise in stillbirths. The risk of meconium-stained liquor increased after 36 weeks and CTG abnormalities from 38 weeks’ gestation. These findings suggest a clinical correlation between factors associated with impaired placental function and increased risk of stillbirth and provide support for the hypothesis that intrauterine fetal death represents the mortality end point in a spectrum of intrauterine hypoxia. Further research should be directed toward determining the effect of treatment of maternal disease states during pregnancy (including encouragement to make lifestyle changes, medical therapy, and induction of labor) in reducing both stillbirth rates and adverse neonatal outcomes. Fig 7. Composite neonatal morbidity and mortality index for singleton and twins delivered at the Women’s and Children’s Hospital, 1993-2000. Closed squares, Singletons; closed diamonds, twins. Comment These findings suggest a clinical correlation between maternal factors associated with impaired placental function and increased risk of stillbirth and provide support to the hypothesis that intrauterine fetal death represents the mortality end point in a spectrum of intrauterine hypoxia. Women with twin pregnancies were shown in this study to have an increased risk of stillbirth, neonatal death, and markers of intrauterine hypoxia compared with singletons at the same gestational age. Attention needs to be directed toward prospectively defining the ‘‘term’’ and ‘‘postterm’’ twin pregnancy and assessing the role of elective timing of birth as a method of reducing the perinatal mortality rate seen in twin pregnancies. We thank the South Australian midwives who provided the perinatal data and completed the supplementary birth records, Rosemary Keane, Joan Scott, and Robyn Kennare of the Pregnancy Outcome Unit for their assistance in retrieval of the data used in this paper, Anne Fitzgerald of the Women’s and Children’s Hospital Clinical Information Service for data provision, and Kristyn Willson of the University of Adelaide for statistical advice and assistance. REFERENCES 1. Chan A, Scott J, Nguyen AM, Keane R. Pregnancy outcome in South Australia, 2000, Pregnancy Outcome Unit, Epidemiology Branch: Department of Human Services, Adelaide, 2001. 2. Yudkin PL, Wood L, Redman CWG. Risk of unexplained stillbirth at different gestational ages. Lancet 1987;1:1192-4. 3. Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality. BJOG 1998;105:169-73. 4. Cnattingius S, Taube A. 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