The outcome of the first pregnancy was grouped into five categories based on premature birth and fetal growth restriction to further explore their association with stillbirth (Table 3). Although numbers of stillbirths in the second pregnancy were small, significant risks were observed for previous SGA term births (HR 1.66, 95% CI 1.01–2.74) and the risk increased if the SGA neonate was also premature (HR 5.65, 95% CI 1.76–18.12). The risk of subsequent stillbirth for women who previously delivered a liveborn SGA neonate at less than 37 weeks of gestation was greater than the risk conferred by previous stillbirth. For women aged 30–34 years (median age group) without any of the risk factors listed in Table 2, the estimated absolute risk of stillbirth at 40 weeks of gestation or before for the second pregnancy was 2.39 per 1,000. Absolute risks of stillbirth in the second pregnancy related to first pregnancy outcomes were: 4.84 per 1,000 among women whose first pregnancy was a stillbirth; 4.17 per 1,000 among women whose first pregnancy was preterm but not SGA; and 4.12 per 1,000 among women whose first pregnancy was SGA but not preterm. The highest risk was 7.19 per 1,000 among women whose first pregnancy was both preterm and SGA.
Perinatal Society of Australia and New Zealand Classification of cause of death was available for 85% of the first pregnancy stillbirths and 81% of the second pregnancy stillbirths (Table 4); the remaining 15% and 19% could not be classified based on incomplete or not forwarded confidential reports. Placental histopathology was performed in 90% of the classified initial stillbirths (560/624) and postmortem examination in 51% (317/624). There remained substantial numbers of stillbirths classified as unexplained despite these two investigations: 49% of the placental examinations (273 of 560) and 52% of the postmortems (166 of 317). The risk of stillbirth in the second pregnancy did not differ based on whether the first stillbirth was explained or not; however it must be noted that there were only three second pregnancy stillbirths to women whose first fetus was stillborn. The adjusted risk for previous explained stillbirth was HR 1.82 (95% CI 0.24–13.75) compared with previous unexplained stillbirth (HR 3.11, 95% CI 0.72–13.50).
This is a large population-based study from Australia examining stillbirth recurrence in consecutive pregnancies. Although absolute risks of stillbirth are approximately doubled in a subsequent pregnancy, the finding is not statistically significant after adjusting for current pregnancy characteristics and previous pregnancy outcome. It confirms the findings of prior research that previous pregnancy outcomes of SGA and preterm birth are particularly important when counseling regarding subsequent risks of stillbirth and, in this cohort, conferred greater risk than a previous stillbirth alone.
The strengths of this study include the large record-linked population-based data set and the ability to assess consecutive pregnancies. New South Wales is representative of national data comprising one third of the country's births and is generalizable to other high-income countries. There were few missing data (1.8%) and the data collection has previously been validated.29 The only other published population-based Australian study to assess recurrence risk for stillbirth was published in 2001 and was likely underpowered.24 The standardized Perinatal Society of Australia and New Zealand Perinatal Death Classification System has been used routinely in New South Wales since 2002 and access to these classifications has enabled this analysis to have some significant advantages. The first is the ability to exclude deaths as a result of congenital abnormality from a recurrence risk analysis. This exclusion is important because 1) many of the diagnosed abnormalities may result in a termination of pregnancy beyond 20 weeks of gestation; 2) genetic abnormalities may have high recurrence risks; and 3) many abnormalities are associated with both prematurity and growth restriction. All of these issues could lead to an overestimate of recurrence risk of stillbirth when these deaths remain in the data set. The second advantage is the ability to assess future risk of stillbirth based on the initial cause of death. We did not find any difference in subsequent risk based on whether the initial stillbirth was explained or not; however, there were only three second pregnancy stillbirths for women in whom the first fetus was stillborn, so a definitive answer to this question remains unanswered. There was also a high proportion of unexplained deaths in the first pregnancy. The contribution of unexplained deaths in studies of stillbirth is variable ranging from 10% to 70%38 – 40 and depends on the classification system used.41 Recent classification systems that are focused toward particular underlying causes or risks for stillbirth such as placental pathologies or growth restriction yield low proportions of unexplained deaths.39,42 Earlier classification systems (eg, the extended Wigglesworth or modified Aberdeen classifications) were usually applied after minimal investigation of perinatal deaths and resulted in high proportions of deaths classed as unexplained.43 – 45 The Perinatal Society of Australia & New Zealand Perinatal Death Classification definition of unexplained antepartum deaths is “deaths of normally formed fetuses before the onset of labor where no predisposing factors are considered likely to have caused the death.”32 Unlike unexplained sudden infant death syndrome, this definition does not require autopsy findings or a mandated set of investigations. The proportion of stillbirths classified as unexplained is lower in studies with an extensive set of investigations and higher autopsy rates.38,46 New South Wales has a low autopsy rate for stillbirths with the most recent report stating that an autopsy was performed in only 30.8% of unexplained antepartum deaths.28 Although the majority of the stillbirths in this cohort had placental pathology performed (90%), only half (51%) had a postmortem. We are unable to assess the extent of other recommended investigations for stillbirth because those data are not routinely collected on a population basis. It is likely, however, that many of the unexplained deaths in this cohort were underinvestigated. The Perinatal Society of Australia & New Zealand Perinatal Death Classification forms are part of a clinical practice guideline on Perinatal Mortality published in 2005.32 Although there has been national consensus to use the classification system, the guideline also recommends a set of core investigations for stillbirth; however, uptake of the full guideline is variable.47 When the recommended investigations are performed in a tertiary hospital setting, the proportion of deaths classified as unexplained using Perinatal Society of Australia & New Zealand Perinatal Death Classification has been shown to decrease from 34% to 13%.48 Because our cohort only extends until 2006, it is likely that uptake of all aspects of the guideline at the time of the data collection was inadequate.
There are inherent limitations in using population-based data. Analysis is limited to what routine variables are collected and we have not been able to assess the effect of maternal obesity because prepregnancy weight or body mass index are not routinely collected in these population-based data sets. It is of note, however, that the most recently published population-based study that assessed subsequent stillbirth and previous infant mortality showed no increase in stillbirth risk with maternal prepregnancy obesity (HR 1.05, 95% CI 0.9–1.20).16 We also were unable to assess the effect of interpregnancy interval because the deidentification of the data set did not include date of birth. We used a definition of SGA as a birth weight less than the 10th percentile using Australian population-based birth weight percentiles rather than customized percentiles because data on maternal weight and height are unavailable. This definition will not identify all neonates who have failed to reach their growth potential and will include both pathologically and constitutionally small neonates; however, it would be consistent with definitions used in other population-based data. We were only able to use time of delivery, not estimated time of death, which could also affect classification of neonates as SGA. A further limitation is that this cohort only comprises 5 years of data and therefore there are relatively small numbers of stillbirths seen for second pregnancies. A priori, we aimed to perform this analysis with the ability to analyze stillbirths classified using the Perinatal Society of Australia & New Zealand classification system and therefore could only start the analysis from 2002 onward when it was in routine use throughout the state. The precision of the recurrence risk estimates of stillbirth in second pregnancies are likely to be affected by the small numbers as indicated by the wide CIs. A database of over a million births would be required to provide a more definitive answer. There are potential benefits of analyzing recent data, which is more representative of current obstetric practice. It is possible that smaller recurrence risks than previously reported are being seen because these women are already being managed differently in a subsequent pregnancy. Findings within our data suggest that this might be the case because although the proportions of women diagnosed with gestational diabetes and preeclampsia are greater in the subsequent pregnancy, these factors are then not associated with the subsequent second pregnancy stillbirth risk. It is also known that many women with a previous stillbirth will be electively induced or delivered in a subsequent pregnancy potentially reducing second pregnancy risks.49
The finding of greater risk of subsequent stillbirth with a previous SGA neonate adds to the increasing literature that supports common underlying mechanisms for stillbirth related to placental dysfunction.20,23,50 Mandating placental examination for every stillbirth and improving adequate investigations of stillbirth will enable population-based data to play a greater role in assisting with further research into potential underlying mechanisms but many of these research questions will need to be answered in a basic science setting. The finding that previous preterm birth increases the association with subsequent stillbirth in the SGA neonates and conveys stronger risks at less than 32 weeks of gestation supports other literature that suggests recurrence of stillbirth occurs within the same “gestational age window.”9,20 Our data suggest that in the absence of growth restriction and preterm, birth women are at low risk of a subsequent stillbirth.
In summary, we found that the delivery of an SGA neonate in a first pregnancy increases the risk of stillbirth in a second pregnancy, especially if the SGA neonate was also premature. These previous pregnancy outcomes conferred greater risk than previous stillbirth. Although absolute risks remain small, all these factors merit improved surveillance and counseling in a subsequent pregnancy. Future population-based studies on stillbirth should include standardized cause of death classifications to assess future risks based on previous cause and also need to address how women are managed in subsequent pregnancies and whether different strategies affect outcome.
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