Incidence of AFE
This analysis demonstrates differences in the reported incidence of AFE in high-resource countries; the reported incidences vary according to the study methodology. Incidence estimates generated from analysis of population databases without additional criteria to exclude false positive cases produce more than double the estimates generated from analyses using specific validated case identification; an estimate from a population database analysis with additional criteria to exclude false positive cases was compatible with the estimates from the validated case identification studies. Comparison of the AFE incidence using a population database with and without criteria to exclude false positive cases also found this pattern, with the estimated incidence from the unselected population database double that when the additional criteria were used. This suggests that the noted European-North American differences in incidence  are also likely to be explained by the differences in methodology used, and may not represent a true difference in incidence between the countries.
It is difficult to determine which of these estimates is likely to represent a value closest to the "true" incidence of AFE. The apparently lower case fatality amongst cases identified through database studies supports the argument that these studies include a number of false positive cases. The observed association with conditions which may form part of the differential diagnosis of amniotic fluid embolism, for example eclampsia, also supports this hypothesis. Conversely, the higher case fatality observed in studies with case validation may simply indicate that these studies identify more severe cases. Database studies without case validation may thus have high sensitivity but conversely low positive predictive value due to the inclusion of a number of false positive cases, whereas studies with case validation may have lower sensitivity, due to lower case ascertainment and false negative cases, but higher positive predictive value. Perhaps the gold standard would be a database study with subsequent case validation through examination of the medical records. Such an approach, however, in the context of a rare condition such as AFE is difficult due to the large number of individual centres at which medical records would need to be accessed. All studies are complicated by the additional fact that AFE is a diagnosis of exclusion; internationally accepted diagnostic criteria for non-fatal cases do not exist, and there is a place for development of such criteria, using as a model, for example, the criteria used within the UK . Differences in the case definitions used are likely to add to the observed variation in incidence estimates.
Thus the optimal approach to investigating AFE may be dependent on the purpose of the study, since each of the practical approaches has both advantages and disadvantages. Population-based database studies, where suitable sources of information exist, are likely to be the most economical option for studying the condition; however, there is likely to be a degree of inclusion of false positive cases, over-estimation of incidence and thus non-uniformity of the cases examined. The use of additional criteria to exclude false positive cases within database studies, the approach taken in New South Wales , may overcome some of these issues. However, without review of the medical records, this approach may exclude true cases that have been poorly coded. Database studies are also limited by a restricted number of available data items; according to the purpose of the original data collection, extremely limited information on management is available, and temporality of events, for example in relation to whether the AFE occurred before or after birth, cannot be studied. For the purposes of examining risk factors and management in detail, studies with specific prospective data collection methods may therefore be the best approach. Such studies are facilitated by available collaborations designed specifically to study rare pregnancy disorders, such as the approach taken by UKOSS , the Australasian Maternity Outcomes Surveillance System (AMOSS) and other members of the International Network of Obstetric Survey Systems (INOSS) .
Recommendation 1: Comparisons of AFE incidence estimates should be restricted to studies using similar methodology. Depending on the available resources and research questions, the recommended approaches would be either population-based database studies using additional criteria to exclude false positive cases, or tailored data collection using existing population-based systems specifically designed to facilitate study of rare pregnancy conditions.
Recommendation 2: Comparisons of AFE incidence between and within countries would be facilitated by development of an agreed case definition, particularly for non-fatal cases, and an agreed set of criteria to minimise inclusion of false positive cases for studies conducted using population-based databases.
We identified very little consistency among countries in the factors associated with occurrence of AFE and no factors consistently associated with fatality from AFE. Maternal age appeared to be associated with the occurrence of AFE in all populations examined, and this may therefore represent a true association, although the mechanisms by which older maternal age predisposes to AFE remain hypothetical and may include disruption of the uterine vasculature or minor degrees of abnormal placental invasion. The available information on placental abnormalities suggests that placenta praevia and placental abruption substantially increase (3-10 times) the risk of AFE. Given the differing methodologies and therefore differing biases due to potential inclusion of false positive cases or selection of more severe cases, other reported associations are very difficult to interpret. One of the most widely reported associations, with induction of labour, was noted to be statistically significant in some studies (UK, Netherlands), with only certain induction methods (Australia, Canada) or the association was not statistically significant, although the estimated odds ratio was compatible with those reported in most other studies (US) . This illustrates the difficulties of comparing data across studies with differing case identification processes and definitions and varying levels of detail about individual risk factors.
With other factors, such as mode of delivery, issues concerning the timing of the event make the data difficult to interpret. The data we examined were often limited, frequently because the timing of the AFE in relation to the delivery was not available, and hence we were unable to identify cases in which a caesarean or operative vaginal delivery was a cause and not a consequence of the AFE. In the studies where timing was available, small numbers of women in certain subgroups, for example the number of cases undergoing operative vaginal delivery, limited statistical power. It is important to note, however, in the context of rising caesarean delivery rates worldwide, that there was a significant association with caesarean delivery in the one country (UK) in which we were able to investigate specifically cases where the AFE occurred after delivery. Analysis of pooled international data, obtained using consistent methodologies with agreed definitions and case validation, would provide more reliable information on these associated factors and hence provide the potential to develop appropriate preventive strategies which would otherwise be limited.
Recommendation 3: Groups conducting detailed population-based studies on AFE should develop an agreed strategy to allow combined analysis of data obtained using consistent methodologies in order to identify potentially modifiable risk factors.
There were no clear differences in maternal mortality ratios due to AFE between countries or by study methodology. Information on other outcomes for women was very limited, although data on cerebral injury  suggest that AFE may have a significant impact in the long term outcomes of survivors, and this requires further investigation. None of the data sets included information on long-term maternal outcome after non-fatal AFE. Data on infant outcomes were only available for sources which can link data on the mother and infant or from studies which collect specific data. Although limited, the available data suggest the perinatal death rate associated with AFE is high (7-38%). Similarly, we were unable to investigate any potential relationship between management and outcomes because of extremely limited data. Further international collaborative studies using specific data collection would allow for more detailed investigation of the outcomes for mother and infant, over both short and longer term, and any relationship with management.
Recommendation 4: Future specific studies on AFE should aim to collect information on management and longer-term outcomes for both mothers and infants in order to guide best practice, counselling and service planning.
Strengths and limitations of this analysis
This analysis used data from five high resource countries, and the results are thus generalizable only to countries with similar resource settings. As discussed above, data on AFE were obtained using different study methodologies, and therefore this limits the comparability of some of the results. AFE is a rare condition, and all studies have limited power to detect true associations as statistically significant. We hope that this may be addressed in the future by further international collaborative studies, an approach that we would advocate for research into all rare conditions in pregnancy.