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Keywords:

  • Amniotic fluid embolism;
  • maternal morbidity;
  • maternal mortality;
  • neonatal morbidity;
  • stillbirth

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Please cite this paper as: Kramer M, Rouleau J, Liu S, Bartholomew S, Joseph K for the Maternal Health Study Group of the Canadian Perinatal Surveillance System. Amniotic fluid embolism: incidence, risk factors, and impact on perinatal outcome. BJOG 2012;119:874–879.

Objective  To extend our previous work on AFE in Canada by including stricter criteria for case identification and by examining risks for stillbirth, neonatal mortality and serious maternal and neonatal morbidity.

Design  Population-based cohort study.

Setting  Canada.

Population or sample  In all, 4 508 462 hospital deliveries from fiscal year 1991/92 to 2008/09.

Methods  To reduce false-positive diagnoses, we restricted our analysis to AFE cases with cardiac arrest, shock or severe hypertension, respiratory distress, mechanical ventilation, coma, seizure, or coagulation disorder. Linkage of maternal and neonatal records, available since 2001/02, enabled us to examine the effects of AFE on neonatal outcomes. Detailed demographic and clinical data facilitated control for a broad array of potential confounding variables.

Main outcome measures  Amniotic fluid embolism, in-hospital neonatal death, asphyxia, mechanical ventilation, bacterial sepsis, seizure, nonimmune haemolytic or traumatic jaundice and length of hospital stay.

Results  A total of 292 AFE cases were identified, of which only 120 (40%) were confirmed after applying our additional diagnostic criteria, yielding an AFE incidence of 2.5 per 100 000 deliveries. Of the 120 confirmed cases, 33 (27%) were fatal. Significant modifiable risk factors included medical induction, caesarean delivery, instrumental vaginal delivery, and uterine or cervical trauma. Amniotic fluid embolism was associated with significantly increased risks of stillbirth and neonatal asphyxia, mechanical ventilation, sepsis, seizures and prolonged length of hospital stay.

Conclusions  Amniotic fluid embolism remains a rare but serious obstetric outcome, with several important modifiable risk factors and major implications for maternal, fetal and neonatal health.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Amniotic fluid embolism (AFE) is a rare obstetric occurrence, yet it is one of the leading causes of maternal mortality in developed countries.1–3 In Canada, it was the cause of 13 of 99 direct maternal deaths in 1988–92 and 7 of 44 direct maternal deaths in 1997–2000, ranking third behind cerebrovascular and hypertensive disorders and ahead of postpartum haemorrhage and other pulmonary embolisms as a cause of maternal deaths.4,5

Amniotic fluid embolism may arise from simultaneous tears in the fetal membranes and the uterine vessels, which permit amniotic fluid to enter the uterine vein and hence the maternal pulmonary arterial circulation,6,7 but its pathogenesis remains poorly understood.3 It is characterised by sudden dyspnoea, cardiopulmonary collapse and coagulopathy. The clinical picture resembles anaphylaxis, and evidence has been reported linking anaphylactic-type physiological mediators, including prostaglandins, leukotrienes, histamine and bradykinin. It is presumed, however, that entry of amniotic fluid into the maternal circulation must occur commonly, and the rarity of AFE strongly suggests a genetic component to the disease.

In recent years, several population-based studies have examined its incidence, temporal trends, or risk factors from Canada,8 Australia,9 the UK10 and the USA.11 Differences in incidence and case fatality rate have been attributed largely to methodological differences in the published studies, with no convincing evidence of significant temporal trends, geographic differences, or effective treatments.12 Moreover, although several previous studies have reported associations between AFE and fetal and neonatal death,9,10,13 none has reported on serious neonatal morbidity.

In this study, we have extended our previous population-based study of AFE in Canada, not only to take advantage of more recent data, but also to apply additional criteria in an attempt to reduce false-positive diagnoses. In addition, since 2001/02, we have been able to link maternal hospital records to those of their newborns, which allows us to examine the impact of AFE on neonatal mortality and serious morbidity, in addition to stillbirth and maternal morbidity.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Ours is a population-based cohort study of 4 508 462 hospital deliveries (i.e. the hospitalisation in which delivery occurred) in Canada from fiscal year 1991/92 to 2008/09. These hospital records were collected by the Canadian Institute for Health Information (CIHI) in its Discharge Abstract Database. Quebec does not provide data to CIHI; nor did Manitoba and Nova Scotia in earlier years, so all three provinces were excluded from this study. Ascertainment of cases of AFE was based on International Classification of Disease, ninth revision (ICD-9) code 673.1 for years up to and including 1999/2000 and ICD-10 code O88.1 since 2000/01, with some differences among the Canadian provinces in the time of switching coding from ICD-9 to ICD-10. To improve the sensitivity of case identification, we also included nondelivery postpartum admissions and hospital transfers with a discharge diagnosis of AFE using fifth-digit ICD codes. Procedures were coded according to the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures from 1991 to 2001, and according to the Canadian Classification of Interventions since 2001.

To reduce false-positive diagnoses of AFE, we adapted additional confirmatory criteria published by Roberts et al.9,13 A confirmed case required the presence of at least one of the following conditions or procedures: cardiac arrest, shock or severe hypertension, respiratory distress, mechanical ventilation, coma, seizure or disseminated intravascular coagulation or other coagulation disorder. Autopsy information was not available to confirm the diagnosis of AFE in fatal cases.

Linkage of the files of maternal and neonatal records and data on parity in the Discharge Abstract Database have been available since 2001/02. Based on this linked file, we were able to include the effects of AFE on neonatal death, as well as the following categories of serious neonatal morbidity: asphyxia, mechanical ventilation, bacterial sepsis, seizure, jaundice due to trauma or haemolysis (other than haemolysis due to immune-mediated blood type incompatibility), as well as neonatal length of stay. These categories were chosen because of their known relationship to the hypoxia and hypotension characteristic of AFE. We also examined the mother’s receipt of any of the following treatments and interventions: blood transfusion, plasma transfusion, clotting factor transfusion, exchange transfusion or hysterectomy.

Statistical methods included overall descriptive statistics, highlighting the effect of the confirmatory maternal diagnostic criteria on incidence, the proportion of confirmed cases with each of the criteria, the proportion receiving the above-noted treatments or interventions, and the case fatality rate. We also examined risk factors for AFE using cross-tabulations and logistic regression analyses to estimate crude and adjusted odds ratios (OR) and their 95% confidence intervals (95% CI), as well as associations of AFE with maternal mortality, hysterectomy and prolonged maternal length of hospital stay; stillbirth; and neonatal mortality, severe morbidity and prolonged neonatal length of hospital stay. Covariates adjusted for in the multivariable logistic regression models included maternal age (≤19, 20–34, ≥35 years), elderly primigravidity (defined by CIHI as a first pregnancy with age ≥35 years) on expected day of delivery, grand multiparity (≥6 previous live births), medical and surgical induction of labour, previous caesarean delivery, presentation (cephalic versus noncephalic), placenta praevia or placental abruption, hypertension (none, pre-eclampsia, eclampsia or other [pregestational hypertension or gestational hypertension without proteinuria]), diabetes (gestational or pregestational), fetal macrosomia, fetal growth restriction, postdates, prelabour rupture of membranes, prolonged first stage (≥18 hours for primiparae, ≥12 hours for multiparae) or second stage of labour (≥2 hours for primiparae, ≥1 hour for multiparae, 1 additional hour with receipt of epidural anaesthesia), cervical laceration, uterine rupture, mode of delivery (spontaneous vaginal, instrumental vaginal, caesarean), fetal distress (ICD-9 codes denoting abnormal fetal heart rhythm, fetal acidaemia, meconium staining of amniotic fluid, or cord prolapse), dystocia and year of delivery.

With the linked maternal–infant files available since 2001/02, we repeated the above-mentioned multivariable logistic regression analyses using actual parity (0, 1–2, 3–4, ≥5) instead of ICD-based diagnoses of elderly primigravidity and grand multiparity; gestational age (<32, 32–36, 37–41, ≥42 completed weeks) instead of postdates; and birthweight-for-gestational age z-score (based on a published Canadian population-based reference14) of <−1, −1 to +1, or >+1 instead of fetal macrosomia and fetal growth restriction. All statistical analyses were carried out using SAS version 9.2 (SAS Institute, Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

Of the 4 058 462 total deliveries in the CIHI file, 292 were coded as having experienced AFE based on the ICD-9 or ICD-10 codes. The overall crude incidence including all 292 cases was 6.5 per 100 000 deliveries. Of the 292 total, however, only 120 (40%) had one or more of the required confirmatory maternal conditions, yielding a confirmed (corrected) AFE incidence of 2.5 per 100 000. Of these 120, 113 were noted on the delivery record, and the remaining seven were noted only after postpartum transfer to another hospital. Of the 42 fatal cases, 33 were confirmed, for a confirmed fatal AFE rate of 0.8 per 100 000 and a confirmed case fatality rate of 27%. Table 1 describes the 120 women with confirmed AFE in greater detail, showing the proportion with each of the confirmatory criteria, as well as the number and percent who received each of the treatments and interventions under study, length of maternal hospital stay and hysterectomy rate.

Table 1.   Description of confirmed AFE cases (n = 120)
CharacteristicNumber%
  1. DIC, disseminated intravascular coagulation.

  2. *For the 87 nonfatal cases, the numbers and percentages are 10 (11.5%) for 0–3 days, 36 (41.4%) for 4–7 days, and 41 (47.1%) for ≥8 days.

Confirmatory diagnostic criteria
Cardiac arrest5646.7
Shock or severe hypotension3932.5
Respiratory distress1714.2
Mechanical ventilation2722.5
Coma21.7
Seizure21.7
DIC or other coagulation disorder3630.0
Treatments/interventions
Blood transfusion6856.7
Plasma transfusion5344.2
Clotting factor transfusion3730.8
Exchange transfusion00.0
Hysterectomy2016.7
Length of hospital stay (days)
0–3*3932.5
4–7*3630.0
≥8*4537.5

Table 2 shows the distribution of potential risk factors and covariates, the number and rate of confirmed AFE cases with or without the risk factors, and the crude and adjusted odds ratios and their 95% confidence intervals. Significant associations were found with older maternal age, grand multiparity, multiple birth, polyhydramnios, eclampsia, pre-eclampsia and placenta praevia or placental abruption. A previous caesarean section was not significantly protective against AFE (adjusted OR 0.5; 95% CI 0.3–1.0). Significant labour and delivery factors that increased the risk of AFE included premature rupture of membranes, medical induction, fetal distress, caesarean delivery, instrumental vaginal delivery and cervical laceration or uterine rupture. Noncephalic presentation was protective for AFE (adjusted OR 0.4; 95% CI 0.2–0.9).

Table 2.   Risk factor analysis for confirmed cases of AFE (n = 120)
CharacteristicProportion (%) of study cohortConfirmed cases, n (rate per 100 000)Crude OR (95% CI)Adjusted OR (95% CI)
Maternal age (years)
≤195.52 (0.8)0.4 (0.1–1.5)0.4 (0.1–1.7)
20–3479.078 (2.2)1.0 (reference)1.0 (reference)
≥3515.540 (5.7)2.6 (1.8–3.8)2.3 (1.5–3.4)
Elderly primigravidity 1.02 (4.4)1.7 (0.4–6.8)0.4 (0.1–1.7)
Grand multiparity 0.31 (7.7)2.9 (0.4–20.8)2.5 (0.3–17.9)
Previous caesarean delivery 10.917 (3.5)1.3 (0.8–2.3)0.5 (0.3–1.0)
Hypertension
None95.6106 (2.5)1.0 (reference)1.0 (reference)
Pre-eclampsia3.812 (7.0)2.8 (1.6–5.2)1.7 (0.9–3.2)
Eclampsia0.12 (75.5)30.7 (7.6–124.5)16.3 (4.0–67.2)
Other5.60 (0.0)UndefinedUndefined
Diabetes 1.34 (6.8)2.6 (1.0–7.1)1.4 (0.5–3.9)
Polyhydramnios 0.54 (19.0)7.3 (2.7–19.9)3.8 (1.4–10.5)
Amnionitis 1.12 (4.0)1.5 (0.4–6.2)0.6 (0.2–2.6)
Placenta praevia or abruption 2.120 (21.6)9.5 (5.9–15.4)5.0 (3.0–8.3)
Multiple pregnancy 1.25 (9.3)3.6 (1.5–8.8)2.5 (1.0–6.2)
Fetal macrosomia 2.57 (6.2)2.4 (1.1–5.2)1.6 (0.7–3.5)
Fetal growth restriction 2.32 (1.9)0.7 (0.2–2.9)0.4 (0.1–1.7)
Postdates 9.121 (5.1)2.1 (1.3–3.4)1.8 (1.1–3.1)
Noncephalic presentation 7.410 (3.0)1.1 (0.6–2.2)0.5 (0.3–1.0)
Prelabour rupture of membranes 8.717 (4.4)1.7 (1.0–2.9)1.6 (0.9–2.7)
Induction of labour
Medical16.236 (4.9)2.2 (1.5–3.3)1.9 (1.2–3.0)
Surgical7.66 (1.8)0.6 (0.3–1.5)0.4 (0.2–1.0)
Prolonged labour
Prolonged first stage1.51 (1.4)0.5 (0.1–3.8)0.5 (0.1–3.7)
Prolonged second stage4.85 (2.3)0.9 (0.4–2.1)0.6 (0.2–1.7)
Long labour, unspecified0.30 (0.0)UndefinedUndefined
Fetal distress 16.047 (6.5)3.4 (2.3–4.9)1.5 (1.0–2.3)
Mode of delivery
Spontaneous vaginal64.717 (0.6)1.0 (reference)1.0 (reference)
Instrumental vaginal13.028 (4.8)8.2 (4.5–15.0)7.6 (4.0–14.4)
Caesarean22.475 (7.4)12.8 (7.5–21.6)11.7 (6.4–21.5)
Dystocia 25.047 (4.2)1.9 (1.3–2.8)0.8 (0.5–1.3)
Cervical laceration or uterine rupture 0.26 (56.2)22.2 (9.8–50.5)12.7 (5.5–29.1)

The sensitivity analysis based on the linked maternal and neonatal files confirmed the association of all the above-noted risk factors. With the data available on actual parity in the more recent maternal and linked files, both parity of 3 or 4 (adjusted OR 1.1; 95% CI 1.03–1.1) and 5 or more (adjusted OR 1.1; 95% CI 1.1–1.2) were associated with a significantly increased risk of AFE. In addition, preterm birth (particularly preterm birth <32 weeks, adjusted OR 10.2; 95% CI 9.8–10.6) and low birthweight for gestational age (z-score < −1) (adjusted OR 1.8; 95% CI 1.8–1.8) were also associated with increased risks of AFE.

Table 3 shows the numbers and rates (%) for stillbirth (for the entire file) and for the studied neonatal outcomes associated with AFE, the latter based on the maternal–infant linked file available since 2001/02. No cases of in-hospital neonatal death occurred among infants born to mothers with AFE. Highly significant increases in risk, however, were observed for stillbirth, asphyxia, mechanical ventilation, bacterial sepsis, seizures and prolonged length of neonatal hospital stay, but not for jaundice. These relationships were even stronger when the analysis was restricted to births ≥37 completed weeks of gestation.

Table 3.   Fetal/infant outcomes among confirmed AFE cases (n = 120 for stillbirths, n = 54 for neonatal outcomes*)
Outcome n (%)Adjusted OR (95% CI)
  1. *Based on linked maternal and infant file available since 2001/02.

Stillbirth5 (4.2)5.9 (2.0–17.4)
Asphyxia15 (27.8)36.0 (18.6–69.7)
Mechanical ventilation17 (31.5)11.8 (6.0–23.4)
Bacterial sepsis5 (9.3)5.0 (1.8–14.0)
Seizure8 (14.8)22.8 (9.7–53.3)
Jaundice (nonimmune haemolytic/traumatic)9 (16.7)1.4 (0.6–3.2)
Length of stay >7 days18 (33.3)18.5 (8.5–40.2)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

As we hypothesised, the use of the additional maternal morbidity confirmation criteria sharply reduced the number of cases and incidence of AFE. Our inference from these findings is that many of the AFE diagnoses without these criteria were false positives. In addition, the effect of including these confirmation criteria reduced the number of nonfatal cases to a greater degree than for fatal cases, hence leading to a sharp increase in the case fatality rate. This finding underscores the findings from our previous study, where we used analysis of fatal AFE to reduce false-positive diagnoses.8

Nonetheless, our updated and improved study confirmed our previously reported association of AFE with medical induction of labour, as well as with all forms of operative delivery, including caesarean, forceps and vacuum deliveries.8 Many of the confirmed cases of AFE were associated with multiple categories of serious maternal morbidity, as well as with hysterectomy and prolonged length of stay. As in our previous study, we found no significant temporal increase of AFE during the 18-year study. Finally, we found major increased risks of stillbirth and serious neonatal morbidity associated with AFE.

The lower incidence rate and higher case fatality rate (compared with our previous report8) bring our data closer in line with those of more recent studies based on similar population-based hospitalisation databases (Australia)9 and tailor-made surveillance studies from the UK.10 All three of these studies found a significant association with labour induction. One study from the USA found a 50% increase in the odds of induction that was not statistically significant.11 The US study, however, did not include confirmatory maternal morbidity criteria to reduce false-positive diagnoses of AFE, hence probably diluting the true effect of induction on AFE occurrence.

Our study has both strengths and limitations. Strengths include a population-based cohort of all hospital births (over 98% of all Canadian births occur in hospital) in Canadian provinces and territories except Quebec, Manitoba and Nova Scotia, comprising over 70% of Canadian births over the study period. This enabled a large number of AFE cases to be confirmed, despite the rarity of the condition, as well as inclusion of a large number of potential risk factors and confounding variables. Finally, the linked files of mothers and infants available since 2001 enabled a sensitivity analysis for a number of risk factors (parity, birthweight and gestational age) not available in the unlinked maternal file, as well as a heretofore unavailable assessment of adverse neonatal outcomes.

One important limitation of our study is the uncertain temporal relationship between caesarean delivery and the first signs and symptoms of AFE, which prevents us from knowing whether caesarean delivery is a true risk factor (and potential cause) of AFE, or a consequence of an attempt to rescue the fetus or the mother with rapid delivery. The same can be said for forceps and vacuum delivery in cases where labour was so advanced that delivery would be more expeditious with instrumental vaginal delivery than with a caesarean. In the UK study,10 however, caesarean delivery was significantly associated with the risk of AFE even when restricted to cases occurring postnatally (after delivery).

Finally, administrative databases like CIHI’s Discharge Abstract Database inevitably imply a risk of coding errors, not only for AFE, but also for confirmatory maternal diagnoses, neonatal diagnoses and demographic and clinical covariates. In addition, the absence of data on parity (which is considered neither a diagnosis nor a procedure under ICD coding) forced us to rely on the ICD ‘diagnoses’ of elderly primigravidity and grand multiparity, both of which are likely to be under-reported. Associations with parity ≥3 were confirmed, however, using the parity variable contained in the file since 2001/02. Moreover, most coding errors would be expected to be nondifferential with respect to the occurrence of AFE and thereby would reduce associations with AFE, rather than bias them upwards.

The extremely high odds ratio associated with eclampsia also merits further comment. This result was reported in our previous study, as well as in a hospital discharge-based study from the USA.11 It is unclear, however, whether the seizures leading to the diagnosis of eclampsia preceded the signs and symptoms of AFE or were consequences of it, i.e. occurred after its onset. Temporality is also an issue for neonatal outcomes. Neonatal morbidity can be a consequence of AFE only for those cases occurring before birth, and so the strong associations we observed may be diluted by our inability to identify and exclude cases of postnatal AFE.

Several other issues should be considered. We did not observe any significant temporal trend in the occurrence of AFE, despite strong temporal trends in medical induction, caesarean delivery, advanced maternal age and other identified risk factors. It is possible that increases in induction and caesarean were counter-balanced by other trends, including reduction in multiparity and in use of operative vaginal delivery. Nonetheless, the lack of temporal trend in AFE confirms findings from other recently published studies.12

Future research in AFE should aim to better understand the biological mechanisms underlying the disease, based on animal models, and to identify specific genes that may increase the risk when amniotic fluid enters the maternal circulation. From the technical and public health perspectives, the strong associations of labour induction and (especially) caesarean delivery with AFE should be kept in mind when balancing the risks and benefits of these procedures, given their increasing use worldwide.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

MSK designed the study, supervised the analysis, and wrote the manuscript. JR carried out the analysis and contributed to the study design and the first draft of the manuscript. SL, SB and KSJ contributed to the study design and reviewed and provided feedback on earlier drafts of the manuscript. Several other members of the Maternal Health Study Group provided feedback on the penultimate draft of the manuscript.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References

This study was supported by the Canadian Institutes of Health Research (MSK) and the Child and Family Research Institute (KSJ).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. Acknowledgements
  12. References
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