Ectopic pregnancy (EP) is a recurrent medical condition. It is a significant cause of maternal mortality and morbidity, especially in low-income and middle-income countries, where the majority of patients present late with tubal rupture and hemodynamic compromise [
Despite the recently observed decline in general and specific maternal mortality due to ectopic pregnancy, this remains the cause of around 4.9% of all maternal deaths in developed countries, with 3-4% in the United States and in England [
Awareness about the impact of this condition on young fertile women and care providers is paramount, since early diagnosis can avoid severe intra-abdominal hemorrhage in tubal EP. The prevention of maternal morbidity in EP represents a major challenge to ensure improvement in women’s health, since there are no identified risk factors that can clearly predict severe bleeding in these cases [
As a secondary analysis from a multicenter cross-sectional study for the surveillance of severe maternal morbidity and near miss in Brazil [
A multicenter cross-sectional study was conducted in 27 referral obstetric units in diverse geographical regions in Brazil. During a 12-month period, from June 2009 to May 2010, prospective surveillance of potentially life-threatening maternal conditions (PLTC), maternal near miss (MNM), and maternal death (MD) was carried out, using the WHO criteria and classification [
Thus, all medical charts of women admitted to participating hospitals to deliver or because they have any severe complication related do pregnancy were reviewed immediately after hospital discharge. Medical charts of women transferred to other healthcare services before completion of the case or those who died were also reviewed, in search of cases showing the WHO identifiers defined as those most frequently associated with organ dysfunction and severe morbidity. The search for information that was unavailable in the chart was carried out in other sources such as the hospital database, prenatal record forms, and transfer documents or was obtained from the healthcare team.
Data collection was conducted in a specific chart that also contained information about adequacy of health care and the occurrence of delays for getting appropriate treatment. After manual collection, the forms were filed to become accessible at the time of technical visits for quality control. The data was entered into electronic forms hosted on the project website, which was hosted on the institutional web page of the coordinating study center and sent to the central database, using the OpenClinica 3.0, a specific platform for management of clinical studies. Further details on the study and methodological aspects are included in other publications [
Quality control was assured by several manners. Initially, before data collection began, a manual of operation was provided and coordinators of each center were trained. During data collection, each coordinator reviewed the forms, checked for typographical errors, and provided the search for data that was unavailable on the charts. The local investigator carried out a new review to identify possible inconsistencies. Finally, the national study coordinators reviewed the database, identified inconsistencies, and sent the correction report to the participating centers which were required to make the corrections [
During the study, consistent auditing with a set of validation and cross-checking rules as part of online data management assigned a systematic evaluation of possible delays and deficiencies in the quality of care and health system inadequacy, with data on interhospital transfer, refusal by a patient to accept treatment (“discharge requested by the patient” or “evasion”), or lack of equipment or medication. Altogether they are operationally defined as a substandard care with or without delays.
For the assessment of ectopic pregnancy associated with severe maternal morbidity, cases were divided into obstetric complications due to ectopic pregnancy and obstetric complications due to other causes. Therefore not all cases of ectopic pregnancy entered the study, but only those complicated with a specific life-threatening condition identified or those undergoing a laparotomy for treatment. Initially, the prevalence of PLTC, MNM, and MD was calculated and compared between these groups. Then the following health indicators related to maternal morbidity and mortality were estimated: the maternal near miss incidence ratio (MNM incidence ratio), severe maternal outcome ratio (SMOR, MNM + MD), maternal near miss to maternal death ratio (MNM : MD ratio), and mortality index and maternal mortality ratio (MMR), according to WHO recommendations [
The diagnostic criteria used for the identification of PLTC, MNM, and MD, as well as the conditions of severity management, were assessed in these same groups (ectopic pregnancy and other causes). The
In a total of 9.555 women identified with severe complications associated with pregnancy, delivery, or postpartum period, 312 (3.3%) had complications secondary to ectopic pregnancy and 9.243 (96.7%) developed complications resulting from other causes. PLTC and MNM, respectively, occurred in a total of 8.359 (90.4%) and 745 (8.1%) women in the group with other causes and in 286 (91.7%) and 25 (8.0%) women in the EP group. MD occurred in a total of 139 (1.5%) women for the morbidity group due to other causes. There was only one death (0.3%) attributed to ectopic pregnancy (Table
Prevalence of potentially life-threatening conditions (PLTC), maternal near miss (MNM), and maternal deaths (MD) among complicated ectopic pregnancy cases and other causes of morbidity and their correspondent health indicators.
Morbidity/mortality | Cause | PR (95% CI) for ectopic | |
---|---|---|---|
Ectopic pregnancy | Other causes | ||
PLTC | 286 (91.7) | 8359 (90.4) | 1.16 (0.69–1.94) |
MNM | 25 (8.0) | 745 (8.1) | 0.99 (0.58–1.69) |
MD | 1 (0.3) | 139 (1.5) | 0.22 (0.05–1.01) |
Total |
|
|
|
Health indicators | LB: 82.144 | ||
MNMR | 0.3/1000 LB | 9.07/1000 LB | |
SMOR | 0.3/1000 LB | 10.8/1000 LB | |
MNM : MD ratio | 25.0 : 1 | 5.4 : 1 | |
Mortality index | 3.8% | 15.7% | |
MMR | 1.2/100.000 LB | 169.2/100.000 LB |
PR: prevalence ratio adjusted for cluster effect; PLTC: potentially life-threatening condition; MNM: maternal near miss; MD: maternal death; LB: live births; MNMR: maternal near miss ratio; SMOR: severe maternal outcome ratio; MMR: maternal mortality ratio.
Flow of women with severe maternal morbidity due to ectopic pregnancy or other causes according to the final outcome in PLTC (potentially life-threatening condition), MNM (maternal near miss), or MD (maternal death).
The maternal near miss incidence ratio was 0.3/1000 LB among ectopic pregnancy cases and 9.07/1000 LB among the remaining causes; the severe maternal outcome ratio (SMOR) was 0.3/1000 LB among ectopic pregnancy cases and 10.8/1000 LB among the remaining causes. The MNM : MD ratio was 25 : 1 for ectopic pregnancy cases and 5.4 : 1 for the remaining causes. The mortality index was 3.8% for ectopic pregnancy cases and 15.7% for the remaining causes and the maternal mortality ratio (MMR) was 1.2/100.000 LB among ectopic pregnancy cases and 169.2/100.000 LB among other causes (Table
Bleeding was the most widely used diagnostic criteria for PLTC in the identification of complicated cases of ectopic pregnancy, while, among the remaining causes, hypertension and clinical-surgical criteria were more frequently used. Infection was not identified as statistically significant for morbidity due to EP, in comparison to the remaining causes (Table
Prevalence of main causes of morbidity among cases complicated with ectopic pregnancy or other conditions and number of cases identified by specific WHO criteria for maternal near miss.
Causes of morbidity | Ectopic pregnancy | Other conditions |
|
---|---|---|---|
Hypertension | 1.3 | 72.5 |
|
Hemorrhage | 94.6 | 21.5 |
|
Infection | 0.3 | 1.1 | 0.195 |
Clinical-surgical | 4.5 | 10.9 |
|
Total |
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|
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|
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WHO criteria for MNM and MD among ectopic pregnancy cases | MNM | MD | |
Clinical | ( |
( |
|
Laboratory | ( |
( |
|
Management | ( |
( |
|
Total | 25 | 1 |
MNM: maternal near miss; MD: maternal death. Values in bold type indicate statistically significant values.
Among the more severe cases, maternal near miss and maternal death (MNM and MD), the most widely used criteria for complicated EP were clinical (16 MNM cases) and management (15 MNM cases), when applying the WHO criteria for identifying near miss events. In the only MD case, clinical, laboratory, and management criteria were observed (Table
When assessing the conditions of severity management, it was observed that patients who had complicated ectopic pregnancy showed a higher estimated risk of blood product transfusion and laparotomy and a lower risk of ICU admission and prolonged hospitalization in comparison to patients presenting with complications secondary to other causes (Table
Estimated risk of ectopic pregnancy among maternal morbidity cases, according to conditions of severity management used.
Conditions of severity management | Ectopic |
Other |
PR for ectopic |
95% CI |
---|---|---|---|---|
Blood transfusion | 37.2 | 15.7 |
|
|
Central venous access | 2.6 | 3.8 | 0.67 | 0.33–1.35 |
ICU admission | 7.7 | 22.6 |
|
|
Prolonged hospital stay (>7 days) | 3.5 | 30.9 |
|
|
Nonanesthetic intubation | 1.6 | 3.1 | 0.51 | 0.19–1.39 |
Return to operating room | 1.6 | 3.4 | 0.48 | 0.14–1.64 |
Laparotomy | 97.1 | 3.1 |
|
|
Use of magnesium sulphate | 0.0 | 50.0 |
|
|
Other major surgical procedures | 1.0 | 0.8 | 1.27 | 0.30–5.31 |
Total |
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|
PR: prevalence ratio adjusted for cluster effect; 95% CI: 95% confidence interval for prevalence ratio; ICU: intensive care unit. Values in bold type indicate statistically significant values.
The variables assessed on bivariate analysis (maternal age, marital status, school education, and skin color/ethnicity) did not show any significantly increased estimated risk of a worse prognosis (maternal near miss event or death) (Table
Estimated risk of worse outcome (MNM + MD) among maternal morbidity cases due to ectopic pregnancy according to some sociodemographic characteristics.
Characteristics | MNM + MD | PLTC | PR | 95% CI |
---|---|---|---|---|
Age (years) | ||||
10–19 | 11.5 | 6.6 | 1.83 | 0.78–4.27 |
20–29 | 46.2 | 52.1 | (Ref.) | |
30–39 | 34.6 | 36.0 | 1.08 | 0.37–3.15 |
40–49 | 7.7 | 5.2 | 1.58 | 0.31–8.08 |
( |
(26) | (286) | ||
Marital status (a) | ||||
Married/cohabitating | 55.6 | 46.9 | 1.38 | 0.49–3.88 |
Single/separated/widow | 44.4 | 53.1 | (Ref.) | |
( |
(18) | (224) | ||
School education (b) | ||||
Fundamental (primary) | 47.1 | 42.8 | (Ref.) | |
Medium (high) | 41.2 | 46.1 | 0.83 | 0.29–2.38 |
Superior (university) | 11.8 | 11.2 | 0.96 | 0.17–5.34 |
( |
(17) | (152) | ||
Skin color/ethnicity (c) | ||||
White | 72.7 | 37.5 | (Ref.) | |
Nonwhite | 27.3 | 62.5 | 0.26 | 0.05–1.32 |
( |
(22) | (192) |
MNM: maternal near miss; MD: maternal death; PLTC: potentially life-threatening condition; PR: prevalence ratio adjusted for cluster effect; 95% CI: 95% confidence interval for prevalence ratio. Missing values for (a) 70 cases; (b) 143; (c) 98.
Estimated risk of worse outcome (MNM + MD) among maternal morbidity cases due to ectopic pregnancy according to some obstetric characteristics.
Characteristics | MNM + MD | PLTC | PR | 95% CI |
---|---|---|---|---|
Previous abortions (a) | ||||
None | 95.7 | 66.8 | (Ref.) | |
1 or more | 4.3 | 33.2 |
|
|
( |
(23) | (271) | ||
Previous C-sections (b) | ||||
None | 86.4 | 76.9 | (Ref.) | |
1 | 9.1 | 18.1 | 0.47 | 0.11–2.01 |
2 or more | 4.5 | 5.0 | 0.82 | 0.10–7.00 |
( |
(22) | (260) | ||
Parity (c) | ||||
0 | 37.5 | 35.8 | (Ref.) | |
1-2 | 45.8 | 48.3 | 0.91 | 0.34–2.45 |
≥3 | 16.7 | 15.9 | 1.00 | 0.29–3.52 |
( |
(24) | (271) | ||
Previous uterine surgery (d) | ||||
Yes | 0.0 | 3.4 |
|
|
No | 100.0 | 96.6 | (Ref.) | |
( |
(17) | (207) | ||
Gestational age at resolution (e) | ||||
<9 weeks | 71.4 | 73.2 | (Ref.) | |
≥9 weeks | 28.6 | 26.8 | 1.09 | 0.32–3.64 |
( |
(14) | (142) | ||
Substandard care—delays (f) | ||||
Yes | 22.7 | 15.0 | 1.59 | 0.55–4.57 |
No | 77.3 | 85.0 | (Ref.) | |
( |
(22) | (266) |
MNM: maternal near miss; MD: maternal death; PLTC: potentially life-threatening condition; PR: prevalence ratio adjusted for cluster effect; 95% CI: 95% confidence interval for prevalence ratio. Values in bold type indicate statistically significant values. Missing values for (a) 18 cases; (b) 30; (c) 17; (d) 88; (e) 156; and (f) 24 cases.
Multivariate analysis (Table
Variables independently associated with a worse outcome (MNM + MD) among maternal morbidity cases due to ectopic pregnancy (
Variable | Coefficient | SE coef. |
|
PRadj (95% CI) |
---|---|---|---|---|
Previous uterine scar | −22.65 | 0.71 |
|
|
Skin color (nonwhite) | −1.84 | 0.87 |
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Constant | −1.74 | 0.38 |
|
MNM: maternal near miss; MD: maternal death.
PRadj: prevalence ratio adjusted for cluster effect and all remaining significant predictive factors.
Multiple Poisson regression, controlled by age (years); marital status (married/cohabitating: 1; others: 0); school education (up to high: 0; superior: 1); skin color (white: 0; nonwhite: 1); BMI (underweight/adequate: 0; overweight/obese: 1); previous abortion (0; ≥1 : 1); previous C-sections (0; ≥1: 1); parity (0; ≥1: 1); previous uterine scar (yes: 1; no: 0); gestational age at resolution (<9 weeks: 0; ≥9: 1); occurrence of substandard care delays (yes: 1; no: 0). Values in bold type indicate statistically significant values.
To the best of our knowledge, this is the first analysis of EP according to the new WHO concepts of potentially life-threatening condition, maternal near miss, and maternal death, in a large well-defined sample of women, with prospective nationwide data collection.
Much has been discussed about the risk factors for the occurrence of complications and death due to ectopic pregnancy, such as nonwhite skin color, presence of previous disorders (particularly diabetes mellitus), unstable marital status, lower level of school education, nulliparity, history of prior ectopic pregnancy, and delay in care provision [
Specific mortality due to ectopic pregnancy alone does not fully describe obstetric care. Therefore, it is important to consider the health indicators described by the WHO in 2009 [
The conditions of severe maternal morbidity related to ectopic pregnancy are associated with tubal rupture, rapid clinical deterioration due to major intra-abdominal bleeding, and posterior progression to hypovolemic shock, requiring blood transfusion [
Another protective factor identified was history of prior abortion. According to Sindos et al., nulliparous patients tend to seek medical care earlier. As soon as these patients perceive any different symptoms such as pain or bleeding, they seek medical treatment and ectopic pregnancy is identified early, before tubal rupture [
On multivariate analysis, apart from history of previous uterine surgery, we also found skin color as a protective factor, in contrast to descriptions in the literature reporting nonwhite skin color as a risk for the occurrence of complications and death from ectopic pregnancy. We should always bear in mind that the risk factors described are not related to near miss cases. There are still no comparative data for near miss cases in the literature and these cases may behave differently [
One of the most interesting findings of the present study was information on the quality of care, with evidence of increased substandard care and/or delays in more severe cases. A similar suggestion was made by van Mello et al. in a case-control study, comparing EP patients developing complications after abdominal hemorrhage to hemodynamically stable EP patients. Those authors emphasized that since patient-related risk factors have not been consistent in identifying a worse outcome as yet, the key point would be to focus on awareness about EP and its clinical management [
Some possible limitations of this study must be considered. As a secondary analysis of a larger study, information about important risk factors usually assessed for EP cases was lacking, for example, previous EP (data collection concerned previous history of abortion), history of pelvic inflammatory disease, and history of infertility. There was also a lack of data on diagnostic tools used for each case: ultrasound findings and hCG levels or clinical findings at diagnosis.
A relatively large number of maternal morbidity cases due to EP were found in the Brazilian population during the surveillance period, raising awareness of this condition and its impact on female reproductive life. No important risk factors for increased severity were identified. However, there seems to be deficient or substandard care associated with complicated EP cases. Further action taken would be to address care providers to develop specific guidelines and interventions for the prevention of severe maternal morbidity due to this specific condition.
The authors denied any conflict of interests.
The idea for the study arose in a group discussion among all the authors. After the end of data collection, Edilberto Alves Rocha Filho, Danielly Scaranello Santana, Jose Guilherme Cecatti, and Maria Helena Sousa prepared a detailed plan of analysis which was then performed by Maria Helena Sousa. The first version of the paper was drafted by Edilberto Alves Rocha Filho and Danielly Scaranello Santana and then complemented with suggestions made by the other authors. Jose Guilherme Cecatti and Maria Laura Costa supervised the entire process. All authors contributed to the development of the study protocol and approved the final version of the paper.
The authors acknowledge the financial support of CNPq/DECIT (The National Research Council and the Department of Science and Technology of the Brazilian Ministry of Health), Grant no. 402702/2008-5, and also the involvement of its Steering Committee members and all other investigators and coordinators from all the centers. The authors also acknowledge the participation of the members of the Brazilian Network for the Surveillance of Severe Maternal Morbidity Group: Joao P Souza, Marilza V Rudge, Iracema M Calderon, Maria V Bahamondes, Simone P Gonçalves, Eliana M Amaral, Olímpio B Moraes Filho, Simone A Carvalho, Francisco E Feitosa, George N Chaves, Ione R Brum, Gloria C Saint’ynes, Carlos A Menezes, Patricia N Santos, Everardo M Guanabara, Elson J Almeida Jr, Joaquim L Moreira, Maria R Sousa, Frederico A Peret, Liv B Paula, Luiza E Schmaltz, Cleire Pessoni, Leila Katz, Adriana Bione, Antonio C Barbosa Lima, Edilberto A Rocha Filho, Melania M Amorim, Debora Leite, Ivelyne Radaci, Marilia G Martins, Frederico Barroso, Fernando C Oliveira Jr, Denis J Nascimento, Cláudio S Paiva, Moises D Lima, Djacyr M Freire, Roger D Rohloff, Simone M Rodrigues, Sergio M Costa, Lucia C Pfitscher, Adriana G Luz, Daniela Guimaraes, Gustavo Lobato, Marcos Nakamura-Pereira, Eduardo Cordioli, Alessandra Peterossi, Cynthia D Perez, Jose C Peraçoli, Roberto A Costa, Nelson L Maia Filho, Jacinta P Matias, Silvana M Quintana, Elaine C Moises, Fátima A Lotufo, Luiz E Carvalho, Elvira A Zanette, Carla B Andreucci, Márcia M Aquino, Maria H Ohnuma, Rosiane Mattar, and Felipe F Campanharo.