Aims: The 2009 H1N1 pandemic illustrated the higher morbidity and mortality from viral infections in peripartum women. We describe clinical features of women who recently died of H1N1 in Colombia.
Methods: This is a case series study that was gathered through a retrospective record review of all maternal H1N1 deaths in the country. The national mortality database of confirmed mortality from H1N1 in pregnancy and up to 42 days after delivery was reviewed during the H1N1 season in 2009. Women with H1N1 infections were confirmed by the laboratory of virology. Demographic, clinical, and laboratory data were reviewed. Statistical analyses were performed and median values of non-parametric data were reported with inter-quartile range (IQR).
Results: A total of 23 H1N1 maternal deaths were identified. Eighty-three percent occurred in the third trimester. None of the mothers who died had received influenza vaccination. The median time from symptom onset to the initiation of antiviral treatment was 8.8 days (IQR 5.8–9.8). Five fatalities did not receive any anti-viral therapy. Median PaO2/FiO2 on day 1 was 80 (IQR, 60–98.5). All patients required inotropic support and mechanical ventilation with barotrauma-related complications of mechanical ventilation occurring in 35% of patients.
Conclusion: In Colombia, none of the women suffering H1N1-related maternal deaths had received vaccination against the disease and most had delayed or had no anti-viral therapy. Given the lack of evidence-based clinical predictors to identify women who are prone to die from H1N1 in pregnancy, following international guidelines for vaccination and initiation of antiviral therapy in suspected cases would likely improve outcomes in developing countries.
A novel pandemic influenza A virus (H1N1 2009pdm) emerged in Mexico in May 2009 . In June 2009, the World Health Organization (WHO) declared a Phase 6 pandemic due to this novel disease, leading to a global health response that identified over 600,000 laboratory confirmed cases and at least 7826 deaths worldwide during the pandemic period. In the post-pandemic period there were indications that the virus may be more aggressive; however, data supporting this observation are scarce .
As previous influenza pandemics have shown [14, 27], pregnant and postpartum women are at an increased risk of death. In pregnant and postpartum women, H1N1 was associated with increased morbidity, high rates of hospitalization and intensive care unit (ICU) admission, and increased mortality . The high mortality rates are thought to be due to the physiologic changes of pregnancy that render pregnant and postpartum women more susceptible to complications from influenza .
Nearly all pregnant and postpartum patients who died from this disease in the United States presented with respiratory failure and needed mechanical ventilation [3, 16, 21], with some analyses showing delays in the initiation of antiviral treatment [3, 16, 29]. There is little research describing the general outcomes of pregnant and postpartum women and the different treatment strategies used during their ICU stay. In addition, there is limited information on risk assessment, clinical course and in-hospital complications of H1N1 2009pdm virus in pregnant and postpartum patients .
Approximately 10% of all H1N1 2009pdm-related deaths in Colombia occurred in pregnant and postpartum women . Given that reporting of both maternal deaths and mortality from H1N1 to the Department of Health in Colombia is mandatory, we aimed to describe the epidemiology, clinical features and complications in H1N1 2009pdm-related maternal deaths in 2009. Such evaluation will improve our understanding of the disease in order to enhance preventive and treatment strategies in this vulnerable population.
This is a case series study gathered through a retrospective record review of all maternal H1N1 deaths in Colombia between July 1, 2009, and November 31, 2009. All H1N1 infections were confirmed by the laboratory of virology of Colombia’s National Institute of Health (Instituto Nacional de Salud, INS).
Case definition and epidemiological surveillance
According to the definition of the Ministry of Social Protection (Ministerio de Protección Social, MPS) established in May 2009, a suspected case of H1N1 2009pdm infection refers to an individual with symptoms of acute respiratory infection (temperature >38°C, cough) for no greater than 7 days . A probable case is defined as a person with an acute respiratory infection requiring hospitalization or resulting in death without an identifiable cause. A confirmed case refers to a suspect or probable case with confirmation of influenza H1N1 2009pdm through real-time reverse-transcriptase (rtRT)-PCR, genetic sequence, or viral culture.
Maternal mortality was defined according to WHO criteria  as death during pregnancy or within 42 days of pregnancy termination, independent of the duration and due to any pregnancy-related and/or aggravated conditions, excluding all accidental causes.
Colombia’s Epidemiological Surveillance System (Sistema de Vigilancia Epidemiológica, SIVIGILA) mandates immediate notification of maternal deaths and analyzes death certificates of all reported cases. For each probable or confirmed maternal death due to an influenza-like illness, a standard questionnaire was completed by the attending physician during the epidemic. Data collected from the patient’s medical record included demographics, gestational age at presentation, vaccination history, diagnosis, treatments, laboratory tests, and clinical data. A national committee further reviewed the medical documentation for the maternal mortality cases confirmed as H1N1 2009pdm virus. Data from this review, which in some cases included home visits to the family for risk assessment, were included as part of the comprehensive review of all collected data for each death.
Data collection and statistical analysis
The extracted data described above were entered into a Microsoft Excel database. The number of live births to establish the maternal mortality ratio in the study period was obtained through data from the National Department of Statistics (Departmento Administrativo Nacional de Estadísticas, DANE) [9, 10].
A descriptive analysis was performed on all baseline characteristics. Because of a non-parametric distribution of the data, continuous data were reported as median, with interquartile range (IQR) as dispersion measure.
This study was approved by the Instituto Nacional de Salud and is in compliance with Colombian law, International Sanitary Regulations, and the National Protocol of Maternal and Perinatal Deaths of Colombia. Since the study was deemed beneficial to the public’s health and was conducted during the peak of the pandemic as a public health response, no informed consent or review by an institutional Ethics Committee was needed.
From July 1 to November 30, 2009, there were 23 maternal deaths due to H1N1 in Colombia. For the study period, the H1N1-specific maternal mortality ratio (MMR) was 7.8 maternal deaths per 100,000 live births. This ratio represented 5.1% of maternal deaths in Colombia in 2009. Of the 23 deaths, five cases were excluded, due to incomplete data (n=4) and molar pregnancy with lung involvement (n=1). The denominator in various sections below varies based on the number of patients with complete data for the specific outcome being studied.
Median age at the time of death was 26.5 years (IQR, 22.2–36.7). A total of 15 patients (83%) had disease onset during the third semester of gestation, two (11.1%) in the second trimester, and one (5.5%) in the postpartum period. Median gestational age at symptom onset was 33 weeks (IQR, 32–36).
In 17 of 18 patients, median duration between symptom onset and hospitalization was four days (IQR, 2–8). One patient was diagnosed during hospitalization for an unrelated condition. Twelve cases (12/17; 64%) were not hospitalized the first time they sought care for influenza-like symptoms. More information is summarized in Table 1.
|Median (IQR)a (n=18)a|
|Gestational weeks at hospitalizationb||33 (32–35)|
|Total number of consultations before hospitalization||1 (0–2)|
|Antiviral treatment||12/17 (70.5%)|
|Oseltamivir and adamantine||12.5%|
|Time between symptoms onset and hospitalization (days)c||4 (2–8)|
|Length of stay (days)||14.0 (6.5–20.2)|
|Time between hospitalization and ICU entrance (days)||1.8 (0.7–4.2)|
|ICU stay (17 cases) (days)||9.3 (3.1–19.4)|
|Time between hospitalization and antiviral treatmentd (days)||2.8 (1.6–4.7)|
|Time between symptoms onset and antiviral treatmentd (days)||8.8 (5.8–9.8)|
|Time between antiviral treatment and deathd (days)||9.2 (3.1–17.9)|
|Time between hospitalization and beginning of rales (days)||1.3 (0.4–3.1)|
|Time between respiratory rate >24 and MVe (h)||24 (3.6–48)|
|Time between SO2<95 and mechanical ventilation (h)e||10.2 h (1.8–50.3)|
|Range: 0 h to 15.2 days|
|Oxygen saturation (SO2) (n=18)|
|SO2<91% during the disease (%)||100%|
|SO2<95% at first determination (%)||88.8%|
|SO2<91% at first determination (%)||76.4%|
MV=Mechanical ventilation, ICU=intensive care unit, SO2=oxygen saturation.
aUnless otherwise specified.
bOne patient was postpartum at hospitalization.
cSymptom onset. One patient was already hospitalized when first symptom presented.
dIn 13 patients who received antiviral treatment.
eDuration of time between SO2<95 or respiratory rate >24 and mechanical ventilation (14 of 16 cases with available data).
Prevention and antiviral treatment
None of the patients in this study had received influenza vaccination during the influenza season.
Five fatalities did not receive any antiviral treatment. Of the remaining patients, 87.5% received oseltamivir alone and 12.5% received both oseltamivir and amantadine. The median time from symptom onset to the initiation of antiviral treatment was 8.8 days (IQR, 5.8–9.8), and the median time from hospitalization to initiation of antiviral treatment was 2.8 days (IQR, 1.6–4.7).
Maternal clinical course
The timeline of all maternal deaths and their clinical course is illustrated in Figure 1. Median time from hospital admission to ICU admission was 1.8 days (IQR, 0.7–4.2). Among the 18 cases, one died prior to ICU admission. The remaining 17 patients developed symptoms of severe pneumonia, received antibiotics, and needed mechanical ventilation. Ampicillin/sulbactam was the most common first-line antibiotic used for treatment (9 of 15 cases) in addition to antiviral therapy.
From 15 cases with adequate data, 11 had a chest X-ray suggestive of multi-lobar pneumonia prior to ICU admission (73.3%).
Seventeen of the eighteen patients required ICU services during their H1N1 hospital-related admission. One patient died before ICU admission. All patients developed multiple organ dysfunction syndrome. Of the 16 patients with adequate ICU data, eight required inotropic support on the first day of ICU admission (50%), and all patients required ventilatory and inotropic support during their ICU stay. Three cases required renal replacement therapy during their ICU stay (16.6%). Of 12 patients with available data, ten received neuromuscular blockers (83%) during mechanical ventilation; five required lung recruitment maneuvers; three (17.6%) required prone positioning (after delivery); three (17.6%) patients were ventilated with airway pressure release ventilation (APRV); two patients needed invasive bi-level ventilation (11.7%); and one patient received nitric oxide (5.8%). The average positive end expiratory pressure (PEEP) levels on day one were 12.3 cm H2O. On day seven the average PEEP was 18.2 cm H2O (see Figure 2). Tracheotomy was performed in 3/17 patients (17.6%). Complications resulting from mechanical ventilation included pneumothorax in 3/17 (17.6%) of patients, pneumomediastinum (2/17), and pneumothorax and pneumo-peritoneum (1/17).
In addition, 2/17 (11.7%) patients were diagnosed with pulmonary hypertension, 2/17 developed intracranial hypertension, and 1/17 had intracerebral bleeding and subarachnoid hemorrhage.
Oxygen-saturation levels of the disease
Most patients (16/18 patients; 89%) had an initial SaO2 of <95% at first determination and median value of the first recorded SaO2 was 88.5% (IQR, 76.7–89.7). Median time between admission and first determination of SaO2 was 17.3 h (IQR, 0.7–97.7). Oxygenation data are shown in Figure 2.
Fetal and pregnancy-specific outcomes
Of 18 confirmed cases, four (22.2%) were identified as having pre-eclampsia and two cases (11.1%) developed HELLP syndrome after the onset of H1N1 infection. One case (1/18) had pre-eclampsia before H1N1 onset. Of 18 maternal deaths, most (15 patients) had preterm deliveries; of these, one occurred before fetal viability (23–24 weeks). Preterm birth resulted from emergency cesarean deliveries performed as a result of maternal or fetal compromise. Of the other patients, 3/17 were at term, and 16/17 cases had cesarean delivery. Among these, 8/16 (50%) delivered after ICU admission. None of the C-sections were perimortem.
Out of 15 cases with available neonatal information, twelve resulted in live newborns requiring resuscitation at birth and 3/15 were stillbirths. Median birth weight was 2299 g (IQR, 1844–2965).
Of the 23 demises due to H1N1 that occurred during pregnancy, only four autopsies were authorized by family members. Pathology revealed changes ranging from severe acute exudative fibrinous pneumonia with lymphocytic infiltration in the interstitium (see Image 1) to necrotizing alveolitis and alveolar hemorrhage and edema (see Images 2–4). There was no evidence of intracytoplasmatic inclusions in any of the cases.
This study reviews the clinical course of pregnant patients who died in Colombia from complications of confirmed 2009 H1N1. Findings from this study suggest that none of the non-survivors of H1N1 disease had received prenatal influenza vaccine and most had a delay in the initiation of antiviral therapy after the development of symptoms and profound hypoxemia with challenges related to mechanical ventilation in all cases. Despite the known epidemic (after mid-2009), one-third of patients failed to receive antiviral therapy. Women who were pregnant at the time of H1N1 diagnosis and died from the disease had high rates of stillbirths and preterm births.
Most of the fatalities were among women in the third trimester. This is consistent with prior studies from other countries [8, 16, 18, 19]. This timing coincides with alterations in T-cell immunity that occurs in late pregnancy and predisposes women to contracting certain infections and to developing more severe disease from these infections.
With regards to antiviral treatment, almost all of the women had an evident delay in the initiation of antiviral therapy after the development of influenza symptoms compared to what has been described in prior studies in critically ill patients who survived [3, 4, 17]. Our experience during the pandemic is in accordance with the empiric treatment of pregnant women with suspected influenza [26, 28]. In addition, almost all of our patients who died were seen in consultation prior to hospitalization and are therefore presumed to have had access to care.
In terms of the natural course of the illness among the 18 deaths, all but one had symptoms 3–5 days prior to ICU admission and subsequent mechanical ventilation. The development of symptoms many days prior to becoming critically ill is consistent with similar experiences in many other countries, including the United States, Turkey, and Canada [4, 8, 18, 24]. Based on lessons learned from 2009 H1N1, earlier recognition during the time period prior to the development of severe hypoxemia and multiple organ dysfunction will result in more rapid initiation of life-saving antiviral therapy .
Consistent with the experiences of other countries, the oxygenation and mechanical ventilation of the patients with 2009 H1N1 who died posed real technical and logistical challenges . At the time of ICU admission, the vast majority were already profoundly hypoxic and met criteria for acute lung injury or acute respiratory distress syndrome (ARDS). Despite the lack of a control group in this series, the presence of hypoxemia (oxygen saturation <91%) on admission in 76.4% of cases deserves some emphasis and additional clinical scrutiny. Though the study design is not such that it would allow the identification of this or other markers as predictors of mortality, based on available literature in the non-pregnant population, women with hypoxemia in the setting of an acute respiratory illness during a pandemic may be more likely to have a more complicated course. More than half of our patients who died were administered some form of rescue therapy, such as airway pressure release ventilation (APRV) or prone ventilation in the hopes of improving oxygenation. In addition, there was a very high rate of barotrauma-related complications from mechanical ventilation, such as pneumothorax that has not been described in many prior studies [8, 11, 18, 27]. While there was no access to extracorpeal membrane oxygenation (ECMO) in Colombia at the time of this pandemic, this intervention has been hypothesized to offer a survival benefit by improving oxygenation early in the course of ARDS from 2009 H1N1 by facilitating a low-tidal volume strategy. So far, there is still limited rigorous data to support its use [1, 6, 13, 22]. Vaccination and early initiation of anti-viral therapy both for prophylaxis and treatment may be the most effective means of reducing maternal mortality of women infected with influenza [7, 26]. The findings in our study raise significant questions about triage and resource allocation that need to be better addressed prior to the next outbreak  and make the recommendation of such extensive measures as ECMO almost irrelevant for this country and similar socioeconomic settings.
In terms of fetal outcomes, 80% of the patients with available neonatal data (12/15) had live births, which is consistent with data in the USA but lower than that reported in the United Kingdom [5, 25]. Many of the surviving babies had low birth weight, however, consistent with previous studies [5, 21, 25].
Strengths of our study include the use of national data, given the fact that all maternal mortality including mortality from H1N1 requires mandatory reporting. Despite limitations, our study points to several valuable lessons that can be used to guide therapy and prevention for the care of pregnant women in future influenza pandemics in developing countries. A limitation of our study is that data was not readily accessible to compare the clinical courses of survivors vs. non-survivors in the country. For that reason, predictors of poor outcomes could not be ascertained.
In summary, in preparation for the next influenza pandemic, the findings of this study suggest that it is important to implement clinical and public health strategies for timely immunization, and educate health care providers regarding the importance of early administration of antiviral therapy according to available guidelines.
We thank all the regional and local Departments of Health in Colombia for their support and commitment to improve maternal health in Colombia. We also would like to acknowledge Olga de La Ossa M.D., researcher of GRICIO, for her support in this project. We express our thanks to Beth Hott for helping with manuscript is preparation.
 ANZIC Influenza Investigators and Australasian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. Br Med J. 2010;340:c1279. Search in Google Scholar
 Beigi RH, Hodges J, Baldisseri M, English D, Magee-Womens Hospital Ethics Committee. Clinical review: considerations for the triage of maternity care during an influenza pandemic-one institution’s approach. Crit Care. 2010;14:225. Search in Google Scholar
 Centers for Disease Control and Prevention (CDC). 2009 pandemic influenza A (H1N1) virus infections-Chicago, Illinois, April-July 2009. MMWR Morb Mortal Wkly Rep. 2009;58:913–8. Search in Google Scholar
 Centers for Disease Control and Prevention (CDC). 2009 pandemic influenza A (H1N1) in pregnant women requiring intensive care-New York City, 2009. MMWR Morb Mortal Wkly Rep. 2010;59:321–6. Search in Google Scholar
 Centers for Disease Control and Prevention (CDC). Maternal and infant outcomes among severely ill pregnant and postpartum women with 2009 pandemic influenza A (H1N1)–United States, April 2009-August 2010. MMWR Morb Mortal Wkly Rep. 2011;60:1193–6. Search in Google Scholar
 Checkley W. Extracorporeal membrane oxygenation as a first-line treatment strategy for ARDS: is the evidence sufficiently strong? J Am Med Assoc. 2011;306:1703–4. Search in Google Scholar
 Choconta-Piraquive LA, Alvis Guzman N, De la Hoz Restrepo F. Costo-efectividad de la vacunacion contra influenza pandemica en mujeres embarazadas en Colombia. [Cost-effectiveness of vaccinating pregnant women against pandemic influenza in Colombia]. Rev Panam Salud Publica. 2012;31:447–53. Search in Google Scholar
 Dede FS, Celen S, Bilgin S, Ure G, Ozcan AO, Buzgan T, et al. Maternal deaths associated with H1N1 influenza virus infection in Turkey: a whole-of-population report. BJOG. 2011;118:1216–22. Search in Google Scholar
 Ellington SR, Hartman LK, Acosta M, Martinez-Romo M, Rubinson L, Jamieson DJ, et al. Pandemic 2009 influenza A (H1N1) in 71 critically ill pregnant women in California. Am J Obstet Gynecol. 2011;204:S21–30. Search in Google Scholar
 Goldkind SF, Sahin L, Gallauresi B. Enrolling pregnant women in research-lessons from the H1N1 influenza pandemic. N Engl J Med. 2010;362:2241–3. Search in Google Scholar
 Grasso S, Terragni P, Birocco A, Urbino R, Del Sorbo L, Filippini C, et al. ECMO criteria for influenza A (H1N1)- associated ARDS: role of transpulmonary pressure. Intensive Care Med. 2012;38:395–403. Search in Google Scholar
 Harris JW. Influenza occurring in pregnant women: a statistical study of thirteen hundred and fifty cases. J Am Med Assoc. 1919;72:978–80. Search in Google Scholar
 Instituto Nacional de Salud. Informe Epidemiológico Nacional 2009. Bogotá: Instituto Nacional de Salud; 2010. Search in Google Scholar
 Jamieson DJ, Honein MA, Rasmussen SA, Williams JL, Swerdlow DL, Biggerstaff MS, et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009;374:451–8. Search in Google Scholar
 Lenzi L, Mello AM, Silva LR, Grochocki MH, Pontarolo R. Pandemic influenza A (H1N1) 2009: risk factors for hospitalization. J Bras Pneumol. 2012;38:57–65. Search in Google Scholar
 Louie JK, Acosta M, Jamieson DJ, Honein MA, California Pandemic Working Group. Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med. 2010;362:27–35. Search in Google Scholar
 Martin-Loeches I, Diaz E, Vidaur L, Torres A, Laborda C, Granada R, et al. Pandemic and post-pandemic influenza A (H1N1) infection in critically ill patients. Crit Care. 2011;15:R286. Search in Google Scholar
 Ministerio de la Protección Social. Definiciones de caso para la vigilancia en Salud Pública de Influenza A H1N1. Bogotá: Ministerio de la Protección Social; 2009. Search in Google Scholar
 Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10–8. Search in Google Scholar
 Noah MA, Peek GJ, Finney SJ, Griffiths MJ, Harrison DA, Grieve R, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A(H1N1). J Am Med Assoc. 2011;306:1659–68. Search in Google Scholar
 Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team, Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009;360:2605–15. Search in Google Scholar
 Oluyomi-Obi T, Avery L, Schneider C, Kumar A, Lapinsky S, Menticoglou S, et al. Perinatal and maternal outcomes in critically ill obstetrics patients with pandemic H1N1 Influenza A. J Obstet Gynaecol Can. 2010;32:443–7, 8–52. Search in Google Scholar
 Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M, UKOSS. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. Br Med J. 2011;342:d3214. Search in Google Scholar
 Rasmussen SA, Jamieson DJ. Influenza and pregnancy in the United States: before, during, and after 2009 H1N1. Clin Obstet Gynecol. 2012;55:487–97. Search in Google Scholar
 Rasmussen SA, Jamieson DJ, Bresee JS. Pandemic influenza and pregnant women. Emerg Infect Dis. 2008;14:95–100. Search in Google Scholar
 Rasmussen SA, Jamieson DJ, Macfarlane K, Cragan JD, Williams J, Henderson Z, et al. Pandemic influenza and pregnant women: summary of a meeting of experts. Am J Public Health. 2009;99(Suppl 2):S248–54. Search in Google Scholar
 Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, Callaghan WM, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. J Am Med Assoc. 2010;303:1517–25. Search in Google Scholar
 World Health Organization. Trends in maternal mortality 1990 to 2008: estimates developed by WHO, UNICEF, UNFPA and The World Bank. Geneva: World Health Organization (WHO); 2010. Search in Google Scholar
 Yates L, Pierce M, Stephens S, Mill AC, Spark P, Kurinczuk JJ, et al. Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant. Health Technol Assess. 2010;14:109–82. Search in Google Scholar
The authors stated that there are no conflicts of interest regarding the publication of this article.
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