From August 1st through December 31st, 2009, 315 pregnant or postpartum women with confirmed 2009 A/H1N1v influenza were included in the R3G database, and subsequent data were collected by the French web-based registry. Among these patients, 164 (52%) were outpatients, 111 (35%) were hospitalized in obstetric or medical wards, and 40 (13%) were hospitalized in an ICU. Dates of symptom onset ranged from July 21st to December 30th, 2009 (), but most of the cases occurred between the 42nd and 49th week of 2009.
Temporal repartition of laboratory-confirmed 2009 A/H1N1v infection among pregnant women in the French registry according to patient status.
Among the 164 outpatient women, 109 (66%) were in the first or second trimester of pregnancy, whereas 87 of the 111 hospitalized non-severe outcome women (78%) and 27 of the 40 ICU (most severe) patients (68%) were in the third trimester of pregnancy (, p<0.001). Only one ICU patient presented with influenza symptoms two days after an elective cesarean section following an uneventful pregnancy and was the single postpartum case. Five patients were twin pregnancies, and none of them had a severe outcome. Four women developed 2009 pandemic A/H1N1v influenza infection despite vaccination with the 2009 H1N1 monovalent vaccine. Notably, these four women had received the first injection of the vaccine less than 10 days before the onset of flu.
Gestational age at onset of symptoms according to the severity of symptoms.
The main characteristics of the patients are summarized in . Coexisting illnesses were frequent, especially among ICU patients (23 of 40, 58%). In contrast, pregnancy per se was the only risk factor in 71% and 73% of the moderate and mild outcomes, respectively (p<0.001). Asthma (9%) and obesity (12%) were the most frequent co-morbidities among the 315 patients. Whereas there was no significant difference in the prevalence of obesity among the three groups, chronic respiratory disease was significantly more frequently reported among women admitted to the ICU (11 of 40, 28%) compared to the two other groups (p<0.001). Among the nine ICU patients with a history of asthma, four reported taking daily medication, which indicated severe chronic disease. The two other ICU patients with pulmonary disease had a restrictive syndrome (Steinert's disease and severe homozygous sickle cell anemia).
Characteristics of pregnant or postpartum women with 2009 A/H1N1v influenza infection.
The most common symptoms of flu observed in this population were fever (86%), cough (84%), muscle aches (54%), headache (36%), and nausea/vomiting (10%), as shown in . Shortness of breath (22%) was more frequently reported among severe outcome ICU patients (p<0.001).
Influenza symptoms, clinical course, and treatments of pregnant or postpartum women with 2009 A/H1N1v influenza.
All patients who presented with severe outcomes received antiviral treatment (oseltamivir alone or in combination with zanamivir in two patients) (). However, the delay from symptom onset to the initiation of antiviral treatment was more than 48 hours in 22 of the 40 (55%) ICU patients (median time 3 days [min-max 0-18]). In contrast, moderate and mild outcomes demonstrated a shorter duration to the initiation of antiviral treatment as compared to severe outcomes: 80 and 88% of moderate and mild outcomes, respectively, were treated less than 48 hours after onset of the illness (p<0.001).
Antibiotic therapy, mainly amoxicillin or cephalosporin combined with spiramycin, was often initially co-prescribed with the antiviral treatment in hospitalized patients (in 80% and 68% of cases of severe or moderate disease, respectively).
Among moderate outcomes, 94 (85%) were observed and treated in obstetric wards and 17 (15%) in medical wards. The most common reason for admission was ILI. Sixteen hospitalized women in the obstetric ward were admitted only for monitoring in the absence of severe influenza symptoms or pregnancy complications, mainly during the third trimester of pregnancy. Other patients were admitted for containment (n
25), especially during the initial phase of the outbreak, pregnancy complications (n
21), or decompensation of an underlying disease (n
Although none of the 164 outpatients required specific obstetric management, 11 of the 111 hospitalized non-severe (10%) and 23 of the 39 pre-partum severe patients (59%) required specific obstetric care, as shown in . Among the hospitalized non-severe patients, this specific obstetric care was mainly the treatment of preterm labor (8 of the 111 patients), whereas in the severe patients, it was mainly a cesarean section (17 of the 39 prepartum severe patients). Most of these 17 cesarean sections were conducted for maternal hypoxemia or a worsening condition. These cesarean sections induced preterm birth in only 13 patients: 1 at less than 29 weeks GA, 4 between 29 and 31 weeks GA, and 8 between 32 and 36 weeks GA. In contrast, there was no short-term fetal impact of the flu pandemic in the fetuses of 260 of 264 pregnant women with moderate or mild outcomes of the disease (98%) for whom data are available.
Forty women (13%) were hospitalized in the ICU. The mean SAPS II and SOFA scores at admission were 28±19 and 4±3, respectively. These patients were slightly younger (p
0.001) than the non-severe patients. Ten (25%) had delivered prior to ICU admission. Most of the women (95%) were admitted to the ICU because of a respiratory failure, as shown in . At the time of admission, 32 of 40 women had pneumonia with an abnormal chest radiography or chest computed tomography (80%). Ten women (25%) presented with a documented secondary pulmonary infection during the hospital stay (Streptococcus sp., Haemophilus influenza
, Escherichia coli
, Pseudomonas aeruginosa
, Aspergillus fumigatus
, cytomegalovirus), and most of them were ventilator-associated pneumonias. Only four ICU patients had a documented bacterial co-infection at the time of admission (Streptococcus sp.
in one woman and Streptococcus pneumoniae
in three women). Cardiac dysfunction was observed in 17 patients (43%), either associated with respiratory failure in 16 patients or as a myocarditis without respiratory failure in the other patient. Twenty patients (50%) required mechanical ventilation for a median time of 13 days [2–55]. Among the twenty patients who required mechanical ventilation, eleven patients also required extracorporeal membrane oxygenation (ECMO) for a median duration of 8 days [4–38], among which nine survived. Five patients (13%) required non-invasive ventilation, and 15 (38%) required only mask or nasal oxygenation. The median ICU length of stay was 10 days [2–80]. Other ICU treatments are detailed in .
Three women died (8%). Two of them were in the third trimester of pregnancy at symptom onset, and the third was in the second trimester. All of these patients had coexisting illnesses: obesity in one (body mass index: 31 kg/m2), severe thrombotic microangiopathy in another, and cardiac valvular disease (mitral stenosis and aortic regurgitation) in the last patient. Only one of them received antiviral medication within 48 hours after symptom onset. The other two received oseltamivir at 8 and 9 days after first symptom onset, likely due to poor access to care. Refractory acute respiratory distress syndrome (ARDS, PaO2/FiO2<200) was diagnosed in two of these three patients for whom ECMO was unsuccessful; the third patient with acute lung injury (ALI, 200<PaO2/FiO2<300) received only protective mechanical ventilation but died due to massive cerebral ischemia in the context of thrombotic microangiopathy.
The multivariate analysis of risk factors for developing a severe outcome is shown in . We found a strong association between the development of a severe outcome from flu and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8; p<0.001) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1, p
0.001, and 61.2; 95% CI, 14.4–261.3, p<0.001, respectively).
Impact of coexisting illnesses and the timing of antiviral treatment on admission to an intensive care unit.
On March 31st, 2009, pregnancy outcomes were known for 146 of the 231 patients with an estimated delivery date prior to March 31st (63%). Most of the outpatients and non-ICU hospitalized women delivered vaginally (85% and 73%, respectively), as shown in . Among the 45 outpatient women who had delivered, only three of their neonates required immediate resuscitation. Moreover, only one of the 45 neonates of the outpatient women for whom data were available was admitted to the neonatal ICU.
In contrast, most of the severe outcome ICU-admitted women were delivered by cesarean section (20 of 33) with a median gestational age of 33 weeks. Most of the cesarean deliveries (17 of 20) were directly related to influenza illness. These cesarean sections were mainly emergent procedures for both fetal indications and critical maternal hypoxemia (9 of 17). In two patients, the cesarean section was performed only for fetal indications (non-reassuring fetal heart rate), and in six patients, it was performed only to improve maternal oxygenation. In two patients, the cesarean section was performed in the ICU because of severe refractory hypoxemia that was incompatible with transfer to an operating room.
Half of the neonates of women admitted to the ICU for whom data were available were admitted to the NICU, as shown in . Among the three maternal deaths, one had delivered a healthy full-term neonate at term by cesarean section (indicated because of thrombotic microangiopathy) before the ICU admission, one experienced an intra-uterine fetal death at 21 weeks of gestation, and the third delivered at 34 weeks of gestation by cesarean section to improve maternal oxygenation and for fetus salvation. This infant was admitted to the neonatal ICU due to prematurity and low Apgar scores (5 at 1 minute, 7 at 5 minutes) and had survived at the time of NICU discharge. Data collection for definitive neonatal morbidity and mortality is still in progress, but to date, no cases of A/H1N1v influenza have been reported in neonates.