H1N1 in Pregnancy: A Tertiary Care Centre Experience

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1 H1N1 in Pregnancy: A Tertiary Care Centre Experience Ann Kinga Malinowski, MD, 1 Allison McGeer, MD, 2 Julie Robertson, MD, 1 Mathew Sermer, MD, 1 Dan Farine, MD, 1 Stephen E. Lapinsky, MD, 3 Cynthia Maxwell, MD 1 1 Maternal-Fetal Medicine Division, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto ON; University of Toronto, Toronto ON 2 Department of Microbiology, Mount Sinai Hospital, Toronto ON; University of Toronto, Toronto ON 3 Division of Critical Care, Mount Sinai Hospital, Toronto ON; University of Toronto, Toronto ON Abstract Objective: To elucidate factors pertinent to the course and outcome of H1N1 infection in pregnancy. Methods: We conducted a retrospective chart review of H1N1- affected pregnant patients at Mount Sinai Hospital in Toronto, Ontario. All women who tested positive for H1N1 from June 1, 2009, to December 5, 2009, were identified. Records were reviewed to determine pregnancy status. Information from clinic and hospital charts of pregnant patients was gathered using data collection forms previously approved by the Mount Sinai Hospital Research Ethics Board. Results: Of 42 patients, 12 were inpatients and 30 were outpatients. Sixty percent of patients (25/42) presented in the third trimester, 33% (14/42) had comorbidities, and 69% were afebrile and therefore did not have a condition that met the United States Centers for Disease Control and Prevention s definition of influenza-like illness. Antiviral agents were administered promptly in most patients, but delays resulted in one third of patients being treated more than 48 hours from the onset of symptoms. Seventyone percent (30/42) did not require hospitalization, and 58% of hospitalized patients (7/12) were admitted for reasons unrelated to H1N1. Although one quarter of hospitalized patients (3/12) had delivered at the time of discharge, no deliveries occurred because of H1N1. Most patients (91%) delivered at term. One half of the deliveries (51%) were by Caesarean section, but none of these were because of H1N1 infection. Most of the infants (88%) were appropriately grown, and none were admitted to the NICU because of H1N1. Conclusion: Infection with H1N1 in pregnant women has the propensity to result in significant maternal and fetal morbidity and mortality, and requires vigilance in assessment and prompt treatment. In contrast to reports published to date, our cohort experienced a largely uncomplicated course of illness, with minimal fetal and maternal impact in most instances. J Obstet Gynaecol Can 2011;33(7): Key Words: H1N1, pregnancy, outcomes Competing Interests: None declared. Received on October 28, 2010 Accepted on December 22, 2010 Résumé Objectif : Élucider les facteurs liés à l évolution et à l issue de l infection au virus H1N1 pendant la grossesse. Méthodes : Nous avons mené une analyse rétrospective des dossiers de patientes enceintes atteintes d une infection au virus H1N1 au Mount Sinai Hospital à Toronto, en Ontario. Toutes les femmes ayant obtenu des résultats positifs au dépistage du virus H1N1 entre le 1 er juin 2009 et le 5 décembre 2009 ont été identifiées. Les dossiers ont été analysés afin de déterminer leur statut en matière de grossesse. Les renseignements issus des dossiers cliniques et hospitaliers des patientes enceintes ont été recueillis au moyen de formulaires de collecte de données qui avaient été préalablement approuvés par le Mount Sinai Hospital Research Ethics Board. Résultats : Douze des 42 patientes étaient des patientes hospitalisées, tandis que les 30 autres étaient des patientes externes. Soixante pour cent des patientes (25/42) en étaient au troisième trimestre, 33 % (14/42) présentaient des comorbidités et 69 % étaient afébriles (ainsi, leur état ne répondait pas à la définition du syndrome grippal des Centers for Disease Control and Prevention américains). Bien que des antiviraux aient été administrés sans retard à la plupart des patientes, certains délais ont fait en sorte qu un tiers des patientes ont été traitées plus de 48 heures à la suite de l apparition des symptômes. Soixante et onze pour cent (30/42) des patientes n ont pas nécessité une hospitalisation et 58 % des patientes hospitalisées (7/12) l ont été pour des raisons n étant pas liées au virus H1N1. Bien que le quart des patientes hospitalisées (3/12) aient déjà connu leur accouchement au moment de l obtention de leur congé de l hôpital, aucun accouchement n a pu être imputé au virus H1N1. La plupart des patientes (91 %) ont accouché à terme. La moitié des accouchements (51 %) ont été effectués par césarienne; toutefois, aucune de ces césariennes n a pu être imputée à la présence d une infection au virus H1N1. La plupart des nouveaunés (88 %) présentaient une croissance appropriée et aucun d entre eux n a été admis à l UNSI en raison du virus H1N1. Conclusion : Chez les femmes enceintes, l infection au virus H1N1 présente le potentiel de donner lieu à une morbidité et à une mortalité maternelles et fœtales significatives et nécessite de la vigilance au moment de l évaluation et la mise en œuvre d un traitement sans délai. Contrairement aux rapports publiés à ce jour, notre cohorte a connu une maladie en grande partie exempte de complications, la plupart des cas n en ayant ressenti que des effets fœtaux et maternels minimes. 698 JULY JOGC JUILLET 2011

2 H1N1 in Pregnancy: A Tertiary Care Centre Experience INTRODUCTION Influenza is an acute respiratory illness caused by RNA viruses in the family orthomyxoviridae. Recently a novel H1N1 subtype of Influenza A emerged. The spread and severity of infection was of a magnitude sufficient to warrant declaration of a Level 6 pandemic by the World Health Organization on June 11, Previous reports describe excess morbidity and mortality in influenza-affected pregnant women. 2,3 Such conclusions were based on experiences of earlier pandemics, including the influenza pandemic of Pregnancy-related alterations in the immune, respiratory, and cardiovascular systems are cited as factors predisposing women to more severe effects of certain pathogens, including influenza, thereby placing pregnant women in the high-risk category. 5 We describe here a cohort of pregnant patients who experienced a more benign course of illness than generally reported previously Two waves of H1N1 activity (periods of time during which > 5% of specimens submitted for respiratory viral testing yielded influenza) occurred in Toronto in 2009: the first was from May 10 to July 12, and the second from October 1 to November The outcomes of pregnant patients infected with H1N1 influenza during this period were examined. METHODS Mount Sinai Hospital is a tertiary care teaching hospital in Toronto, Ontario, which accommodates approximately 6500 deliveries annually. We conducted a retrospective chart review of H1N1-affected pregnant patients seen at this institution to elucidate factors pertinent to the course and outcome of H1N1 in pregnancy. Starting in May 2009, testing for H1N1 by polymerase chain reaction was performed daily on-site. From May to December 2009, all patients hospitalized with acute respiratory illness, and all who developed such illness while hospitalized, were tested for H1N1. During periods of influenza activity, all emergency department and case room patients and all patients admitted to the hospital were screened for fever and symptoms of acute respiratory illness, and tested for influenza (including H1N1) if symptomatic. Before the second wave, all pregnant women were provided with information letters regarding symptoms of H1N1, with a recommendation to report all acute respiratory illness either to their physician or to a departmental hotline established for pandemic information. For the first four weeks of each wave, everyone presenting to the emergency department or the case room with acute respiratory illness was tested. During the subsequent weeks of each wave, testing was reserved for pregnant women who declined antiviral therapy without confirmation of diagnosis. We identified all individuals whose specimens yielded H1N1 from June 1, 2009, to December 5, Their records were checked to determine pregnancy status and a detailed review of relevant clinic and hospital charts was conducted. Information from clinic and hospital charts of pregnant patients was gathered using data collection forms previously approved by the Mount Sinai Hospital Research Ethics Board, which also approved the study. RESULTS Three hundred ninety-three patients experiencing a spectrum of disease severity tested positive for H1N1 at Mount Sinai Hospital from June 1 to December 5, 2009 (Figure). Of these, 42 were pregnant, and their data were analyzed further. The average gestational age at presentation for medical assessment was 27+6 weeks (range 5+0 to 40+6 weeks). Median maternal age was 31 years (range 19 to 41 years). The characteristics of affected women are shown in Table 1. The average time from onset of symptoms to presentation for medical assessment was 2 days (range 1 to 14). Thirty women (73%) presented within 48 hours of symptom onset, while 11 (27%) presented more than 48 hours after symptom onset. Thirty-eight women (90%) were treated with antiviral agents, on average at 2.5 days (range 1 to 15) from the onset of symptoms. Twenty-six patients (68%) were treated within 48 hours of symptom onset, and 12 (32%) more than 48 hours after symptom onset. Seven inpatients (58%) and none of the outpatients received additional antibiotics. As shown in Table 2, women disclosed a variety of symptoms, most admitting to more than one. Twenty-six patients (62%) complained of fever, but only 11 (31%) of the 35 whose temperatures were recorded were febrile. Twelve patients (29%) were hospitalized, with an average length of stay of 8.8 days (range 2 to 27); 58% of these admissions were for reasons unrelated to H1N1. The reasons for admission included fetal hydrops, induction of labour, short cervix, scheduled Caesarean section, and threatened preterm labour. Three patients (25%) were admitted to the ICU, with an average length of stay of 7 days (range 1 to 19). One of these patients required mechanical ventilation and remained intubated for 14 days. There was no maternal mortality. JULY JOGC JUILLET

3 Spectrum of illness in patients positive for H1N1 ph1n1 n=393 Non-pregnant n=351 (89%) Pregnant n=42 (11%) Inpatients n=38 (11%) Outpatients n=313 (89%) Inpatients n=12 (29%) Outpatients n=30 (71%) ICU n=19 (50%) ICU n=3 (25%) Of the hospitalized patients, 75% were undelivered at discharge. Of the three who delivered, none did so as a consequence of H1N1. Specifically, two patients were admitted for a scheduled induction of labour and the third for a scheduled Caesarean section. They reported symptoms on admission to hospital. Three types of H1N1-related complications were encountered, and they all involved inpatients. The complications included one case each of pan-sinusitis and acute respiratory distress syndrome and five cases of pneumonia. Seven patients had chest X-rays, and five of these were abnormal. No bacterial pathogens were identified in association with any of the cases of pneumonia. Data for obstetrical and neonatal outcomes were available for 25 patients; eight patients remained undelivered, four had deliveries elsewhere, and five were lost to follow-up. The average gestational age at delivery was 38+3 weeks (range 28+0 to 41+5 weeks). There were four preterm deliveries. One occurred at 28 weeks (termination of pregnancy for homozygous alpha thalassemia), two followed spontaneous preterm labour (at 36+4 and 36+6 weeks), and the fourth resulted from preterm prelabour rupture of membranes (PPROM) at 36+1 weeks. The termination of pregnancy could not be attributed to H1N1; therefore, 12% of pregnancies (3/25) resulted in a preterm delivery. The course of labour and delivery in women with H1N1 is shown in Table 3. Twenty-four infants (96%) were liveborn and one (4%) was stillborn following termination of pregnancy. There were no neonatal deaths. Average birth weight was 3234 g (range 1780 to 4670 g). Four infants (16%) had low birth weight (< 2500 g). Mean Apgar scores were 8 (range 5 to 9) at one minute and 9 (range 9 to 10) at five minutes. Two newborns (8%) were admitted to the NICU, one because of prenatally diagnosed congenital heart block, and one because of PPROM, low birth weight, and prematurity (36+1 weeks). DISCUSSION Studies published since April 2009 have consistently demonstrated increased morbidity and mortality among pregnant women with H1N1 infection Jamieson et al. 6 reported that pregnant women with H1N1 influenza were 4.3 times more likely than the general population to require admission to hospital. 6 Thirteen percent of initial H1N1- related deaths were in pregnant women; this is 13 times higher than expected from the prevalence of pregnant women in the population. 6 Similarly, pregnant women accounted for 6.4% of hospitalized cases and 4.3% of 700 JULY JOGC JUILLET 2011

4 H1N1 in Pregnancy: A Tertiary Care Centre Experience Table 1. Characteristics of pregnant women positive for H1N1 n Age, years 15 to to to to to to 45 1 Median (range) 31 (19 to 41) Race Caucasian 19 Asian 14 African 2 Other 2 Unknown 5 Education Postsecondary 28 Unknown 14 Smoking status Smoker 2 Non-smoker 35 Unknown 5 Comorbid conditions Healthy 28 Cardiovascular disease 3 Pulmonary disease 4 Diabetes mellitus 6 Malignancy 1 Gravidity 1 15 > 2 27 Parity Nulliparous 20 > 1 22 Type of pregnancy Singleton 41 Twin 1 Timing of infection First trimester 2 Second trimester 15 Third trimester 25 Antiviral treatment Treated 38 Within 2 days of 26 symptoms Antibiotic treatment Yes 7 No 35 H1N1 vaccine Yes 5 No 5 Unknown 6 H1N1 before vaccine developed 26 deaths from H1N1 in a cohort of 62 pregnant and 74 non-pregnant patients in New York City, and they were 7.2 times more likely to be admitted than their non-pregnant counterparts. 7 This corresponds to the disproportionate rates of critical illness observed in Canada, where pregnant women accounted for 7.7% of critically ill patients with H1N1, 8 and in Australia and New Zealand, where this proportion was 9.1%. 9 In the Manitoba experience, 6/33 pregnant women with H1N1 were admitted to the ICU, and two died. 10 Our study is distinct because it reports on outcomes of both hospitalized and non-hospitalized H1N1-infected pregnant women in a setting in which screening was recommended for all patients with acute respiratory illness. Because all hospitalized patients were tested, but empiric therapy (rather than testing) was recommended for outpatients at the peak of influenza activity, hospitalized cases are over-represented in our cohort, suggesting that the average course of H1N1 infection is even more benign than we observed. At the time of peak influenza activity, 80% of adults with fever and respiratory symptoms have influenza, 12,13 and delaying treatment to wait for test results reduces treatment efficacy In this setting, testing adds to the cost of management but does not alter it. Thus testing at the time of peak influenza activity was reserved for women whose symptoms caused concern with respect to H1N1, but who were unwilling to accept treatment without laboratory confirmation. Of the 393 patients who tested positive for H1N1, 11% were pregnant at the time of diagnosis. Ethnicity was diverse, and different ethnicities were well represented. The study population included mostly patients with postsecondary education, in keeping with the demographic served by Mount Sinai Hospital. One third of patients had comorbidities, analogous to the report of Jamieson et al. 6 Median age at presentation in our cohort was 31 years; in the report by Jamieson et al., the median age was 26 years. 6 The average gestational age at presentation was 27+6 weeks, with 4%, 36%, and 60% presenting in the first, second, and third trimester, respectively. This contrasted with the cohort of Jamieson et al., in which 65% of subjects presented in the first or second trimester and 26% in the third, 6 but was similar to the cohort of Creanga et al., in which 54.8% presented in the third trimester. 7 As in earlier reports, 14,17 the most commonly reported symptoms in our cohort included cough, fever, myalgia, and shortness of breath. However, unlike previous reports of fever in 97%, 6,7 only 26 of our patients (63%) had this complaint. Furthermore, of 35 patients with recorded temperature, only 31% were actually febrile. Sixty-nine JULY JOGC JUILLET

5 Table 2. Symptoms at presentation Symptom n % Cough Fever Sore throat Myalgias Shortness of breath Chest pain Rhinorrhea Headache 5 12 Nausea/vomiting 6 15 Diarrhea 2 5 Undocumented 1 2 Table 3. Course of labour and delivery in women with H1N1 Type n % Labour Spontaneous Induced* 7 28 Delivery Spontaneous vaginal delivery 9 36 Assisted vaginal delivery 3 12 Elective Caesarean section 5 20 Urgent Caesarean section 8 32 * termination of pregnancy (1), postdates (2), maternal cardiac condition (1), cholestasis (1), term PROM with group B streptococcus (1), preeclampsia (1) repeat (3), prenatally diagnosed congenital heart block (1), transverse lie (1) failure to progress in labour (3), non-reassuring fetal heart rate pattern (2), breech presentation in labour (1), PPROM and history of myomectomy (1), preeclampsia with previous CS (1) percent of women did not meet the criteria of the United States Centers for Disease Control and Prevention case definition of influenza-like illness (fever >37.8ºC and cough and/or sore throat). 5 The diagnosis of H1N1 in this subgroup would have been missed on clinical grounds alone if not for the heightened surveillance of the time. Yet it is reassuring that all patients in this category had a mild course of illness. In the study by Creanga et al., 7 the proportion of women who did not meet the criteria for influenza-like illness was somewhat lower at 25%. Pregnant women, however, were found to have fever and influenzalike illness less often than non-pregnant women (86% vs. 93%, P = 0.01 and 77% vs. 89%, P = 0.06, respectively), 7 suggesting that a heightened level of awareness is necessary for timely diagnosis of influenza in pregnancy. Also of interest is the finding of Miller et al. 18 that patients with H1N1 infection had a higher proportion of individuals presenting with gastrointestinal symptoms than patients with other types of influenza. In our study, 15% of patients had nausea or vomiting and 5% had diarrhea, while Miller et al. 18 reported gastrointestinal symptoms in 50% of their cohort of 18 patients. The average time from symptom onset to presentation for assessment in our study was two days, with 73% presenting within 48 hours, and 27% presenting more than 48 hours after symptom onset. Bearing in mind the United States Centers for Disease Control and Prevention recommendation that prompt empiric antiviral treatment should be provided to pregnant women with H1N1 infection, and that treatment is most effective when started in the first 48 hours of illness, 16 any further delay in treatment places a number of individuals outside that efficacy window. Ninety percent of patients in our study were treated with antiviral agents, on average within 2.5 days of symptom onset. Specifically, 68% were treated within 48 hours and 32% after more than 48 hours. However, delays in presentation for medical assessment coupled with delays in receiving antiviral agents following presentation left one third of patients outside the 48-hour window of efficacy. Beyond educating patients, the medical profession has little control over the first of these causes of delay, but the use of empiric treatment without swab confirmation of disease can minimize the effects of the second cause of delay. Diligence in providing treatment at presentation would have allowed another 8% of our patients to be treated inside the 48-hour window. Nevertheless, the fact that 68% of women received treatment within 48 hours of symptoms may partially explain the high prevalence of benign outcomes in our cohort, as it contrasts with the report of Creanga et al. 7 of antiviral treatment within two days of symptom onset in 48.4% of pregnant women and lack of treatment in 6.5%. The disparity is also evident in the report of Hewagama et al., 17 which highlights the higher proportion of pregnant women experiencing H1N1-related complications, but also describes antiviral treatment in 77% of their cohort of 43 women and treatment within two days of symptom onset in only 28% of patients overall. Similarly, Siston et al. 15 found that pregnant women treated more than four days after symptom onset were more likely to be admitted to an ICU (56.9% vs. 9.4%; RR 6.0) than those treated within two days, and they concluded that early antiviral treatment results in fewer ICU admissions and fewer deaths in pregnant women with H1N JULY JOGC JUILLET 2011

6 H1N1 in Pregnancy: A Tertiary Care Centre Experience While 62% of patients were affected by H1N1 before the vaccine was available and 12% did not receive the vaccine, a further 12% received the adjuvanted H1N1 vaccine, yet tested positive for H1N1 despite this. Vaccination in these individuals was administered within two weeks of their diagnosis, thereby negating the possibility of development of full immunity. It is unknown if their disease course would have been more serious if they had not received the vaccine. The first wave of H1N1 infection in the summer was responsible for 26% of total identified cases, and the second, in the autumn and winter, was responsible for 74%. Both waves resulted in similar rates of admission to hospital. Overall, 29% of patients were hospitalized. Of these, 58% of patients were admitted for reasons unrelated to H1N1: these patients either had concurrent H1N1 infection not requiring admission when hospitalized for another reason, or developed symptoms of H1N1 infection in hospital. Twenty-five percent of hospitalized patients were admitted to the ICU, and while one was critically ill and required mechanical ventilation, the other two were admitted directly following transfer from a community hospital. Each of these two patients had an uneventful 24-hour ICU stay prior to transfer to the ward. It appeared that their ICU admissions were cautionary in view of the heightened vigilance on the part of physicians with respect to the possibility of serious sequelae of H1N1 in pregnancy, and in view of the recent experience with the other severely affected patient. Chest X-rays were performed in 17% of cases, and 71% showed abnormal findings. These results highlight the judicious and proper selection of patients in whom this test proved to be beneficial in further guiding treatment. 19 Three quarters of hospitalized patients were undelivered at the time of discharge. None of the deliveries were a result of H1N1 infection. The average gestational age at delivery was 38+3 weeks, with only three patients delivering preterm. It is difficult to know whether H1N1 contributed to these preterm deliveries, although it seems unlikely, as all three mothers had a benign course. It also contrasts with the report of Creanga et al. 7 of adverse neonatal outcomes (NICU admission or death) in 5/6 severely ill women and 2/16 women with moderate illness. 7 However, it is difficult to compare these two reports, because most patients in our cohort had a mild illness, and the severely ill woman had a term delivery with a good neonatal outcome. Labour was spontaneous in 44% of our patients and induced in 28%. It resulted in spontaneous vaginal delivery in 36%, assisted vaginal delivery in 12%, and urgent Caesarean section in 32%. Scheduled Caesarean sections were performed in an additional 20%. Although overall 52% of patients had a Caesarean section, none were a consequence of H1N1. The Caesarean section rate is higher in this cohort than our institutional rate of approximately 35%. The reason for this is unclear and may represent a potential bias related to the relatively small sample size. Neonatal outcomes were reassuring. The live birth rate was 96%, with no neonatal deaths. The only stillbirth followed an elective termination of pregnancy. Only four infants had low birth weight. Although two newborns were admitted to the NICU, it is unlikely that their admissions stemmed from maternal H1N1 diagnosis. One infant had prenatally diagnosed congenital heart block that was clearly unrelated to H1N1; the other was admitted following PPROM and preterm delivery at 36+1 weeks. It is possible that maternal H1N1 infection was a contributing factor in this delivery, but the maternal illness again was benign, making this unlikely. This is in contrast to previous reports of poor neonatal outcomes, 10,17,18 but is very much in keeping with mild maternal disease. This study has several limitations. It is descriptive in nature and based on a cohort from a single centre, so its generalizability is limited. It involved patients who were identified through screening during a period of heightened awareness and thus included patients tested because of symptoms that at another time would likely not have attracted medical attention. CONCLUSION Reports to date have emphasized that pregnancy increases the risk of severe disease due to H1N1, and that early therapy reduces the risk of severe disease. In contrast to these reports, which largely describe illness in patients requiring hospital admission, the course of disease in our cohort of both inpatients and outpatients under surveillance was mild overall. The difference in severity is most likely due to our active surveillance, but it may also in part be because antiviral agents were administered promptly in a large proportion of patients. Nonetheless, delays resulted in one third of our patients being treated at more than 48 hours after symptom onset, when the efficacy of treatment is diminished. The majority of patients did not require hospitalization, and many of those who did were admitted for reasons unrelated to H1N1. Virtually all patients delivered at term and none as a consequence of H1N1. Most infants were appropriately grown. There were no fetal or neonatal deaths resulting from H1N1. Thus, although H1N1 does have the propensity to cause significant maternal and fetal morbidity and mortality, requiring vigilance in assessment and prompt treatment, it is reassuring that our cohort experienced an uncomplicated course of illness with minimal fetal and maternal impact in most. JULY JOGC JUILLET

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