Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study

BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c1279 (Published 19 March 2010)
Cite this as: BMJ 2010;340:c1279

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Although it has been widely believed that pregnant women have a greatly increased risk of developing severe pneumonitis and of death associated with pandemic (H1N1) 2009 (1, 2) pregnant women accounted for only 0.42% of all 17,646 patients who required hospitalisation and there was no maternal mortality during pandemic (H1N1) 2009 in Japan, according to the information released by the Japanese Ministry of Health, Labour and Welfare (JMLHW), whilst the JMHLW estimated that approximately 12% of the Japanese population visited clinics or hospitals seeking treatment for flu by mid- December 2009. Thus, it is apparent that pregnant Japanese women were less likely to develop severe complications compared with non-pregnant Japanese women and pregnant women in other countries.

The Japan Society of Obstetrics and Gynecology (JSOG) aggressively intensified outreach to pregnant women, policy-makers and medical workers, to minimise the number of cases of pandemic (H1N1) 2009 infection among pregnant women. For example, JSOG recommended prompt use of antiviral drugs for treatment of pregnant women on May 8 via their website, active use of antiviral drugs for prophylaxis after close contact with an infected person on August 4, and vaccination against pandemic (H1N1) 2009 on September 7.

Our study performed during pandemic (H1N1) 2009 (in preparation for publication) suggested that more than 50% of pregnant patients with pandemic (H1N1) 2009 took antiviral drugs for prophylaxis after coming into close contact with an infected person, and more than 60% of pregnant women had been vaccinated within 1.5 months after the availability of a vaccine for pandemic (H1N1) 2009 in Japan.

The vaccination rate and use of antiviral drugs for seasonal flu was considered to be less than 10% among pregnant Japanese women. These changes in behaviour may have contributed to the lack of maternal mortality associated with this pandemic in Japan.

References

(1) 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. BMJ 2010;340:c1279.

(2) Lapinsky SE. Critical illness as a result of influenza A/H1N1 infection in pregnancy. BMJ 2010;340:721-722

Competing interests: None declared

Competing interests: None declared

Takahiro Yamada, Assistant Professor, Hokkaido Univ., Sapporo, Japan

Takashi Yamada, Tsuyosi Saito, Kazuo Sengoku, and Hisanori Minakami

060-8638

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The ANZIC Influenza Investigators and Australian Maternity Outcomes Surveillance System reported, that pregnant women are at high risk of A(H1N1) influenza complications: respiratory distress, death (1). Comparable data was reported in United States to the Centers for Disease Control and Prevention (2). These data support the decision of public health authorities to consider pregnant women as a priority group for vaccination. In France, it has been recommended to vaccinate all pregnant women from the second trimester of pregnancy with a nonadjuvanted vaccine but there is no available data about effects of new A(H1N1) vaccines on pregnant women. Thus, we report results of the French Pharmacovigilance survey of Adverse Drug Reactions (ADRs) occurring in vaccinated pregnant women during winter 2009.

We investigated spontaneous reports of ADRs following A(H1N1) vaccination in pregnant women recorded during the whole vaccination campaign. Between October 20, 2009 and March 28, 2010, 30 “serious” ADRs occurring in pregnant women were notified to the French network of Pharmacovigilance: among them, 13 intra-uterine deaths and 12 spontaneous abortions.

Intra-uterine death rates range from 2 to 9 per 1000 of pregnancies in European countries (3).The number of vaccinated pregnant women in France during winter 2009 was around 100 000. Thus, the estimated number of vaccinated pregnant women who could have experienced a fetal death would be higher than the number of reported Intra-uterine deaths. According to Black et al (4), 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination (basal risks without vaccine). Thus, the numbers of notified intra-uterine deaths and spontaneous abortion are considerably lower than the expected number of cases.

Despite limits of this kind of survey (especially underreporting), this survey does not allow detecting any safety signal of concern at least with a short term follow-up (5 months). Other epidemiological studies are necessary to evaluate long term potential risk of A(H1N1) vaccines in pregnant women.

1. The ANZIC influenza investigators and Australian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010, 340: c1279.

2. Siston AM, Rasmussen SA, Honein, MA Fry AM, Seib K, Callaghan WM, Louie J, Doyle TJ, Crockett M, Lynfield R, Moore Z, Wiedeman C, Anand M, Tabony L, Nielsen CF, Waller K, Page S, Thompson JM, Avery C, Springs CB, Jones T, Williams JL, Newsome K, Finelli L, Jamieson DJ: Pandemic 2009 Influenza A(H1N1) Virus Illness Among Pregnant Women in the United States. JAMA 2010, 303: 1517-25.

3. EURO-PERISTAT Project, with SCPE, EUROCAT, EURONEOSTAT. European Perinatal Health Report. 2008. Available: www.europeristat.com

4. Black S, Eskola J, Siegrist CA, Halsey N, Macdonald N, Law B, Miller E, Andrews N, Stowe J, Salmon D, Vannice K, Izurieta HS, Akhtar A, Gold M, Oselka G, Zuber P, Pfeifer D, Vellozzi C: Importance of background rates of disease in assessment of vaccine safety

Competing interests: None declared

Competing interests: None declared

Isabelle Lacroix, Dr

Christine Damase-Michel, Carmen Kreft-Jais, Anne Castot, Jean-Louis Montastruc, the French Association of Regional Pharmacovigilance Centres

Service de Pharmacologie, Faculté de Médecine, 37 allées Jules Guesde, 31000 Toulouse, France

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The ANZIC Influenza Investigators and Australian Maternity Outcomes Surveillance System reported, that pregnant women are at high risk of A(H1N1) influenza complications: respiratory distress, death (1). From June to August 2009, 64 pregnant women with 2009 A(H1N1) influenza were admitted to an intensive care unit in Australia or New Zealand. 44 women were mechanically ventilated and 7 died. Of 60 births, 4 were stillbirths and 3 infant deaths. From April to August 2009, 788 cases of A(H1N1) influenza in pregnant women were reported in United States to the Centers for Disease Control and Prevention (2). Among them, 65% were hospitalized and 3.8% died.

It has been postulated that the risk of influenza complications might be higher in the second and third trimester of pregnancy. These data support the decision of public health authorities to consider pregnant women as a priority group for vaccination. In France, it has been recommended to vaccinate all pregnant women from the second trimester of pregnancy with a nonadjuvanted vaccine. Several studies suggest that inactivated seasonal influenza vaccines are safe during pregnancy (3-5) but there is no available data about effects of new A(H1N1) vaccines on pregnant women. Thus, we report results of the French Pharmacovigilance survey of Adverse Drug Reactions (ADRs) occurring in vaccinated pregnant women during winter 2009.

The French Pharmacovigilance system consists of a network of 31 Regional Centres. According to the law, physicians must report "serious" or "unexpected" ADRs as defined by WHO. During winter 2009, an intensive pharmacovigilance survey of H1N1 influenza was performed by the French network of Regional Pharmacovigilance Centres. We investigated spontaneous reports of ADRs following A(H1N1) vaccination in pregnant women recorded during the whole vaccination campaign. During this period, 6 million persons were vaccinated and pregnant women were the second group who had priority to access to the vaccine after health professionals.

Between October 20, 2009 (beginning of the vaccination campaign) and March 28, 2010, 30 "serious" ADRs occurring in pregnant women were notified to the French network of Pharmacovigilance: among them, 13 intra-uterine deaths and 12 spontaneous abortions. Intra-uterine deaths were diagnosed 7.9 ± 7.5 [1-23[ days after vaccination. Mean gestational age of intra uterine death occurrence was 28 ± 4 weeks of pregnancy. In 6 cases, risk factors were identified (umbilical cord striction, eclampsia, hydatiform mole, infections). Spontaneous abortions were reported at 11 ± 4 weeks of pregnancy. They occurred 17.2 ± 16 [1-56[ days after vaccination. In 3 cases, other potential causes were identified: 1 umbilical cord striction, 1 infection HHV8 in a VIH infected woman and 1 anaphylactic shock one hour after vaccination. The remaining ADRs were stillbirth, fetal tachycardia, uterine contractions/fetal arythmia, respiratory distress and anamnios/intra-uterine growth retardation.

Intra-uterine death rates range from 2 to 9 per 1000 of pregnancies in European countries (6).The number of vaccinated pregnant women in France during winter 2009 was around 100 000. Thus, the estimated number of vaccinated pregnant women who could have experienced a fetal death would be higher than the number of reported Intra-uterine deaths. According to Black et al (7), 397 per 1 million vaccinated pregnant women would be predicted to have a spontaneous abortion within 1 day of vaccination (basal risks without vaccine). Thus, the numbers of notified intra-uterine deaths and spontaneous abortion are considerably lower than the expected number of cases.

This report summarizes initial French data about spontaneous notifications of ADRs following A(H1N1) vaccination in pregnant women. Despite limits of this kind of survey (especially underreporting), this survey does not allow detecting any safety signal of concern at least with a short term follow-up (5 months). Other epidemiological studies are necessary to evaluate long term potential risk of A(H1N1) vaccines in pregnant women.

1. The ANZIC influenza investigators and Australian Maternity Outcomes Surveillance System. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study. BMJ 2010, 340: c1279.

2. Siston AM, Rasmussen SA, Honein, MA Fry AM, Seib K, Callaghan WM, Louie J, Doyle TJ, Crockett M, Lynfield R, Moore Z, Wiedeman C, Anand M, Tabony L, Nielsen CF, Waller K, Page S, Thompson JM, Avery C, Springs CB, Jones T, Williams JL, Newsome K, Finelli L, Jamieson DJ: Pandemic 2009 Influenza A(H1N1) Virus Illness Among Pregnant Women in the United States. JAMA 2010, 303: 1517-25.

3. Deinard AS, Ogburn P Jr: A/NJ/8/76 influenza vaccination program: effects on maternal health and pregnancy outcome. Am J Obstet Gynecol 1981, 140: 240-5.

4. Munoz FM, Greisinger AJ, Wehmanen OA, Mouzoon ME, Hoyle JC, Smith FA, Glezen WP: Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 2005, 192: 1098-106.

5. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, Omer SB, Shahid NS, Breiman RF, Steinhoff MC: Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med 2008, 359: 1555-64.

6. EURO-PERISTAT Project, with SCPE, EUROCAT, EURONEOSTAT. European Perinatal Health Report. 2008. Available: www.europeristat.com

7. Black S, Eskola J, Siegrist CA, Halsey N, Macdonald N, Law B, Miller E, Andrews N, Stowe J, Salmon D, Vannice K, Izurieta HS, Akhtar A, Gold M, Oselka G, Zuber P, Pfeifer D, Vellozzi C: Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet 2009, 19, 374: 2115-22.

Competing interests: None declared

Competing interests: None declared

Isabelle Lacroix, Dr

Christine Damase-Michel, Carmen Kreft-Jais, Anne Castot, Jean-Louis Montastruc, the French Association of Regional Pharmacovigilance Centres

Service de Pharmacologie, Faculté de Médecine, 37 allées Jules Guesde, 31000 Toulouse, France

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Editor, I read the report by The ANZIC Influenza Investigators and Australasian Maternity Outcomes Surveillance System with a great interest [1]. The ANZIC Influenza Investigators and Australasian Maternity Outcomes Surveillance System concluded that "Pregnancy is a risk factor for critical illness related to 2009 H1N1 influenza, which causes maternal and neonatal morbidity and mortality [1]." Indeed, the problem of swine flu on pregnant subjects is very interesting. The first concern on this topic was raised by Wiwanitkit since its early outbreak in May 2009 [2]. There are many possible explanation for the increased severity of swine flu in pregnancy. First, the lung function in pregnant, especially the near term case, is not as good as normal non pregnant. Second, if viremia occure, the virus, which is smaller than the placenta pore, can pass thorough the newborn and might cause fetal disease and complications.

References

1. The 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. BMJ 2010; 340: c1279

2. Wiwanitkit V. Obstetrical concern on new emerging swine flu. Arch Gynecol Obstet. 2010 Feb;281(2):369.

Competing interests: None declared

Competing interests: None declared

professor viroj wiwanitkit, physician, director

wiwanitkit house, bangkhae, bangkok thailand 10160

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The findings of the study are a real eye-opener. Despite the advanced facilities, the impact of influenza H1N1 on the maternal & neonatal mortality & morbidity was found to be substantial.

It is worth speculating the impact of HINI infection on the mother & child health in developing countries like mine. I wish similar studies are conducted in the third world nations. It is essential to find a solution where pregnancy rate is higher and because of lack of appropriate facilities and ‘health-aid seeking’ behaviour, the maternal & infant mortality rates (MMR & IMR) are significantly higher compared to those of the developed countries. In this existing scenario, a touch of any epidemic can send these rates sky-rocketing.

If not conducting a study, at least application of the finding of this study (that Intensive management for maternal hypoxia, including caesarean section and extracorporeal membrane oxygenation lead to decrease in the mortality & morbidity) will lead to significant reduction in the mortality rates.

To conclude, the study can have an immense social impact.

Competing interests: None declared

Competing interests: None declared

Dr. Padmesh S. Jain, General Practitioner-MBBS

Mumbai, India

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Bravo Dr. Peter Lewis for pointing out the obvious.

It is indeed shameful that a government can look pregnant women into the eyes and make a statement that is demonstrably not supported by ANY evidence.

He then proceeds to show that one can (and therefore should) make a (perhaps at first glance) seemingly wild suggestion concerning the subject AND that this statement is based on solid evidence.

It is amazing that the world of medicine only now is beginning to sense that there may be truth in them thar yesteryears!

For me personally, the efficacy of Vitamin D (and Vitamin A) in the prevention and treatment of numerous infections, was spoon fed to us students by old fashioned professors who did their doctoring prior to the advent of antibiotics.

Butter, lard, fatty fish, full fat cream, (unflavoured) cod liver oil and free range eggs rang in the flu season. Pneumonia did not visit the family farms often.

I recall the simple words of the late Dr. Abram Hoffer when I fist met him, "why not use substances that are not foreign to the body."

Competing interests: None declared

Competing interests: None declared

Dr. Herbert H. Nehrlich, Private Practice

Bribie Island, Australia

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Whilst the Australian Government is recommending the H1N1 vaccine for pregnant women, and claim that ‘The Panvax H1N1 vaccine, just like the seasonal flu vaccine, is safe for mum and her unborn baby’, it is important to realise that ‘the safety profile of the vaccine in pregnant women is unknown’ (manufacturer’s Product Information).

In Australia, the Panvax H1N1 vaccine has been produced in multi-dose vials, containing the preservative thiomersal (also known as thimerosal in the United States). Each dose of the vaccine contains approximately 25 mcg of mercury, and injecting a known neurotoxin into pregnant women seems foolish to say the least, as the developing foetal nervous system is particularly vulnerable to mercury exposure.

Data on the clinical efficacy of the H1N1 vaccine is limited too. Although it assumed that it will work as well as the regular influenza vaccination, a recent Cochrane review (which included 75 studies) on vaccines for preventing influenza in the elderly (the group who might be most likely to benefit), concluded that ‘Due to the poor quality of the available evidence, any conclusions regarding the effects of influenza vaccines for people aged 65 years or older cannot be drawn’ (1). The available evidence in pregnant women is even less!

A far more sensible and safe approach to preventing ‘swine flu’ in pregnant women would be to ensure optimal vitamin D status, as compelling evidence indicates that vitamin D deficiency is the main factor underlying the seasonality of influenza (2).

The results of a double-blind, placebo-controlled trial of vitamin D3 supplementation (1,200 IU/day) to prevent seasonal influenza A in schoolchildren have been recently published (3). This study demonstrated that vitamin D3 supplementation during winter significantly reduces the incidence of influenza A. In those children who had not previously been taking vitamin D supplements, there was a 64% reduction in influenza A in the vitamin D group compared with the placebo group.

Whilst as yet, there are no randomised trials in pregnant women, a reasonable and very safe dose of vitamin D3 in pregnancy would be 5,000 IU/day, although ideally dosage could be individualised to attain and maintain 25-hydroxyvitamin D levels in the optimal range (100-200 nmol/L).

Perhaps it is also time to make a switch from mass influenza A and H1N1 vaccination to mass vitamin D supplementation as prophylaxis against influenza (and indeed, many other diseases too).

(1) Vaccines for preventing influenza in the elderly. Jefferson T et al. Cochrane Database of systemic Reviews 2010, Issue 2. Art. No.: CD004876

(2) On the epidemiology of influenza. John J Cannell et al. virology Journal 2008;5:29

(3) Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Mitsuyoshi Urashima et al. Am J Clin Nutr 2010; published online, March 10, 2010

Competing interests: None declared

Competing interests: None declared

Peter J Lewis, Integrative physician

15 South Steyne, Manly, NSW 2095, Australia

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