Articles

H1N1 2009 inﬂuenza virus infection during pregnancy in
the USA
Denise J Jamieson, Margaret A Honein, Sonja A Rasmussen, Jennifer L Williams, David L Swerdlow, Matthew S Biggerstaﬀ, Stephen Lindstrom,
Janice K Louie, Cara M Christ, Susan R Bohm, Vincent P Fonseca, Kathleen A Ritger, Daniel J Kuhles, Paula Eggers, Hollianne Bruce,
Heidi A Davidson, Emily Lutterloh, Meghan L Harris, Colleen Burke, Noelle Cocoros, Lyn Finelli, Kitty F MacFarlane, Bo Shu, Sonja J Olsen,
and the Novel Inﬂuenza A (H1N1) Pregnancy Working Group*

Summary
Background Pandemic H1N1 2009 inﬂuenza virus has been identiﬁed as the cause of a widespread outbreak of febrile
respiratory infection in the USA and worldwide. We summarised cases of infection with pandemic H1N1 virus in
pregnant women identiﬁed in the USA during the ﬁrst month of the present outbreak, and deaths associated withthis virus during the ﬁrst 2 months of the outbreak.
Methods After initial reports of infection in pregnant women, the US Centers for Disease Control and Prevention(CDC) began systematically collecting additional information about cases and deaths in pregnant women in the USA
with pandemic H1N1 virus infection as part of enhanced surveillance. A conﬁrmed case was deﬁned as an acuterespiratory illness with laboratory-conﬁrmed pandemic H1N1 virus infection by real-time reverse-transcriptase PCRor viral culture; a probable case was deﬁned as a person with an acute febrile respiratory illness who was positive forinﬂuenza A, but negative for H1 and H3. We used population estimates derived from the 2007 census data to calculate
rates of admission to hospital and illness.
Findings From April 15 to May 18, 2009, 34 conﬁrmed or probable cases of pandemic H1N1 in pregnant women werereported to CDC from 13 states. 11 (32%) women were admitted to hospital. The estimated rate of admission forpandemic H1N1 inﬂuenza virus infection in pregnant women during the ﬁrst month of the outbreak was higher thanit was in the general population (0·32 per 100 000 pregnant women, 95% CI 0·13–0·52 vs 0·076 per
100 000 population at risk, 95% CI 0·07–0·09). Between April 15 and June 16, 2009, six deaths in pregnant women
were reported to the CDC; all were in women who had developed pneumonia and subsequent acute respiratory
distress syndrome requiring mechanical ventilation.
Interpretation Pregnant women might be at increased risk for complications from pandemic H1N1 virus infection.
These data lend support to the present recommendation to promptly treat pregnant women with H1N1 inﬂuenza
virus infection with anti-inﬂuenza drugs.
Funding US CDC.

Introduction
Pandemic H1N1 2009 inﬂuenza virus infection has been
identiﬁed as the cause of a widespread outbreak of febrile
respiratory infection in the USA1 and worldwide.2
Although the severity of this illness has ranged frommild to severe, little has been reported about how thisoutbreak has aﬀected pregnant women.3,4 During bothseasonal inﬂuenza epidemics5,6 and previous pandemics,7–9
pregnant women have increased morbidity and mortality from inﬂuenza infection compared with women
who are not pregnant. In the present outbreak beginning
April, 2009, the second documented death from pandemic
H1N1 virus infection in the USA was in a healthy pregnant woman.3 Because of concerns about the severity of
disease during pregnancy, the US Centers for Disease
Control and Prevention (CDC) implemented enhanced
surveillance for pandemic H1N1 inﬂuenza virus
infections in pregnant women in the USA. This reportsummarises the cases of infection with pandemic H1N1
inﬂuenza virus in pregnant women that have beenreported to the CDC during the ﬁrst month of theoutbreak (April 15–May 18, 2009) and deaths associatedwith this virus during the ﬁrst 2 months of the outbreak(April 15–June 16, 2009).

Methods
Setting
On April 15 and 17, 2009, CDC identiﬁed a novel
inﬂuenza A virus of swine origin in two children in two
diﬀerent counties in California. The children did nothave any epidemiological links to each other, and neither
had recent exposure to pigs. In response, CDC implemented enhanced surveillance for novel inﬂuenza A
virus infection.
Pandemic H1N1 is diagnosed from respiratory
specimens with a real-time reverse-transcriptase PCR
testing assay that was developed at the CDC.1 Initially,
CDC tested all specimens that were identiﬁed as
unsubtypable inﬂuenza A by state public healthlaboratories. On May 6, 2009, CDC began to supply state

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-0

Published Online
July 29, 2009
DOI:10.1016/S01406736(09)61304-0*Members listed at end of paper
National Center for Chronic
Disease Prevention and Health
Promotion (D J Jamieson MD,
K F MacFarlane CNM), National
Center on Birth Defects andDevelopmental Disabilities(M A Honein PhD,S A Rasmussen MD,
J L Williams MSN), National
Center for Immunization andRespiratory Diseases(D L Swerdlow MD,
M S Biggerstaﬀ MPH,
S Lindstrom PhD, L Finelli DrPH,
B Shu MD, S J Olsen PhD), and EIS
Program, Oﬃce of Workforce
and Career Development(E Lutterloh MD), Centers for
Disease Control and Prevention,
Atlanta, GA, USA; California
Department of Public Health,Richmond, CA, USA(J K Louie MD); Arizona
Department of Health Services,
Phoenix, AZ, USA(C M Christ MD); Michigan
Department of Community
Health, Lansing, MI, USA(S R Bohm MS); Texas
Department of State HealthServices, Austin, TX, USA(V P Fonseca MD); Chicago
Department of Public Health,
Chicago, IL, USA (K A Ritger MD);
Nassau County Department of
Health, Uniondale, NY, USA(D J Kuhles MD); Delaware
Division of Public Health, Dover,
DE, USA (P Eggers RN);
Snohomish Health District,
Everett, WA, USA(H Bruce MPH); DeKalb County
Board of Health, Atlanta, GA,
USA (H A Davidson MPH);
Kentucky Department for
Public Health, Frankfort, KY,
USA (E Lutterloh); Iowa
Department of Public Health,
Des Moines, IA, USA(M L Harris MPH);
Philadelphia Department of
Public Health, Philadelphia, PA,
USA (C Burke MSN);

1

Articles

and Massachusetts Departmentof Public Health, Jamaica Plain,
MA, USA (N Cocoros MPH)
Correspondence to:Denise J Jamieson, Division of
Reproductive Health,
CDC/NCCDPHP (Mail Stop K-34),
4770 Buford Hwy, NE, Atlanta,
GA 30341-3717, USA
DJamieson@cdc.gov

For the CDC protocol ofreal-time reverse-transcriptase
PCR for inﬂuenza A (H1N1) see
http://www.who.int/csr/
resources/publications/swineﬂu/
realtimeptpcr/en/index.html
For CDC interim guidance on
case deﬁnition to be used forinvestigations of novel
inﬂuenza A (H1N1) cases see
http://www.cdc.gov/h1n1ﬂu/
casedef.htm

public health laboratories with assays for testing, and by
May 18, 2009, 40 states were certiﬁed to do their own
testing.

Case deﬁnition and reporting
CDC developed nationally standardised case deﬁnitions
for conﬁrmed and probable cases of pandemic H1N1
virus infection that were disseminated via the Internet. A
conﬁrmed case was deﬁned as an acute respiratory illness
with laboratory-conﬁrmed pandemic H1N1 virus
infection by real-time reverse-transcriptase PCR or viralculture. A probable case was deﬁned as a person with anacute febrile respiratory illness who was positive forinﬂuenza A, but negative for H1 and H3 by inﬂuenza
real-time reverse-transcriptase PCR. In one report,4 about
96% of unsubtypable specimens were later conﬁrmed as
pandemic H1N1 virus.
CDC requested that state and local health departmentscomplete a ﬁve-page standardised case-report form forevery conﬁrmed and probable case of pandemic H1N1
virus infection. As part of this reporting system, CDC
began to receive some preliminary reports of infection inpregnant women, and on May 4, CDC developed aone-page standardised addendum to collect additional
information about cases in pregnant women withpandemic H1N1 virus infection. Both forms werecompleted by state and local health departments for any
pregnant woman who was a conﬁrmed or probable case.
The de-identiﬁed information about pregnant womenwith pandemic H1N1 virus infection was reported bystates to CDC, and these reports were compiled at CDC.
After the ﬁrst death in a patient with pandemic H1N1
virus infection occurred on May 4, 2009, CDC initiatedactive follow-up with state health departments to obtain
additional information about people with this virus
infection who died.
This study was reviewed by CDC and determined to bea public health response and to not need approval froman institutional review board nor written informed
consent. Additionally, the privacy rule of the Health
Insurance Portability and Accountability Act did not
apply since this activity was an emergency public healthresponse.

Statistical analysis
For more about the population
estimates see http://www.cdc.
gov/nchs/about/major/dvs/
popbridge/popbridge.htm

2

To calculate rate of admission to hospital and illness,population estimates were derived from the 2007 census
data. In 2007, the US Census Bureau and the National
Center for Health Statistics estimated that there were
301 621 157 people, including 62 097 211 women of
reproductive age (15–44 years) in the USA. Similar topreviously published methods,10 we calculated the numberof pregnant women as follows: the fertility rate (69·5 per1000 women of reproductive age) was multiplied bynine-twelfths of the population of women of reproductive
age, since pregnancy lasts roughly 9 months. Similarly,
the abortion rate (15·0 per 1000 women of reproductiveage) was multiplied by a sixth of the population of womenof reproductive age since these pregnancies last an
average of 2 months. These two numbers were added
together to estimate the number of women who are
pregnant. We calculated that there were 3 392 060 womencurrently pregnant in the USA. We compared admission
rates in three groups: pregnant women, non-pregnant
women of reproductive age (15–44 years), and the general
population. Because of changes in the information thatstates reported to the CDC, admission rates for
non-pregnant women of reproductive age could be
calculated only until May 12, 2009, rather than the fullreporting period ending May 18, 2009.
Admission rates were expressed as the number ofcases per 100 000 population at risk. 95% CIs for rates
were estimated with exact binomial methods. For
proportions with denominators greater than 10 000, we
manually calculated 95% CIs with standard methods
that assume a normal distribution. We used χ² tests, andFisher’s exact test for small numbers, to assess
diﬀerences in proportions. The proportions of cases withspeciﬁc manifestations were compared for pregnant
women, non-pregnant women of reproductive age(15–44 years of age), and the non-pregnant general
population. Risk ratios (RRs) for speciﬁc manifestations
and admission were calculated with standard methods,
and 95% CIs were calculated with the Taylor series
method. Most states began reporting aggregate data to
the CDC, and we were therefore unable to calculate
illness and admission rates for pregnant women after
May 18, 2009. We were able, however, to calculate theproportion of all deaths from pandemic H1N1 in
pregnant women for 2 months from April 15 to June 16,
2009.

Role of the funding source
The US CDC, the funding source for this study, employssome of the study authors, who had responsibility forstudy design and analysis and interpretation of the data.
The report received approval for publication from other
employees of the US Government. Additionally, somestudy authors are employed by local and state healthdepartments, which report public health information to
the US Government. DJJ and MAH had full access to alldata in the study and had ﬁnal responsibility for thedecision to submit for publication.

Results
From April 15 to May 18, 2009, CDC received reports of
31 pregnant women with conﬁrmed pandemic H1N1
virus infection and of three pregnant women meetingthe deﬁnition as a probable case. The women werereported from 13 states: Arizona (n=4), California (13),Colorado (3), Delaware (2), Georgia (1), Iowa (1),Kentucky (1), Massachusetts (1), Michigan (3),Oklahoma (1), Pennsylvania (1), Texas (2), andWashington state (1). They ranged in age from 15–42 years

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-0

Articlesn (%)
Maternal age (years)n (%)(Continued from previous column)<18

5 (15%)

18–29

17 (50%)Yes

4 (12%)

30–39

11 (32%)No

27 (79%)≥40

1 (3%)

Unknown

3 (9%)

Maternal race/ethnic origin

Travel to Mexico in 7 days before illness onset

History of asthma

Non-Hispanic white

9 (26%)

Yes, currently receiving prescription drugs

1 (3%)

Non-Hispanic black

2 (6%)

Yes, no current prescription drugs

6 (18%)

Hispanic

15 (44%)No

18 (53%)Asian

1 (3%)

Unknown

9 (26%)

American Indian/Alaskan native

1 (3%)

Unknown

6 (18%)

GravidityOne

6 (18%)≥Two

16 (47%)

Unknown

12 (35%)

ParityOther drugs for chronic health disordersYes

2 (6%)

No

25 (73%)

Unknown

7 (21%)

Seasonal inﬂuenza vaccine in 2008–09 seasonYes

3 (9%)

No

19 (56%)
12 (35%)

Nulliparous

7 (21%)

UnknownOne

5 (15%)

Antiviral drugs≥Two

10 (29%)Oseltamivir*

Unknown

12 (35%)

Weeks pregnant at time of infection

Started within 2 days of symptom onset
Acetaminophen for fever treatment

17 (50%)8 (24%)
16 (47%)0–13

3 (9%)

Admitted to hospital

14–28

19 (56%)

Any admission>29

9 (26%)≤24 h

3 (9%)

Unknown

3 (9%)>24 h

11 (32%)Admitted to intensive care unit

3 (9%)

Intubated/required mechanical ventilation

1 (3%)

Prenatal care initiated in ﬁrst trimesterYes

11 (32%)No

5 (15%)

Unknown

18 (53%)

Family member or close contact with pneumonia or inﬂuenza-like illness
in 7 days before illness onset
Yes

11 (32%)No

15 (44%)

Unknown

8 (24%)(Continues in next column)(median 26). Nearly half of the women were Hispanic
and a ﬁfth were nulliparous (table 1). 22 (65%) women
were in the ﬁrst or second trimester of pregnancy andnine (26%) were in the third trimester. 11 (32%) started
prenatal care in the ﬁrst trimester. 11 (32%) womenreported a family member or close contact withpneumonia or inﬂuenza-like illness in the 7 days before
illness onset, and four (12%) reported recent travel to
Mexico. 22 (65%) women had no reported epidemiologicallink (ie, travel or close contact) with pandemic H1N1
virus. Three women were health-care workers, none ofwhom reported close contact with a patient withinﬂuenza in the past 7 days. Although seven (21%)
women reported a history of asthma, only one was taking
medication for it. In addition to the woman with asthma,
two others reported taking drugs for chronic healthdisorders: one was using insulin for diabetes in

14 (41%)*One woman also received amantadine and one woman also received zanamivir.

Table 1: Characteristics and reported treatment of 34 pregnant womenwith pandemic H1N1 inﬂuenza virus infections in the USA, from
April 15 to May 18, 2009

pregnancy and one who was in the ﬁrst trimester andunaware that she was pregnant was taking labetalol for
hypertension and methimazole for hyperthyroidism.
Vaccination for seasonal inﬂuenza in the 2008–09 season
was reported by three (9%) of the 34 pregnant women.
Of the 34 pregnant women with pandemic H1N1 virus
infection, symptom onset ranged from April 14 to May 6,
2009. 33 (97%) women with pandemic H1N1 virus
infection presented with a febrile illness (table 2).
32 (94%) women had inﬂuenza-like illness, which was
deﬁned as having a fever plus either cough or sore throat.
Other than fever, the most common symptoms were
cough, rhinorrhoea, sore throat, headache, shortness ofbreath, and myalgia, with vomiting and diarrhoea
reported less frequently (table 2). Generally, manifestations of pandemic H1N1 inﬂuenza virus infection
reported by pregnant women were similar to thosereported by the non-pregnant general population.
However, pregnant women were more likely to report
shortness of breath compared with non-pregnant women

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-03Articles

Pregnant Non-pregnant women Risk ratio(95% CI)*of reproductive age
women(15–44 years) (n=142)(n=34)
Fever
Above 37·8°C
Subjective

33 (97%)131 (92%)24

114

1·1 (1·0–1·1)

Non-pregnant Risk ratio(95% CI)‡
people†(n=730)678 (93%)

1·0 (1·0–1·1)

567

9

17

Cough

32 (94%)133 (94%)

1·0 (0·9–1·1) 642 (88%)

111

Rhinorrhoea

20 (59%)71 (50%)1·2 (0·8–1·6) 357 (49%)

1·2 (0·9–1·6)

Sore throat§

17 (50%)97 (68%)0·7 (0·5–1·0)

437 (60%)

0·8 (0·6–1·2)

Headache

1·1 (1·0–1·2)

16 (47%)90 (63%)0·7 (0·5–1·1)

368 (50%)

0·9 (0·6–1·3)

Shortness of breath¶ 14 (41%)

35 (25%)

1·7 (1·0–2·7)

128 (18%)

2·3 (1·5–3·6)

Myalgia||

12 (35%)····

Vomiting

6 (18%)

22 (15%)1·1 (0·5–2·6)

Diarrhoea

4 (12%)

28 (20%)0·6 (0·2–1·6) 130 (18%)

0·7 (0·3–1·7)

Conjunctivitis

3 (9%)

12 (8%)

1·0 (0·3–3·5)

0·8 (0·3–2·4)··
157 (22%)81 (11%)··0·8 (0·4–1·7)

Data are number (%), unless otherwise indicated. *Pregnant women compared with non-pregnant women of
reproductive age. †Includes men, non-pregnant women, and children of all ages. ‡Pregnant women compared withall non-pregnant people. §p=0·05 for pregnant women compared with non-pregnant women of reproductive age.
¶p=0·05 for pregnant women compared with non-pregnant women of reproductive age; p=0·0005 for pregnant
women compared with non-pregnant people. ||Information about myalgias not consistently collected for
non-pregnant people because it was only ascertained in an “other, specify” ﬁeld.

Table 2: Presenting manifestations in cases with pandemic H1N1 inﬂuenza virus infections in the USA,
from April 15 to May 18, 2009of reproductive age (RR 1·7, 95% CI 1·0–2·7) and thenon-pregnant general population (RR 2·3, 1·5–3·6).
17 (50%) women took oseltamivir; eight (24%) beganoseltamivir within 2 days of symptom onset (table 1). Twoof the 17 women receiving oseltamivir also received asecond antiviral drug (zanamivir [n=1] and amantadine [1]).
Of the pregnant women with known date of symptom
onset, 40% (eight of 20) with symptom onset from
April 14 to April 30, 2009, took oseltamivir and 73% (eightof 11) with symptom onset from May 1 to May 6, 2009,
took oseltamivir (RR 0·55, 95% CI 0·29–1·05; p=0·08).
16 (47%) women reported use of acetaminophen for fever
treatment. Of the 34 cases, three women were admitted
for less than 24 h and 11 were admitted for more than
24 h, with lengths of stay ranging from 2 to 15 days. Three
women were admitted to the intensive care unit during
their admission. A 33-year-old woman at 35 weeks’gestation was admitted in severe respiratory distress, wasintubated and mechanically ventilated, and underwent
an emergency caesarean delivery. The patient continued
to need mechanical ventilation, developed pneumonia
and acute respiratory distress syndrome, and died on the
15th hospital day.3
Six women had conﬁrmed or suspected pneumonia,
including four with pneumonia conﬁrmed by plain chest
radiograph. Two women were diagnosed withdehydration. Two women gave birth to their child during
their admission to hospital and both were febrile
intrapartum. A 42-year-old woman with a twin gestation
at 34 weeks’ gestation presented with fever and cough,was diagnosed with inﬂuenza, and started taking
oseltamivir. 6 days later she presented with preterm
4premature rupture of membranes and underwent
caesarean delivery of two healthy babies. A 34-year-old
woman at 9 weeks’ gestation presented to a local
emergency department with complaints of shortness ofbreath, cough, and fever for the past 5 days. In theemergency department she had vaginal bleeding and apositive serum human chorionic gonadotropin test
supporting a diagnosis of a 9-week spontaneous abortion,
based on the date of her last menstrual period. She wasadmitted with a diagnosis of dehydration with electrolyte
abnormalities.
Pregnant cases represented 0·62% (34/5469) of thetotal number of conﬁrmed or probable cases reported
nationally of pandemic H1N1 virus infection during theﬁrst month of the outbreak. We recorded 34 reported
cases of pandemic H1N1 in an estimated
3 392 060 pregnant women in the USA (1·0 reported caseper 100 000 pregnant women). A higher proportion ofpregnant women were admitted than in the general
population (11/34 [32·4%, 95% CI 17·4–50·5] vs 229/5469[4·2%, 3·7–4·8]). Admission rates were also higher inpregnant women than in the general population. The
estimated admission rate for pregnant women was
0·32 per 100 000 pregnant women (95% CI 0·13–0·52);
the estimated admission rate in the general population
was 0·076 per 100 000 population at risk (0·07–0·09).
Thus, pregnant women were more than four times more
likely to be admitted than was the general population(RR 4·3, 95% CI 2·3–7·8).
To account for the uncertainty in the estimated numberof pregnant women in the USA, we did a sensitivity
analysis assuming that there were 10% more pregnant
women (n=3 731 266) and 10% fewer pregnant women(3 052 854) than was estimated. With use of theseestimates, the resulting RRs for admission ranged from
3·9 (95% CI 2·1–7·1) to 4·7 (2·6–8·7). Although we wereunable to compare admissions for non-pregnant womenof reproductive age during the same reporting period
because of changes in the information that states reported
to the CDC, we calculated the proportion of admissions
and an admission rate for a reporting period until May 12,
2009. In non-pregnant women of reproductive age, 24 of
569 (4·2%, 95% CI 2·7–6·2) were admitted and theestimated admission rate was 0·04 cases per 100 000(95% CI 0·03–0·06).
Of the 45 deaths from pandemic H1N1 virus infection
reported to the CDC from April 15 to June 16, 2009, six(13%) were in pregnant women, including one deathfrom the original case series of 34 pregnant cases. Of
the pregnant women who died, one was in the ﬁrst
trimester, one in the second trimester, and four were in
the third trimester. All the women were fairly healthy
before their inﬂuenza illness (table 3). The time fromsymptom onset to initial presentation for clinical care
ranged from 1 to 7 days (median 3·5). Two patients wereadmitted on the same day that they initially presented
for care. The other three presented 3–4 days before

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-0

Articles

admission, and one woman was assessed three times as
an outpatient (on 3 consecutive days) before admission
to the hospital. During the course of their illness, allwomen received treatment with oseltamivir. The lengthof time from symptom onset to receipt of antiviral
medication ranged from 6 to 15 days (median 9), andthe length of time from initial presentation to medicalcare until receipt of antiviral treatment ranged from
2 to 14 days (median 4·5).
All patients developed primary viral pneumonia andsubsequent acute respiratory distress syndrome
requiring mechanical ventilation. None of the patients
had evidence of secondary bacterial pneumonia or
haemorrhagic pneumonia. All ﬁve patients with viablepregnancies underwent caesarean delivery. In threecases, the patient or her fetus was not stable enough totransport to the labour and delivery unit, and thecaesarean delivery was done in the intensive care unit
or emergency department. The time from initialpresentation to medical care until death ranged from
6 to 19 days (median 12). None of the ﬁve infants bornto the women who died had any evidence of inﬂuenza
infection. Four infants were discharged home from thehospital in good health. The infant born at 27 weeks’gestation remains admitted and is doing well, with
supplemental oxygen via nasal cannula and feeding via
a nasogastric tube.

Discussion
This study summarises the cases of pregnant womenwith pandemic H1N1 virus infection in the USA andshows that this virus can cause serious illness in healthy
pregnant women. Before the present outbreak,published work of inﬂuenza virus of swine origin in
pregnant women was limited to a single case in 1988: a32-year-old previously healthy pregnant woman at
36 weeks’ gestation was infected with a swine inﬂuenza
virus, contracted through exposure to pigs, andlater died of complications related to primary viralpneumonia.11,12
On the basis of our investigation, pregnant women
seem to be at increased risk for complications frompandemic H1N1 virus infection, with a higher estimatedrate of hospital admission than in the general
population. Although the decision to admit a pregnant
woman is complex and might include considerations
beyond simply the severity of disease, that a highproportion (>10%) of inﬂuenza-related deaths in the
USA have been in pregnant women is concerning. In
the previous inﬂuenza pandemics of 1918 and 1957,
mortality seemed to be higher in pregnant women thanin non-pregnant populations, although appropriatecomparison groups were often not available. In a seriesof 1350 pregnant women reported during the1918 pandemic,8 about 50% developed pneumonia andof these women, more than half died (overall casefatality rate 27%), with the highest mortality in the third

Underlying
Weeks’
gestation medical(at time of conditionsdelivery)Receipt ofantiviral drug

Pregnancy
Days fromsymptom onset outcome
to receipt ofantiviral drugs

Case
33
number 1

35

Mild asthma,
psoriasis

Oseltamivir

14

Livebirth bycaesarean delivery

Case
24
number 2

32

Obesity*

Oseltamivir

10

Livebirth bycaesarean delivery

Case
20
number 3

27

None

Oseltamivir andrimantadine

6

Livebirth bycaesarean delivery

Case
21
number 4

11

Factor V Leiden Oseltamivir anddeﬁciency
rimantadine

8

Fetal loss at timeof mother’s deathCase
22
number 5

36

None

Oseltamivir

15

Livebirth bycaesarean delivery

Case
30
number 630

None

Oseltamivir andamantidine

8

Livebirth bycaesarean delivery

Age(years)*In patient’s medical record she was reported as morbidly obese. Her body-mass index at 32 weeks of gestation was
49·6 kg/m², but her pre-pregnancy weight was not available.

Table 3: Deaths in pregnant women due to pandemic H1N1 inﬂuenza virus infection in the USA, from
April 15 to June 16, 2009

trimester. During the pandemic of 1957, 50% of deaths
due to Asian inﬂuenza in Minnesota among women of
reproductive age occurred in pregnant women.7 The
groups of women selected for inclusion in reports fromthe 1918 and 1957 pandemics might have been biased
towards more severe cases, and in 1918, the diagnosis
of inﬂuenza was based on the clinical syndrome alone
because human inﬂuenza viruses were not identiﬁed
until 1933. Thus, comparison of severity of disease inpregnant women in previous pandemics comparedwith the present outbreak, particularly in view of the
few documented cases so far, is diﬃcult. However, thatall six deaths reported during the present outbreak werein relatively healthy pregnant women is noteworthy.
Pregnant women are also at increased risk for
pregnancy complications during seasonal inﬂuenza
epidemics. In one study,6 pregnant women were more
likely to be admitted for a cardiopulmonary event during
inﬂuenza season than were those who were post partum(a group considered similar to pregnant womendemographically and by health status). The risk varied by
weeks of gestation, with odds ratios of 1·06
(95% CI 0·68–1·67) during weeks 1–7, 2·52 (1·74–3·65)
during weeks 21–26, and 4·67 (3·42–6·39) during
weeks 37–42. A study from Nova Scotia5 showed thatwomen were more likely to be admitted to the hospitalfor respiratory illness during inﬂuenza season during
pregnancy than during the year before pregnancy. In
pregnant women with no comorbidities (deﬁned as
pre-existing diabetes, pulmonary disease, heart disease,renal disease, and anaemia), rate ratios for hospital
admissions by trimester of pregnancy compared with theyear before pregnancy were 1·7 (1·0–2·8) for ﬁrst,
2·1 (1·3–3·3) for second, and 5·1 (3·6–7·3) for third
trimesters. The eﬀects of pregnancy were greatest in
women with one or more comorbidities, with rate ratios

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-05Articles

For CDC guidance on pregnant
women and novel inﬂuenza A(H1N1) virus: considerations
for clinicians see http://www.
cdc.gov/h1n1ﬂu/clinician_pregnant.htm

For more on the CDC interim
guidance on antiviralrecommendations for patientswith novel inﬂuenza A (H1N1)
virus infection and their close
contacts see http://www.cdc.
gov/h1n1ﬂu/recommendations.
htm

6

of 2·9 (1·5–5·4), 3·4 (1·9–6·0), and 7·9 (5·0–12·5), respectively. In our investigation, a ﬁfth of women admitted
to hospital had a history of mild asthma, but only one
reported using any medications for asthma.
The present circulating pandemic H1N1 virus issensitive to the neuraminidase inhibitors oseltamivirand zanamivir. In randomised controlled clinical trials,13
these drugs have reduced the severity of seasonal
inﬂuenza if started within 48 h of illness onset. Althoughdata suggest that oseltamivir can reduce mortality inadmitted patients even when started more than 48 h
after illness onset, CDC recommendations for pregnant
patients are that antiviral drugs be started as soon as
possible after the onset of inﬂuenza symptoms. The
beneﬁt is expected to be greatest if started within 48 h ofonset. However, many pregnant women in our series
were not treated with either of these drugs at the timeof their presentation with inﬂuenza-like illness. Furthermore, none of those who died were treated within 48 h ofillness onset.
We did not record a delay in diagnosis of inﬂuenza in
pregnant women. However, in many cases, there seemto have been delays in initiation of antiviral therapy.
Health-care providers might have been reluctant totreat patients with antiviral drugs because they werepregnant, or before laboratory conﬁrmation of disease,or the pregnant woman might have been reluctant totake an antiviral drug. As with most drugs,14,15
information about the safety and eﬀectiveness of theseanti-inﬂuenza drugs during pregnancy is scarce.16–18 In
view of the expected eﬀects of pandemic H1N1 inﬂuenza
virus on the pregnant woman, the beneﬁts of treatment
with these drugs are likely to outweigh potential risks
to the fetus.19,20 Current CDC guidance suggests that
antiviral treatment with oseltamivir or zanamivir is
recommended for groups at high risk for inﬂuenza
complications from infection with H1N1 virus,
including pregnant women (oseltamivir is preferred).
However, some women were diagnosed before theavailability of these guidelines. Communication
messages aimed at pregnant women and their healthcare providers should include information about the
beneﬁts and risks of anti-inﬂuenza drugs, and about
the increased risk of inﬂuenza complications in
pregnant women. Additionally, improved understandingof the eﬀects of inﬂuenza during pregnancy, bothseasonal inﬂuenza and novel strains, and of antiinﬂuenza drugs used for treatment is crucial; additional
data could be obtained through establishment of anational pregnancy registry.
Since most women in this series are still pregnant,little is known about the eﬀects of the pandemic H1N1
virus on the fetus. Although no infections have beenreported in infants born to women with H1N1 virus
infection, these infants might have had more subtle
eﬀects from maternal pandemic H1N1 virus infection.
Furthermore, the eﬀects of seasonal inﬂuenza on thefetus are not well understood. Although viraemia seems
to be rare in seasonal inﬂuenza21 and placental
transmission seems to occur infrequently,22 highly
pathogenic strains of inﬂuenza virus, such as avian
inﬂuenza A (H5N1), might be transmitted across theplacenta. This was shown in a pregnant woman infectedwith H5N1, with viral genomic sequences identiﬁed in
the placental cytotrophoblasts and in the fetal respiratory
tract.23,24 Additionally, even in the absence of placental
transmission, the fetus could be adversely aﬀected byinﬂuenza or its eﬀects. For example, fever, which often
accompanies inﬂuenza, has been associated with anincreased risk for neural tube defects when occurring inthe ﬁrst trimester25 and with other adverse neonatal ordevelopmental outcomes, when occurring later inpregnancy;26–28 thus, treatment of fever withacetaminophen is recommended.20 Seasonal inﬂuenza
has been associated with a small increased risk of birthdefects in some studies, although others have notreported this association.29
Concerns about inﬂuenza’s eﬀects on the fetus wereraised during previous pandemics. In the pandemic of1918, high rates of pregnancy loss and preterm delivery
were reported,8,9 and during the pandemic of 1957–58,
possible increases in CNS defects and other adverse
outcomes were shown.30–33 Follow-up of outcomes ofpregnancy to women infected with H1N1 virus is needed
to improve understanding of the possible eﬀects of thisnovel virus.
Once available, vaccination will be an essential
component of the public health response to this inﬂuenza,
and US guidelines place pregnant women in ahigh-priority group for receipt of pandemic inﬂuenza
vaccine.20 However, in one study,34 pregnant women had
the lowest vaccine coverage level (14·4% in 2004) of all
adult population groups recommended to receiveinﬂuenza vaccination,34 despite trivalent inactivatedvaccine being recommended by the US Advisory
Committee on Immunization Practices and the American
College of Obstetricians and Gynecologists during any
trimester of pregnancy.13,35 The low level of use of
inﬂuenza vaccine in pregnant women34 is disconcertingand has important implications for future pandemic
vaccination planning.
In addition to the protection provided to mothers,
inﬂuenza vaccination also seems to provide beneﬁt to
infants; in a randomised study in Bangladesh,36
inactivated inﬂuenza vaccine reduced proven inﬂuenza
illness by 63% in infants aged 6 months or younger. The
reasons for the low level of inﬂuenza vaccination coveragein the USA are not well understood, although concerns
about vaccine safety are often cited by mothers as barriers
to vaccination.37 Information about safety of inﬂuenza
vaccine during pregnancy is scarce, but available data
show no evidence of adverse eﬀects on women or theirinfants.38 Knowledge gaps in women and their health-careproviders must be addressed39 to improve vaccination

www.thelancet.com Published online July 29, 2009 DOI:10.1016/S0140-6736(09)61304-0

Articles

coverage for pregnant women during interpandemic
periods and during a pandemic.20
Our investigation has several limitations. Ascertainment of women infected with pandemic H1N1 inﬂuenza
virus was dependent on surveillance and laboratory
testing methods used by state public health authorities
during the outbreak. These methods varied by state andby the timing during the outbreak. For example, becauseof limitations on laboratory capacity and the likelihoodthat results of testing would be unlikely to change
clinical care, laboratory testing for the virus varied as
the outbreak progressed: early in the outbreak, mostpeople with inﬂuenza-like illness who presented for
medical care were tested, but later in the outbreak,testing was focused on more severe cases (eg, thoseadmitted). Furthermore, data from a survey ofobstetricians and gynaecologists in 2004,40 suggested
that pregnant women might be less likely to be tested
than were those who were not pregnant. Of theobstetricians and gynaecologists who had seen pregnant
women whom they suspected of having inﬂuenza,
84% reported that they rarely or never tested pregnant
women for inﬂuenza. This report also summarises
information that was collected by the states and reported
to the CDC. In view of the substantial stress on the
public health system during this outbreak, states might
not have reported all cases and might have been most
likely to report severe cases.
Another limitation is that health-care providers might
be more likely to admit a pregnant woman than a
non-pregnant person with similar ﬁndings, which could
lead to an exaggerated admission rate in pregnant
women. Last, the estimated proportion of all pandemic
H1N1 deaths in pregnant women is an unstable estimate,in view of the small number of deaths reported so far. If
we increased the reporting period by 1 week, theproportion of pandemic H1N1 inﬂuenza deaths in
pregnant women would be 8% (seven of 87) instead of
13% (six of 45).
Findings from this study will be crucial to informpublic health planning for pregnant women, both forthis virus and for other novel pathogens. Crucially,
health-care providers have to realise that pregnant
women are at increased risk for severe disease andcomplications from pandemic H1N1 inﬂuenza virus
infection, and should start treatment with anti-inﬂuenza
drugs promptly.
Contributors
DJJ was involved with designing the study, wrote the report, andcollected and reviewed clinical information about cases from clinicians.
MAH was involved with designing the study, assisted with reportwriting, collected information about cases, and analysed data. SAR was
involved with designing the study, interpreted and analysed data, andassisted with report writing. JLW reviewed clinical information aboutcases and multiple versions of the report. DLS, LF, and SJO wereinvolved with designing and implementing the study, provided oversightof data collection, and assisted with interpretation of data including
reviewing multiple versions of the report. KFM reviewed multiple
versions of the report, assisted with interpretation of data, and provided

oversight of data collection. MSB analysed data and reviewed multiple
versions of the report. SL and BS provided laboratory testing ofspecimens and reviewed multiple versions of the report. JKL, CMC,
SRB, VPF, KAR, DJK, PE, HB, HAD, EL, MLH, KAR, CB, and NC workat health departments with cases and helped to collect information about
the reported cases. They also reviewed multiple versions of the report.
Members of the Novel Inﬂuenza A (H1N1) Pregnancy Working Group
Asterisks indicate member of the Epidemic Intelligence Service, Oﬃce
of Workforce and Career Development, Centers for Disease Control andPrevention. California Department of Public Health G Chavez,
K Harriman, K Winter; Colorado Department of Public Health andEnvironment D Aragon, N Comstock, S Cosgrove, J Kenﬁeld, J Sadlowski;
Georgia Department of Public Health K Arnold, C L Drenzek; Iowa
Department of Public Health P Quinlisk, D Von Stein; Kentucky
Department for Public Health T Sugg; Massachusetts Department of Public
Health D Heisey-Grove, S Soliva, S Lett; Michigan Department ofCommunity Health: R Sharangpani, S Vagasky, E V Wells; New York State
Department of Health K Noyes, M Anand, B Backenson; Northern
Kentucky Independent District Health Department J Hunter, J Rice;
Oklahoma Department of Public Health C McDonald, L Burnsed;
Pennsylvania Department of Public Health K Waller; SciMetrika:
P Mersereau; Snohomish Health District G Goldbaum; Texas Departmentof State Health Services M Davis, B Smith, J Walker, R Wing; Washington
State Department of Health A Marﬁn, M Nelson; Centers for Disease
Control and Prevention N Barnes, E J Barzilay, L Berman, M D Brantley,
C Bridges, N Dharan*, S Emery, A Fiore, D Gross, J Kendrick, A Klimov,
M Menon, C E O’Reilly, M Patel*, T Uyeki, J Villanueva, K-H Wu.
Conﬂicts of interest
We declare that we have no conﬂicts of interest.
Acknowledgments
The US CDC provided funding for this study. The ﬁndings andconclusions in this report are those of the authors and do not necessarily
represent the oﬃcial position of the Centers for Disease Control andPrevention.
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