Download Pandemic Influenza in Each Trimester of Pregnancy

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This is a review of the literature on influenza and pregnancy by Dr Susan Knowles,
(Consultant Microbiologist, member of the influenza subgroup of the scientific advisory
committee, HPSC) and Dr Niamh O’Sullivan (Consultant Microbiologist)
Influenza in Each Trimester of Pregnancy
‘Pandemic Influenza Expert Group advice on use of antivirals in pregnancy’ was
published on the HPSC website on 5th October 2009, following an extensive review of
the literature and recommendations from international agencies.
Since that time there have been many publications on the 2009 pandemic and the WHO
systematic review of the pharmacological management of pandemic (H1N1) 2009 has
been updated. This discussion paper primarily reviews the literature relating to influenza
in pregnancy since 2009.
Background
It is accepted that each viral influenza season is different and that when shift occurs in the
viral genome, it is a case of ‘wait and see’ to determine global infectivity and virulence.
A number of studies have reviewed pregnant women and their risk of serious outcomes.
Neuzil et al reviewed 4,369 pregnant women versus 21,845 population controls between
1974 and 1993.15 There was no influenza season in Tennessee in 1978-79 and 1979-90
thus the remaining 17 influenza seasons were reviewed. The odds ratio (OR) for any
cardiopulmonary event was 1.06 for weeks 1-7 and 1.23 for weeks 8-13 versus a nonpregnant OR of 1.11. The risk increased significantly from week 21 (OR 2.52) and
increased to 4.67 for weeks 37-42.
Dodds et al reviewed 134,188 pregnant women for impact of influenza exposure on rates
of hospital admission between 1990-2002 in Canada.16 The data was compared with year
before pregnancy data and expressed as a rate per 10,000 woman months. The rate ratio
was 1.0 for the year before pregnancy as compared with 1.7 (95% C.I. 1.0-2.8), 2.1 (95%
C.I. 1.3-3.3) and 5.1 (95% C.I. 3.6-7.3) for first, second and third trimester respectively.
Objectives
1. Assess the risk of severe influenza in each trimester
2. Assess the risk: benefit of use of oseltamivir for ILI in the first trimester
3. Make recommendations for prescribing oseltamivir for ILI during the influenza
season for pregnant women in the first trimester
Recent Publications: Data on Trimesters and Co-Morbidities
WHO systematic review: review of evidence up to January 2010, using the GRADE
methodology for the development of recommendations, was published in February 2010.
The recommendations were: patients who have uncomplicated illness due to confirmed or
strongly suspected virus infection and are in a group known to be at higher risk of
developing severe or complicated illness, should be treated with oseltamivir or zanamivir
as soon as possible (strong recommendation, low quality evidence). This
recommendation applies to all patient groups, including pregnant and post-partum
Discussion document produced by Dr N O’Sullivan and Dr S Knowles
Agreed on December 20th 2011 Reviewed on 02122015
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women up to 2 weeks following delivery and breastfeeding women. The recommendation
needs to be applied in the context of clinical judgement and local or national guidance.
No distinction is made between women in the first and subsequent trimesters.
In Australia and New Zealand pregnant or post-partum women with 2009 H1N1
influenza were at increased risk of admission to an intensive care unit (RR 7.4) compared
with non-pregnant women of childbearing age.1 This risk was 13-fold greater for women
20 weeks or more gestation. The corresponding risk for post-partum women was 6.4 and
for pregnant women with a gestation <20 weeks the risk was 2.4. This paper did not
differentiate based on the traditional trimesters. However, 64 pregnant or post-partum
women were admitted to ICU; 10 women were <20 weeks gestation and among these
only 2 women were in the first trimester. Detailed population data is given and with an
analysis of this data, the risk of ICU admission in women in the first trimester is not
greater than the risk among non-pregnant women of childbearing age.
In the US, among a population of 788 pregnant women with pandemic flu, 11.3% were in
the first trimester, 42.2% were second trimester and 46.5% were third trimester.2 Among
those with severe illness, 8.2% (8/115) of pregnant women admitted to an ICU were first
trimester, 39.2% were second and 52.6% were third trimester. Among maternal deaths
due to influenza, 7.1% were first, 26.8% second and 64.3% third trimester. This paper
highlighted that 5% of all influenza related deaths were pregnant, although only 1% of
the population were pregnant. If we assume that ~ one third of all pregnant women are in
each trimester (although more women are in the first trimester and fewer in the third due
to pregnancy loss and preterm birth), then the rate of death in the first trimester due to
pandemic influenza is similar to the non-pregnant population (7.1% of 5% = 0.355).
In a UK paper, co-morbidities had a significant impact on risk of hospitalisation in
pregnancy.3 Women hospitalised with pandemic influenza in pregnancy were more likely
to be overweight (adjusted OR 1.7) or obese (aOR 2.0) than the comparison cohort. They
were also more likely to have asthma requiring inhaled or oral steroids (aOR 2.3).
Many other papers note the risk is greatest as the pregnancy progresses. In the US, 95%
were in the second or third trimester and approximately a third had established risk
factors for complications.4 Six of 8 patients who died had underlying medical conditions
in addition to pregnancy. In Australia, of 43 pregnant women with influenza, 2 (5%) were
in the first trimester, 30% second and 65% third trimester.5 Co-morbidity was present in
51% of cases. In a paper from Singapore of 42 pregnant women with pandemic flu, none
were in the first trimester, 26.2% second and 73.8% third trimester.6 In New York,
among 17 pregnant women admitted to ICU’s, 12 (70.6%) had no recognised risk factors
for severe complications other than pregnancy (unknown whether asthma or obesity were
included as recognised risk factors).7 This same paper found that 2/17 (11.8%) of ICU
admissions were first trimester, 17.6% were second, 64.7% were third and 5.9% were
post-partum. In Canada, a predisposition for critical illness was noted in the third
trimester (4/6) and 5/6 were obese.8 In Singapore, the odds ratio for hospitalisation in
pregnant women with pandemic flu was 1.0 in the first trimester, 1.21 in the second and
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2.34 in the third trimester.9 In the US, among pregnant women with severe pandemic flu,
12.5% were first trimester, 25% second and 62.5% third.10
Safety of Oseltamivir in Pregnancy
No drug should be prescribed in pregnancy unless the benefit is likely to outweigh the
risk. It is recognised that prescribing any medication during the first trimester requires
careful consideration. Potential adverse effects vary from spontaneous pregnancy loss,
structural malformation, intrauterine growth retardation, preterm delivery and
neurobehavioral abnormalities, among others.12 The crucial period is about 4-11 weeks
after the start of the last menstrual period (LMP), a date which is not always provided
with accuracy and hence the default to first trimester.
There is evidence that some teratogenic medications have a narrow window of exposure
when their use results in malformations. For example, thalidomide is believed to produce
malformations only when used 34-50 days after the beginning of the last menstrual
period.13 Traditionally pregnant women are excluded from clinical trials. Although
animal studies are useful for predicting adverse reproductive effects, they are not always
predictive of effects in humans.
Information about the effects of medications and vaccines in pregnancy is based on
adverse events, reports, outcomes and following prospective exposure registries.
Conclusive information is difficult to obtain. A 2001 review of FDA approved
medications concluded that insufficient information existed to assess the teratogenic
potential of over 90% of these drugs.14
Neuraminidase inhibitors were introduced into clinical practice from 1999-2002. The
manufacturer advises to avoid use in pregnancy unless the potential benefit outweighs the
risk. Oseltamivir has been placed in category C use-in-pregnancy rating by the US FDA
(i.e. insufficient information available to assess potential risks to the foetus).21 Limited
long term safety data of use of oseltamivir during all trimesters is available. In July 2009,
Tanaka et al reported data from two Japanese teratogen information services, which
prospectively followed 90 pregnant women who took therapeutic doses of oseltamivir
during the first trimester. In these 90 cases, there was one malformation (1.1%), which is
within the incidence of major malformations in the general population (1-3%).22 A paper
published in 2010 on maternal and neonatal outcomes after antepartum treatment of
influenza with antiviral medications, reported data from 135 women treated with
oseltamivir during pregnancy.11 Of these, 18 were first trimester, 40 second trimester and
75 third trimester. Although the data was encouraging, the overall numbers of patients
treated was small, especially in the first trimester. Accordingly, the authors acknowledge
that the ‘subgroup analysis in each trimester may be underpowered to detect an increased
risk of major malformations’.
The UK Health Technology Assessment paper noted that further research is needed on
long term outcomes for infants exposed to pandemic influenza, antiviral drugs and
vaccines during pregnancy, including the effects on foetal development and congenital
malformations, postnatal developments and potentially associated conditions such as
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childhood leukaemia. Further follow up of women included in the primary care cohort
and in those who were hospitalised will continue until 6 months after the latest expected
dates of delivery, and these will be reported and published when available.3
Timing of Oseltamivir and Outcome
It is known that the benefit of Oseltamivir is greatest when it is commenced early in the
course of the disease. One paper compared the effect of early (within 2 days of symptom
onset), intermediate (3-4 days) and late (more than 4 days) treatment in pregnancy on
outcome. They found that women in the first and second trimester receiving intermediate
treatment did not differ statistically from women who received early treatment.2 However,
women in the third trimester who received intermediate treatment were 3.5 times more
likely to be admitted to the ICU than those treated early. Also, women in the first
trimester receiving late treatment had an increased risk of ICU admission. Based on the
findings of this paper, we feel that if rapid PCR tests for H1N1 are available, it is
reasonable to postpone oseltamivir treatment for women in the first trimester with mild
ILI symptoms and no co-morbidities, until laboratory results confirm influenza, assuming
the woman presents to her health service <4 days since symptom onset. A group of
experts also recommended that clinicians may consider linking the result of diagnostic
testing to treatment if highly sensitive and specific rapid influenza tests are available. 18 If
rapid PCR tests are not available or may not be available until 4 days or more since
symptoms onset, then empiric oseltamivir may be indicated.
Hyperthermia
A meta-analysis showed that maternal hyperthermia during the first trimester was
associated with a doubled risk of neural tube defects.17 Data are less certain for other
birth defects and adverse outcomes, but associations have been documented.18 Two
studies suggest that the risk for birth defects associated with fever may be mitigated by
antipyretic medications and multivitamins that contain folic acid. 19,20
Conclusion
Pregnancy is a significant risk for severe disease from pandemic influenza. When that
data is broken down by trimesters, the risk is greatest in the third trimester, followed by
the second trimester. There is limited data on the risk in the first trimester, although it
appears from data in recent publications and from previous pandemics, that the risk of
severe disease in the first trimester in women without other co-morbidities is not
significantly greater than the risk of severe disease in non-pregnant women of child
bearing age.
Data available from use of oseltamivir in pregnancy have not shown an increased risk of
malformations. However, limited data is available on use of oseltamivir in the first
trimester and at specific gestations during the first trimester when the foetus and the
major organs are developing. Long term safety data on use of oseltamivir in pregnancy is
not available. There is insufficient data to recommend widespread use of oseltamivir for
pregnant women in the first trimester without other recognised risk factors and with mild
ILI, unless laboratory confirmation is available.
Discussion document produced by Dr N O’Sullivan and Dr S Knowles
Agreed on December 20th 2011 Reviewed on 02122015
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Early use of oseltamivir (<2 days) should be prescribed for pregnant women with ILI in
the third trimester. For women in the first trimester with influenza, the outcome is similar
whether early (<2 days) or intermediate (3-4 days) treatment is given; however, late
treatment (>4 days) in the first trimester is associated with an increased risk of ICU
admission.
Recommendations
Unchanged from 2010/2011 influenza season
The influenza subgroup of the scientific advisory committee of HPSC recommends
that:

Pregnant women should be advised of the early signs and symptoms of influenzalike illness. All pregnant women with influenza like illness should seek medical
advice.

Pregnant women at less than 14 weeks gestation who have moderate to severe
symptoms or who have a medical condition that puts them at high risk of
complications from influenza are commenced on Oseltamivir treatment as soon as
possible following diagnosis of influenza like illness

All pregnant women at 14 to 42 weeks gestation, and women up to 2 weeks post
partum, are commenced on Oseltamivir treatment as soon as possible following
diagnosis of influenza like illness. (ideally within 48 hours of illness onset).
However, some studies of hospitalised patients with influenza including an
analysis of hospitalised pregnant women have suggested benefit of antiviral
treatment even when started treatment was started more than 48 hours after illness
onset.(2)

Evidence to date suggests that Oseltamivir or Zanamivir are safe to use at less
than 14 weeks gestation, but like all other medications administered at less than
14 weeks gestation, should only be used when the benefit to the mother justifies
the potential risk to the foetus. Therefore, pregnant women at less than 14 weeks
gestation who have mild influenza like illness and no co-morbidities may be
managed symptomatically with paracetamol and fluids and observed closely for
any deterioration. The clinical picture is not always clear-cut initially, and hence
the need for observation of the patient. Antivirals should be used if symptoms are
severe; if there are other risk factors as well as pregnancy; or if based on a
discussion between the mother and the clinician on the risks of infection, and the
information available on the safety of antiviral use in pregnant women, the
clinician judges it to be appropriate. All pregnant women at less than 14 weeks
gestation (and those planning to conceive) should be advised to take folic acid
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
Chemoprophylaxis is not routinely recommended for pregnant women. However,
clinical judgement may be exercised in individual cases if the benefit outweighs
the risk. A suggested approach for pregnant women who have had close contact
with a patient with laboratory proven influenza is to provide information on the
early signs and symptoms of influenza, and advise them to contact their doctor
immediately for evaluation and possible early treatment if clinical signs or
symptoms develop following a risk assessment.
See also Guidance on the use of antiviral agents for the treatment and prophylaxis of
influenza and Guidelines on the management of pregnant women with suspected
influenza
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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. AM Siston, SA Rasmussen, MA Honein et al. Pandemic 2009 influenza A(H1N1)
virus illness among pregnant women in the United States. JAMA 2010;303:1517.
3. L Yates, M Pierce, S Stephens et al. Influenza A/H1N1v in pregnancy : an
investigation of the characteristics and management of affected women and the
relationship to pregnancy outcomes for mother and infant. HTA 2010;14:109-182.
4. JK Louie, M Acosta, DJ Jamieson et al. Severe 2009 H1N1 inlfuenza in pregnant
women and postpartum women in California. NEJM 2010;362:27-35.
5. S Hewagama, SP Walker, RL Stuart et al. 2009 H1N1 Influenza A and pregnancy
outcomes in Victoria, Australia. CID 2010;50:686-690.
6. ML Lim, WY Lim, NWS Tee; SH Lim, JJ Chee. Obstetric outcomes of Influenza
A H1N1 (2009) infection in pregnancy – experience of a Singapore tertiary
hospital. Ann Acad Med Singapore 2010;39:295-8.
7. 2009 Pandemic influenza A (H1N1) in pregnant women requiring intensive care –
New York City, 2009. MMWR 2010;59:321.
8. T Oluyomi-Obi, L Avery, C Schneider et al. Perinatal and maternal outcomes in
critically ill obstetrics patients with pandemic H1N1 Influenza A. J Obstet
Gynaecol Can 2010;32:443-447.
9. ML Lim, CY Chong, WSN Tee, WY Lim, JJ Chee. Influenza A/H1N1 (2009)
infection in pregnancy – an Asian perspective. BJOG 2010;117:551-556.
10. AA Creanga, TF Johnson, SB Graitcer et al. Severity of 2009 pandemic Influenza
A (H1N1) virus infection in pregnant women. Obstet Gynecol 2010;115:717.
11. LG Greer, JS Sheffield, VL Rogers et al. Maternal and neonatal outcomes after
antepartum treatment of influenza with antiviral medications. Obstet Gynecol
2010;115:711.
12. J Cono, JD Cragan, DJ Jamieson, SA Rasmussen. Prophylaxis and treatment of
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13. JM Friedman, JE Polifka. Teratogenic effects of drugs: a resource for clinicians
(TERIS). 2nd ed. Baltimore: Johns Hopkins University Press; 2000.
14. WY Lo, JM Friedman. Teratogenicity of recently introduced medications in
human pregnancy. Obstet Gynecol 2002;100:465-73.
15. KM Neuzil, GW Reed, EF Mitchel, L Simonsen and MR Griffin. Impact of
influenza on acute cardiopulmonary hospitalisations in pregnant women. A J
Epidemiol 1998;148:1094.
16. L Dodds, SA McNeil, DB Fell et al. Impact of influenza exposure on rates of
hospital admissions and physician visits because of respiratory illness among
pregnant women. CMAJ 2007;176:463-8.
17. Moretti ME, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for
neural tube defects in offspring: systematic review and meta-analysis.
Epidemiology 2005;16:216-9.
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18. Rasmussen et al. Pandemic influenza and pregnant women: summary of a
meeting of experts. A J Public Health 2009;99:S1-S7.
19. Acs N et al. Maternal influenza during pregnancy and risk of congenital
abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005;73:989-996.
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evidence of interaction? Birth Defects Res A Clin Mol Teratol 2002;13:485-88.
21. Briggs GG, Freeman RK and Yaffe SJ (2008). Drugs in pregnancy and lactation,
eighth edition. Lippincott, Williams & Wilkins.
22. Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito S.
Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant
and breastfeeding women. CMAJ 2009;181:55-8.
Discussion document produced by Dr N O’Sullivan and Dr S Knowles
Agreed on December 20th 2011 Reviewed on 02122015