Research
Original Investigation
Risk of Invasive Haemophilus influenzae Infection During Pregnancy and Association With Adverse Fetal Outcomes Sarah Collins, MPH: Mary Ramsay, FFPHM: Mary P. E. Slack, FRCPath; Helen Campbell, MSc; Sally Flynn, FIBMS; David Litt, PhD: Shamez N. Ladhani, MRCPCH, PhD Editorial page 1115 IMPORTANCE Unencapsulated Haemopfillus influenzae frequently causes noninvasive upper respiratory tract infections in children but can also cause invasive disease, especially in older adults. A number of studies have reported an increased incidence in neonates and suggested that pregnant women may have an increased susceptibility to invasive unencapsulated H influenzae disease. OBJECTIVE To describe the epidemiology, clinical characteristics, and outcomes of invasive H influenzae disease in women of reproductive age during a 4-year period. DESIGN. SETTING, AND PARTICIPANTS Public Health England conducts enhanced national surveillance of invasive H influenzae disease in England and Wales. Clinical questionnaires were sent prospectively to general practitioners caring for all women aged 15 to 44 years with laboratory-confirmed invasive H/nf/uenzoe disease during 2009-2012, encompassing 45 215 800 woman-years of follow-up. The final outcome was assessed in June 2013. EXPOSURES Invasive H infiuenzae disease confirmed by positive culture from a normally sterile site. MAIN OUTCOMES AND MEASURES The primary outcome was H influenzae infection and the secondary outcomes were pregnancy-related outcomes. RESULTS In total, 171 women had laboratory-confirmed invasive H influenzae infection, which included 144 (84.2%; 95% CI, 779%-89.3%) with unencapsulated, 11 (6.4%; 95% CI, 3.3%-11.2%) with serotype b, and 16 (9.4%; 95% CI, 5.4%-14.7%) with other encapsulated serotypes. Questionnaire response rate was 100%. Overall, 75 of 171 women (43.9%; 95% CI, 36.3%-51.6%) were pregnant at the time of infection, most of whom were previously healthy and presented with unencapsulated H ;nf/uenzoe bacteremia. The incidence rate of invasive unencapsuiated H influenzae disease was 172 (95% CI, 12.2-24.1; P < .001) times greater among pregnant women (2.98/100 0 0 0 woman-years) compared with nonpregnant women (0.17/100 000 woman-years). Unencapsulated H influenzae infection during the first 24 weeks of pregnancy was associated with fetal loss (44/47; 93.6% [95% CI, 82.5%-98.7%]) and extremely premature birth (3/47; 6.4% [95% CI, 1.3%-175%]). Unencapsulated H inftuenzae infection during the second half of pregnancy was associated with premature birth in 8 of 28 cases (28.6%; 95% CI, 13.2%-48.7%) and stillbirth in 2 of 28 cases (7.1%; 95% Cl, 0.9%-23.5%). The incidence rate ratio for pregnancy loss was 2.91 (95% CI, 2.13-3.88) for all serotypes of H influenzae and 2.90 (95% CI, 2.11-3.89) for unencapsulated H influenzae compared with the background rate for pregnant women. CONCLUSIONS AND RELEVANCE Among women in England and Wales, pregnancy was associated with a greater risk of invasive H influenzae infection. These infections were associated with poor pregnancy outcomes.
JAMA. 2014,311(11):n25-1132. doi:1O.lOOl/jama.2O14.1878
Author Aff iliations: Immunisation, Hepatitis, and Blood Safety Department, Public Health England, London, England (Collins, Ramsay, Campbell, Ladhani); Respiratory and Vaccine Preventable Bacterial Reference Unit, Public Health England, London, England (Slack, Flynn, Litt); Paediatric Infectious Diseases Research Group, St George's university of London, London, England (Ladhani). Corresponding Author: Shamez N. Ladhani, MRCPCH, PhD, Health Protection Services, Immunisation, Hepatitis, and Blood Safety Department, Public Health England, 61 Colindale Ave, London NW9 SEQ, England ([email protected] .uk).
1125
Research Original Investigation
Haemophilus influenzae Infection During Pregnancy
H
aemophilus influenzae is a gram-negative coccobacil- hospital laboratories in England and Wales as part of an enlus that can cause severe invasive disease in humans. hanced national surveillance effort. Public Health England also Haemophilus influenzae can be distinguished into 6 dis-receives electronic reports of clinically significant infections tinct serotypes (a-f) according to its polysaccharide capsule or from NHS hospitals and routinely requests submission of cliniit can be unencapsulated. Haemophilus influenzae serotype b cal isolates to the Haemophilus Reference Unit if this has not is the most virulent and, prior to routine vaccination in 1992, already been done. All reports are reconciled into a single dawas responsible for more than 80% of all invasive H influen- tabase. During 2009-2012, clinicians caring for 15- to 44-yearzae disease and a major cause of bacterial meningitis in young old women with laboratory-confirmed invasive H influenzae children.''^ Routine vaccination against H influenzae sero- disease were asked to complete a standardized questionnaire''' type b has resulted in rapid and sustained declines in inci- approximately 3 months after infection. dence across all age groups through direct and indirect (herd) Nonresponders and those with incomplete or inconsisprotection. In England and Wales, invasive H influenzae sero- tent surveillance forms were followed up by letter, teletype b disease incidence among children younger than 5 years phone, or both. For fatal cases, the cause of death was ascerdecreased from 22.9/100 000 in 1991 to 0.06/100 ooo (equiva- tained from postmortem reports (if performed) or death lent to 2 cases) in 2012.^ registration data provided by the Office for National Statistics Consequently, invasive infections caused by unencapsu- to Public Health England for surveillance purposes, or both. Invasive H influenzae disease was defined as the isolation lated H influenzae have become comparatively more common.^''' Unencapsulated H influenzae is a common colo- of H influenzae from a normally sterile site. Localized H influnizer of the human respiratory tract and frequently causes non- enzae infections such as epiglottitis or pneumonia were ininvasive upper respiratory tract infections.^ Occasionally, un- cluded if accompanied by a sterile site isolate. Isolates were encapsulated H influenzae may cause invasive disease, confirmed as H influenzae by their growth requirement for X including pneumonia, septicemia, and meningitis.^''' A previ- and V factors and ompP2-specific polymerase chain reaction ous European study^ noted that neonates had a greater than positivity.^''* Haemophilus influenzae capsulation status was 10-fold increased risk of invasive unencapsulated H influen- determined by polymerase chain reaction using bexAzae disease compared with H influenzae serotype b, mainly dur- specific primers. Capsular type was confirmed as types a ing the first week of life, suggesting perinatal infection, which through f by using capsule-specific primers and slide agglutiwas consistent with a number of previous reports.*''' It was also nation. noted that, although invasive unencapsulated H influenzae disease was more common in males than in females overall, the Ethical Approval opposite was true for those aged 18 to 44 years.^ Public Health England has approval under the Patient InforOther population-based surveillance studies have sug- mation Advisor Group §60 of the Health and Social Care Act gested an increased risk of invasive H influenzae disease dur- of 2001 (now subsumed into the Heath Research Authority with ing pregnancy, although the analyses were based on only 5 §60 now being §251 of the National Health Service Act of 2006) pregnant cases,' 7 cases,** 9 cases,^ and li cases.^° Several case to process confidential patient information for public health reports and small case series have suggested that H influen- purposes. The enhanced surveillance did not require addizae (mainly unencapsulated H influenzae but also encapsu- tional ethical approval. lated H influenzae) can cause serious illness in pregnant women, often resulting in fetal death or premature birth with Statistical Analysis serious illness in the infant.""^^ Data were analyzed using Stata version 11.0 (StataCorp). The To better understand the association between invasive a level was set at .05 for all statistical tests. Data that did not H influenzae disease and pregnancy. Public Health England ini- follow a normal distribution were described as medians with tiated enhanced national surveillance of all laboratory- interquartile ranges; differences were compared using the confirmed invasive H influenzae cases in women of child- Kruskal-Wallis or Wilcoxon rank sum test. Categorical varibearing age during 2009-2012. The objective of this study was ables were expressed as proportions with binomial 95% conto describe the epidemiology, clinical characteristics, and out- fidence intervals and compared using 2-sided x^ or Fisher excomes of invasive H influenzae disease in pregnant and non- act tests. Bivariable logistic regression was used to investigate pregnant women in England and Wales. the relationships between variables using the largest group as the baseline and where appropriate, age in years was included as a continuous variable in the model. Models were assessed for goodness offitusing the HosmerMethods Lemeshow goodness-of-fit test. Data from the Office for NaPublic Health England undertakes enhanced national surveil- tional Statistics on population'" and maternity'^'^^ (including lance for invasive H influenzae disease through a combina- live births, miscarriages, stillbirths, and terminations) were tion of isolate submission, routine laboratory reporting, and used to ascertain denominator populations. Incidence rates clinical reporting schemes as previously described.^'^'' Briefly, with Poisson 95% confidence intervals for pregnant and nonthe Haemophilus Reference Unit of Public Health England con- pregnant women along with incidence rate ratios for pregducts species confirmation and serotyping of all invasive clini- nant vs nonpregnant women were calculated. Associations becal H influenzae isolates for all National Health Service (NHS) tween pregnancy outcome, H influenzae strain, and maternal
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Haemophiius infiuenzae Infection During Pregnancy
Original Investigation Research
Table 1. Characteristics of Women With Invasive Haemophiius influenzae Disease by Serotype, 2009-2012 No. (%) of Women With H influenzae' Unencapsulated (n = 144)
Serotype e or f (n = 16)"
Serotype b (n = 11)
Total (N = 171)
Incidence/100 000 woman-years (95% CI)
0.42 (0.36-0.48) 0.05 (0.03-0.07) 0.03 (0.02-0.05)
0.50 (0.43-0.56)
Age, median (IQR), y
32.1 (24.5-38.7) 34.8(31.2-37.4)
32.3(24.7-38.7)
30.6(22.4-37.7)
Concurrent conditions None
92 (63.9)
8 (50.0)
6 (54.6)
106(61.6)
1
35 (24.3)
6(37.5)
1 (9.1)
42 (24.6)
>1
17(11.8)
2 (12.5)
4 (36.4)
23(13.5)
Type of disease Heart
4 (2.8)
Lung
21 (14.6)
0
2 (18.2)
6 (3.5)
3(18.8)
2 (18.2)
26 (15.2)
Liver
4 (2.8)
1 (6.3)
2 (18.2)
7 (4.1)
Renal
5 (3.5)
1 (6.3)
0
5(3.5)
Metabolic
5 (3.5)
0
0
5 (2.9)
Malignancy or immunosuppression
16(11.1)
3(18.8)
1 (9.1)
20(11.7)
Other conditions'
12 (8.3)
3 (18.8)
2 (18.2)
17 (9.9)
Abbreviation: IQR, interquartile range.
Bacteremia''
89(61.8)
2 (12.5)
1 (9.1)
92 (53.8)
' Unless otherwise indicated.
Pneumonia'
33 (22.9)
10 (62.5)
7 (63.6)
50 (29.2)
Meningitis
6 (4.2)
1 (6.3)
0
'' Includes 14 women who had encapsulated serotype f and 2 with serotype e.
Pelvic inflammatory disease
9 (6.3)
0
0
9(5.3)
Epiglottitis
0
2 (12.5)
2 (18.2)
4(2.3)
Other presentation'
7 (4.9)
1 (6.3)
1 (9.1)
9(5.3)
72 (50.0)
2(12.5)
1 (9.1)
75 (44.4)
2 (1.4)
1 (6.3)
0
10 (6.9)
1 (6.3)
1(9.1)
12 (7.2)
2 (1.4)
1 (6.3)
1(9.1)
4(2.3)
Disease presentation
7(4.1)
Pregnancy status Pregnant Postpartum
3 (1.8)
Outcome Deaths Deaths associated with H infiuenzae
•^ Includes asplenia, central nervous system disease, respiratory infection, hemogiobinemia, and congenital conditions. '' Includes 67 cases in which the women were pregnant. " Includes 8 cases in which the women were pregnant. ' Includes ceiluiitis. septic arthritis, osteomyelitis, and a positive blood culture with urinary tract infection.
concurrent conditions were tested for using 2-sided x^ or Fisher exact tests. Logistic regression was used to assess the effect of week of gestation on the odds of fetal survival as a continuous variable.
not significantly different across the H influenzae groups (Kruskal-Wallis x' = 2.88, P = .24) (Table 1). Overall, 65 of 171 women (38.4%; 95% CI, 3O.7%-45.7%) had at least 1 concurrent condition reported (Table 1), which was not associated with age at infection or serotype. The most prevalent concurrent condition was chronic respiratory disease followed by malignancy or immunosuppression. BacterResults emia was the most common presentation (53.8%), followed by During 2009-2012 (encompassing 45 215 800 woman-years), pneumonia (29.2%) (Table 1). Few women presented with men2568 cases of invasive of H influenzae were identified, includ- ingitis (n = 7) and only 1 was due to encapsulated H influening 1906 isolates (74.2%; 95% CI, 72.5%-75.9%) that were se- zae (serotype f). Nine women (all with unencapsulated H inrotyped. Women of reproductive age accounted for 8.7% (95% fluenzae) presented with pelvic inflammatory disease. CI, 7.7%-9.9%; n = 224) of all cases and 9.0% (95% CI, 7.7%By June 2013,12 women had died but only 4 deaths were 10.3%; n = 171) ofcases with serotyped isolates. Clinical ques- associated with H influenzae. In 8 cases, the cause of death was tionnaires were completed for all 171 cases with serotyped iso- attributed to an underlying medical condition and occurred lates. There were 144 cases (84.2%; 95% CI, 77.9%-89.3%) with more than 30 days after infection. The case-fatality rate assounencapsulated H influenzae, 11 cases (6.4%; 95% CI, 3.3%- ciated with H influenzae was 2.3% (95% CI, O.6%-5.9%; 4/171) 11.2%) with H influenzae serotype b, and 16 cases (9.4%; 95% and the responsible strains were unencapsulated H influenCI, 5.4%-l4.7%) with other encapsulated serotypes, includ- zaein = 2), H influenzae seiotypeh(n = 1), and H influenzae seing 14 cases (8.2%; 95% CI, 4.5%-l3.4%) with H influenzae se- rotype f (n = 1). Three deaths were due to pneumonia; 1 woman rotype fand 2 cases (1.2%; 95% CI, O.i%-4.2%) with H influen- had recently undergone chemotherapy for breast cancer, 1 had zae serotype e (Table 1). The median age of women at diagnosis chronic liver and neurological disease, and 1 was previously was 32.3 years (interquartile range, 24.7-38.7 years), which was healthy but died from myocarditis as a complication of pneu-
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Haemophilus infiuenzae Infection During Pregnancy
Research Original Investigation
Table 2. Characteristics of Women With Invasive Haemophilus infiuenzae Disease No. (%) of Women With H/n//uenzoe (N = 171)' Cases, No. (%) [95% Ci]
Not Pregnant
Pregnant
96 (55.1) [48.4-63.7]
75 (43.9) [36.3-51.6]
lncldence/100 000 woman-years (95% CI)
0.22(0.18-0.27)
3.01(2.37-3.77)
Age, median (IQR), y
35.5(28.1-40.4)
28.2 (24.1-33.8)
Odds Ratio (95% CI) 13.40(9.77-18.31)"
P Value < .001 < .001'
H inftuenzae serotype Unencapsulated
72 (75.5)
72 (96.0)
1 [Reference]
eorf
14 (14.6)"
2 (2.7)'
0.15(0.03-0.65)
.01
b
10(10.4)
1 (1.3)
0.10(0.12-0.80)
.03
Unencapsulated H infiuenzae cases only Cases
72 (50.0)
72 (50.0)
Incidence/100 000 woman-years (95% CI)
0.17(0.13-0.21)
2.98(2.26-3.54)
Age, median (IQR), y
35.7 (27.6-41.0)
28.1 (24.0-33.7)
17.15(12.20-24.11)"
< .001 < .001'
Concurrent conditions None
32 (44.4)
50(83.3)
1 [Reference]
1
24(33.3)
11(15.3)
0.24(0.11-0.56)
.001
>1
16(22.2)
1(1.4)
0.03 (0-0.26)
.001
.04
"'"'
Type of disease
1
Heart
4(5.6)
Lung
15 (20.8)
6 (8.3)
0.35 (0.13-0.95)
Liver
3 (4.2)
1 (1.4)
0.32 (0.03-3.19)
.33
Renal
4(5.6)
1 (1.4)
0.24(0.03-2.20)
.21
.006
Metabolic
5 (6.9)
0
0
14 (19.4)
2 (2.8)
0.12 (0.03-0.54)
Bacteremia
24(33.3)
65 (90.3)
18.57 (7.39-45.54)
Original Investigation
Risk of Invasive Haemophilus influenzae Infection During Pregnancy and Association With Adverse Fetal Outcomes Sarah Collins, MPH: Mary Ramsay, FFPHM: Mary P. E. Slack, FRCPath; Helen Campbell, MSc; Sally Flynn, FIBMS; David Litt, PhD: Shamez N. Ladhani, MRCPCH, PhD Editorial page 1115 IMPORTANCE Unencapsulated Haemopfillus influenzae frequently causes noninvasive upper respiratory tract infections in children but can also cause invasive disease, especially in older adults. A number of studies have reported an increased incidence in neonates and suggested that pregnant women may have an increased susceptibility to invasive unencapsulated H influenzae disease. OBJECTIVE To describe the epidemiology, clinical characteristics, and outcomes of invasive H influenzae disease in women of reproductive age during a 4-year period. DESIGN. SETTING, AND PARTICIPANTS Public Health England conducts enhanced national surveillance of invasive H influenzae disease in England and Wales. Clinical questionnaires were sent prospectively to general practitioners caring for all women aged 15 to 44 years with laboratory-confirmed invasive H/nf/uenzoe disease during 2009-2012, encompassing 45 215 800 woman-years of follow-up. The final outcome was assessed in June 2013. EXPOSURES Invasive H infiuenzae disease confirmed by positive culture from a normally sterile site. MAIN OUTCOMES AND MEASURES The primary outcome was H influenzae infection and the secondary outcomes were pregnancy-related outcomes. RESULTS In total, 171 women had laboratory-confirmed invasive H influenzae infection, which included 144 (84.2%; 95% CI, 779%-89.3%) with unencapsulated, 11 (6.4%; 95% CI, 3.3%-11.2%) with serotype b, and 16 (9.4%; 95% CI, 5.4%-14.7%) with other encapsulated serotypes. Questionnaire response rate was 100%. Overall, 75 of 171 women (43.9%; 95% CI, 36.3%-51.6%) were pregnant at the time of infection, most of whom were previously healthy and presented with unencapsulated H ;nf/uenzoe bacteremia. The incidence rate of invasive unencapsuiated H influenzae disease was 172 (95% CI, 12.2-24.1; P < .001) times greater among pregnant women (2.98/100 0 0 0 woman-years) compared with nonpregnant women (0.17/100 000 woman-years). Unencapsulated H influenzae infection during the first 24 weeks of pregnancy was associated with fetal loss (44/47; 93.6% [95% CI, 82.5%-98.7%]) and extremely premature birth (3/47; 6.4% [95% CI, 1.3%-175%]). Unencapsulated H inftuenzae infection during the second half of pregnancy was associated with premature birth in 8 of 28 cases (28.6%; 95% CI, 13.2%-48.7%) and stillbirth in 2 of 28 cases (7.1%; 95% Cl, 0.9%-23.5%). The incidence rate ratio for pregnancy loss was 2.91 (95% CI, 2.13-3.88) for all serotypes of H influenzae and 2.90 (95% CI, 2.11-3.89) for unencapsulated H influenzae compared with the background rate for pregnant women. CONCLUSIONS AND RELEVANCE Among women in England and Wales, pregnancy was associated with a greater risk of invasive H influenzae infection. These infections were associated with poor pregnancy outcomes.
JAMA. 2014,311(11):n25-1132. doi:1O.lOOl/jama.2O14.1878
Author Aff iliations: Immunisation, Hepatitis, and Blood Safety Department, Public Health England, London, England (Collins, Ramsay, Campbell, Ladhani); Respiratory and Vaccine Preventable Bacterial Reference Unit, Public Health England, London, England (Slack, Flynn, Litt); Paediatric Infectious Diseases Research Group, St George's university of London, London, England (Ladhani). Corresponding Author: Shamez N. Ladhani, MRCPCH, PhD, Health Protection Services, Immunisation, Hepatitis, and Blood Safety Department, Public Health England, 61 Colindale Ave, London NW9 SEQ, England ([email protected] .uk).
1125
Research Original Investigation
Haemophilus influenzae Infection During Pregnancy
H
aemophilus influenzae is a gram-negative coccobacil- hospital laboratories in England and Wales as part of an enlus that can cause severe invasive disease in humans. hanced national surveillance effort. Public Health England also Haemophilus influenzae can be distinguished into 6 dis-receives electronic reports of clinically significant infections tinct serotypes (a-f) according to its polysaccharide capsule or from NHS hospitals and routinely requests submission of cliniit can be unencapsulated. Haemophilus influenzae serotype b cal isolates to the Haemophilus Reference Unit if this has not is the most virulent and, prior to routine vaccination in 1992, already been done. All reports are reconciled into a single dawas responsible for more than 80% of all invasive H influen- tabase. During 2009-2012, clinicians caring for 15- to 44-yearzae disease and a major cause of bacterial meningitis in young old women with laboratory-confirmed invasive H influenzae children.''^ Routine vaccination against H influenzae sero- disease were asked to complete a standardized questionnaire''' type b has resulted in rapid and sustained declines in inci- approximately 3 months after infection. dence across all age groups through direct and indirect (herd) Nonresponders and those with incomplete or inconsisprotection. In England and Wales, invasive H influenzae sero- tent surveillance forms were followed up by letter, teletype b disease incidence among children younger than 5 years phone, or both. For fatal cases, the cause of death was ascerdecreased from 22.9/100 000 in 1991 to 0.06/100 ooo (equiva- tained from postmortem reports (if performed) or death lent to 2 cases) in 2012.^ registration data provided by the Office for National Statistics Consequently, invasive infections caused by unencapsu- to Public Health England for surveillance purposes, or both. Invasive H influenzae disease was defined as the isolation lated H influenzae have become comparatively more common.^''' Unencapsulated H influenzae is a common colo- of H influenzae from a normally sterile site. Localized H influnizer of the human respiratory tract and frequently causes non- enzae infections such as epiglottitis or pneumonia were ininvasive upper respiratory tract infections.^ Occasionally, un- cluded if accompanied by a sterile site isolate. Isolates were encapsulated H influenzae may cause invasive disease, confirmed as H influenzae by their growth requirement for X including pneumonia, septicemia, and meningitis.^''' A previ- and V factors and ompP2-specific polymerase chain reaction ous European study^ noted that neonates had a greater than positivity.^''* Haemophilus influenzae capsulation status was 10-fold increased risk of invasive unencapsulated H influen- determined by polymerase chain reaction using bexAzae disease compared with H influenzae serotype b, mainly dur- specific primers. Capsular type was confirmed as types a ing the first week of life, suggesting perinatal infection, which through f by using capsule-specific primers and slide agglutiwas consistent with a number of previous reports.*''' It was also nation. noted that, although invasive unencapsulated H influenzae disease was more common in males than in females overall, the Ethical Approval opposite was true for those aged 18 to 44 years.^ Public Health England has approval under the Patient InforOther population-based surveillance studies have sug- mation Advisor Group §60 of the Health and Social Care Act gested an increased risk of invasive H influenzae disease dur- of 2001 (now subsumed into the Heath Research Authority with ing pregnancy, although the analyses were based on only 5 §60 now being §251 of the National Health Service Act of 2006) pregnant cases,' 7 cases,** 9 cases,^ and li cases.^° Several case to process confidential patient information for public health reports and small case series have suggested that H influen- purposes. The enhanced surveillance did not require addizae (mainly unencapsulated H influenzae but also encapsu- tional ethical approval. lated H influenzae) can cause serious illness in pregnant women, often resulting in fetal death or premature birth with Statistical Analysis serious illness in the infant.""^^ Data were analyzed using Stata version 11.0 (StataCorp). The To better understand the association between invasive a level was set at .05 for all statistical tests. Data that did not H influenzae disease and pregnancy. Public Health England ini- follow a normal distribution were described as medians with tiated enhanced national surveillance of all laboratory- interquartile ranges; differences were compared using the confirmed invasive H influenzae cases in women of child- Kruskal-Wallis or Wilcoxon rank sum test. Categorical varibearing age during 2009-2012. The objective of this study was ables were expressed as proportions with binomial 95% conto describe the epidemiology, clinical characteristics, and out- fidence intervals and compared using 2-sided x^ or Fisher excomes of invasive H influenzae disease in pregnant and non- act tests. Bivariable logistic regression was used to investigate pregnant women in England and Wales. the relationships between variables using the largest group as the baseline and where appropriate, age in years was included as a continuous variable in the model. Models were assessed for goodness offitusing the HosmerMethods Lemeshow goodness-of-fit test. Data from the Office for NaPublic Health England undertakes enhanced national surveil- tional Statistics on population'" and maternity'^'^^ (including lance for invasive H influenzae disease through a combina- live births, miscarriages, stillbirths, and terminations) were tion of isolate submission, routine laboratory reporting, and used to ascertain denominator populations. Incidence rates clinical reporting schemes as previously described.^'^'' Briefly, with Poisson 95% confidence intervals for pregnant and nonthe Haemophilus Reference Unit of Public Health England con- pregnant women along with incidence rate ratios for pregducts species confirmation and serotyping of all invasive clini- nant vs nonpregnant women were calculated. Associations becal H influenzae isolates for all National Health Service (NHS) tween pregnancy outcome, H influenzae strain, and maternal
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Haemophiius infiuenzae Infection During Pregnancy
Original Investigation Research
Table 1. Characteristics of Women With Invasive Haemophiius influenzae Disease by Serotype, 2009-2012 No. (%) of Women With H influenzae' Unencapsulated (n = 144)
Serotype e or f (n = 16)"
Serotype b (n = 11)
Total (N = 171)
Incidence/100 000 woman-years (95% CI)
0.42 (0.36-0.48) 0.05 (0.03-0.07) 0.03 (0.02-0.05)
0.50 (0.43-0.56)
Age, median (IQR), y
32.1 (24.5-38.7) 34.8(31.2-37.4)
32.3(24.7-38.7)
30.6(22.4-37.7)
Concurrent conditions None
92 (63.9)
8 (50.0)
6 (54.6)
106(61.6)
1
35 (24.3)
6(37.5)
1 (9.1)
42 (24.6)
>1
17(11.8)
2 (12.5)
4 (36.4)
23(13.5)
Type of disease Heart
4 (2.8)
Lung
21 (14.6)
0
2 (18.2)
6 (3.5)
3(18.8)
2 (18.2)
26 (15.2)
Liver
4 (2.8)
1 (6.3)
2 (18.2)
7 (4.1)
Renal
5 (3.5)
1 (6.3)
0
5(3.5)
Metabolic
5 (3.5)
0
0
5 (2.9)
Malignancy or immunosuppression
16(11.1)
3(18.8)
1 (9.1)
20(11.7)
Other conditions'
12 (8.3)
3 (18.8)
2 (18.2)
17 (9.9)
Abbreviation: IQR, interquartile range.
Bacteremia''
89(61.8)
2 (12.5)
1 (9.1)
92 (53.8)
' Unless otherwise indicated.
Pneumonia'
33 (22.9)
10 (62.5)
7 (63.6)
50 (29.2)
Meningitis
6 (4.2)
1 (6.3)
0
'' Includes 14 women who had encapsulated serotype f and 2 with serotype e.
Pelvic inflammatory disease
9 (6.3)
0
0
9(5.3)
Epiglottitis
0
2 (12.5)
2 (18.2)
4(2.3)
Other presentation'
7 (4.9)
1 (6.3)
1 (9.1)
9(5.3)
72 (50.0)
2(12.5)
1 (9.1)
75 (44.4)
2 (1.4)
1 (6.3)
0
10 (6.9)
1 (6.3)
1(9.1)
12 (7.2)
2 (1.4)
1 (6.3)
1(9.1)
4(2.3)
Disease presentation
7(4.1)
Pregnancy status Pregnant Postpartum
3 (1.8)
Outcome Deaths Deaths associated with H infiuenzae
•^ Includes asplenia, central nervous system disease, respiratory infection, hemogiobinemia, and congenital conditions. '' Includes 67 cases in which the women were pregnant. " Includes 8 cases in which the women were pregnant. ' Includes ceiluiitis. septic arthritis, osteomyelitis, and a positive blood culture with urinary tract infection.
concurrent conditions were tested for using 2-sided x^ or Fisher exact tests. Logistic regression was used to assess the effect of week of gestation on the odds of fetal survival as a continuous variable.
not significantly different across the H influenzae groups (Kruskal-Wallis x' = 2.88, P = .24) (Table 1). Overall, 65 of 171 women (38.4%; 95% CI, 3O.7%-45.7%) had at least 1 concurrent condition reported (Table 1), which was not associated with age at infection or serotype. The most prevalent concurrent condition was chronic respiratory disease followed by malignancy or immunosuppression. BacterResults emia was the most common presentation (53.8%), followed by During 2009-2012 (encompassing 45 215 800 woman-years), pneumonia (29.2%) (Table 1). Few women presented with men2568 cases of invasive of H influenzae were identified, includ- ingitis (n = 7) and only 1 was due to encapsulated H influening 1906 isolates (74.2%; 95% CI, 72.5%-75.9%) that were se- zae (serotype f). Nine women (all with unencapsulated H inrotyped. Women of reproductive age accounted for 8.7% (95% fluenzae) presented with pelvic inflammatory disease. CI, 7.7%-9.9%; n = 224) of all cases and 9.0% (95% CI, 7.7%By June 2013,12 women had died but only 4 deaths were 10.3%; n = 171) ofcases with serotyped isolates. Clinical ques- associated with H influenzae. In 8 cases, the cause of death was tionnaires were completed for all 171 cases with serotyped iso- attributed to an underlying medical condition and occurred lates. There were 144 cases (84.2%; 95% CI, 77.9%-89.3%) with more than 30 days after infection. The case-fatality rate assounencapsulated H influenzae, 11 cases (6.4%; 95% CI, 3.3%- ciated with H influenzae was 2.3% (95% CI, O.6%-5.9%; 4/171) 11.2%) with H influenzae serotype b, and 16 cases (9.4%; 95% and the responsible strains were unencapsulated H influenCI, 5.4%-l4.7%) with other encapsulated serotypes, includ- zaein = 2), H influenzae seiotypeh(n = 1), and H influenzae seing 14 cases (8.2%; 95% CI, 4.5%-l3.4%) with H influenzae se- rotype f (n = 1). Three deaths were due to pneumonia; 1 woman rotype fand 2 cases (1.2%; 95% CI, O.i%-4.2%) with H influen- had recently undergone chemotherapy for breast cancer, 1 had zae serotype e (Table 1). The median age of women at diagnosis chronic liver and neurological disease, and 1 was previously was 32.3 years (interquartile range, 24.7-38.7 years), which was healthy but died from myocarditis as a complication of pneu-
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JAMA March 19,2014 Volume 311, Number 11
1127
Haemophilus infiuenzae Infection During Pregnancy
Research Original Investigation
Table 2. Characteristics of Women With Invasive Haemophilus infiuenzae Disease No. (%) of Women With H/n//uenzoe (N = 171)' Cases, No. (%) [95% Ci]
Not Pregnant
Pregnant
96 (55.1) [48.4-63.7]
75 (43.9) [36.3-51.6]
lncldence/100 000 woman-years (95% CI)
0.22(0.18-0.27)
3.01(2.37-3.77)
Age, median (IQR), y
35.5(28.1-40.4)
28.2 (24.1-33.8)
Odds Ratio (95% CI) 13.40(9.77-18.31)"
P Value < .001 < .001'
H inftuenzae serotype Unencapsulated
72 (75.5)
72 (96.0)
1 [Reference]
eorf
14 (14.6)"
2 (2.7)'
0.15(0.03-0.65)
.01
b
10(10.4)
1 (1.3)
0.10(0.12-0.80)
.03
Unencapsulated H infiuenzae cases only Cases
72 (50.0)
72 (50.0)
Incidence/100 000 woman-years (95% CI)
0.17(0.13-0.21)
2.98(2.26-3.54)
Age, median (IQR), y
35.7 (27.6-41.0)
28.1 (24.0-33.7)
17.15(12.20-24.11)"
< .001 < .001'
Concurrent conditions None
32 (44.4)
50(83.3)
1 [Reference]
1
24(33.3)
11(15.3)
0.24(0.11-0.56)
.001
>1
16(22.2)
1(1.4)
0.03 (0-0.26)
.001
.04
"'"'
Type of disease
1
Heart
4(5.6)
Lung
15 (20.8)
6 (8.3)
0.35 (0.13-0.95)
Liver
3 (4.2)
1 (1.4)
0.32 (0.03-3.19)
.33
Renal
4(5.6)
1 (1.4)
0.24(0.03-2.20)
.21
.006
Metabolic
5 (6.9)
0
0
14 (19.4)
2 (2.8)
0.12 (0.03-0.54)
Bacteremia
24(33.3)
65 (90.3)
18.57 (7.39-45.54)
