Download Infectious Diseases and Obstetrics: Then and Now

Infectious Diseases and
Obstetrics: Then and Now
How Microbes have Shaped Obstetrics
Jeanne S. Sheffield, MD
Maternal-Fetal Medicine
Johns Hopkins Medicine
I have no financial disclosures
Infectious Diseases in Obstetrics
• The single most common
medical condition
encountered by the
obstetrician
• The obligatory
immunologic changes
that allow for diminished
inflammatory response
and fetal tolerance
increases many infection
related complications
Data from Berg 2010
Causes of Pregnancy Related Maternal
Deaths in the United States
1991–1999
n = 4200 (%)
1998–2005
n = 4693(%)
Embolism
19.6
10.2
Hemorrhage
17.2
12.5
Gestational
hypertension
15.7
12.3
Infection
12.6
10.7
Other pregnancy-related
34.1
33.2
Cardiomyopathy
8.3
11.5
Stroke
5.0
6.3
Anesthesia
1.6
1.2
Otherse
19.2
14.2
Unknown
0.7
2.1
Cause of Death
Williams Obstetrics 24th edition
Ignaz Semmelweis 1818-1865
• Hungarian physician considered the
“Saviour of Mothers”
• Handwashing with chlorinated lime
solutions
– Decreased fatal puerperal fever
from 10% to 1-2%
• The Etiology, Concept and
Prophylaxis of Childbed Fever
1861
Ignaz Semmelweis 1818-1865
• Ridiculed and dismissed from the Vienna
hospital where he practiced
– 1865 committed to an asylum and died 15
days later
• His work however has saved millions of
women over the last 2 centuries
Louis Pasteur 1822-1895
• French Chemist and microbiologist
• Developed the germ theory of disease and
vindicated Semmelweis
• Father of microbiology and developed some
of the earliest vaccines e.g.anthrax and
chicken cholera
Intrauterine Infection and
Obstetric Outcomes
Cause or Consequence?
• Bradford Hill Criteria
– Biologic sense
– Specificity of the association
– Temporal relationship
– Consistency of the association
– Strength of the association
– Dose-response curve
– Human experimentation
History of the Preterm Birth and
Infection Association
• It has been known for over a century that certain
infections are associated with stillbirth and PTL
• 1943 Zahal et al
– Injected Salmonella and Shigella endotoxin into
pregnant animals, resulting in abortion and PTL
• Multiple animal studies since that time have
shown similar findings
– 1990 Dombroski et al Ascending uterine infection
model
• Focus in the last century has been on the
specific organisms
• There are so many organisms that have
shaped obstetrical practice. To name just a
few….
–
–
–
–
–
–
–
–
Syphilis
Bacterial vaginosis
Group B streptococcus
Malaria
HIV
Influenza
Tuberculosis
Viral and parasitic infections
The “TORCH” infections
“He who knows Syphilis,
knows Medicine”
Sir William Osler(1849-1919)
Ricard Tennant Cooper (1912)
Wellcome Library, London
The History of Syphilis
• First reported as a venereal disease in the 15th
century in Italy
– Spanish exploration and colonization of the American
continent
– There is evidence of treponemal infections among
natives in the pre-Columbian period
• Rapidly reached epidemic proportions in the
early 16th century “The Great Pox”, spreading to
all parts of the globe
• 19th century 10-20% of the population thought to
be infected
Radolf and Lekehart Pathogenic Treponema
The History of Syphilis
• Syphilis initially was devastating disease
• First World War an arsenic compound (salvarsan)
was used for treatment and for the first time saw a
decrease in prevalence
• The wonder drug penicillin was discovered in the
1940s
• We have intermittent increases over the last few
decades associated often with drug issues but
overall a significant decrease.
• Prenatal screening has played a significant part in
decreasing vertical and heterosexual transmission
Syphilis — Rates of Reported Cases by
Stage of Infection, United States, 1941–2015
NOTE: Data collection for syphilis began in 1941; however, syphilis became nationally notifiable in 1944. Refer to the
National Notifiable Disease Surveillance System (NNDSS) website for more information:
https://wwwn.cdc.gov/nndss/conditions/syphilis/.
Primary and Secondary Syphilis — Rates of
Reported Cases by Sex and Male-to-Female Rate
Ratios, United States, 1990–2015
Primary and Secondary Syphilis — Rates of
Reported Cases Among Women Aged 15–44 Years
by Age Group, United States, 2006–2015
Congenital Syphilis — Reported Cases by Year of Birth
and Rates of Primary and Secondary Syphilis Among
Women, United States, 2006–2015
* CS = Congenital syphilis; P&S = Primary and secondary syphilis.
Why is Congenital Syphilis on
the Rise?
• There was a 28% increase in CS cases
during 2013-2014
– 23% increase in primary and secondary
syphilis rates during the same time period
– 22% of the cases in 2014 had no prenatal
care
• If they had prenatal care, 43% did not receive
prenatal treatment
– 16% not tested
– 39% seroconverted during pregnancy
• 17% were treated <30 days prior to delivery
CDC STD Surveillance data 2014
Congenital Syphilis at Parkland
Hospital 1988 to 1998
Primary (N=26)
23%
60%
Secondary (N=53)
Early Latent (N=145)
36%
Late Latent (N=27)
7%
20%
Unknown (N=97)
0%
10%
Stillbirth
20%
30%
40%
50%
60%
Congenital Syphilis
Sheffield and colleagues
The only way to prevent
congenital syphilis is to prevent
or at least treat maternal
syphilis
Identification of pregnant
women infected with syphilis
• Screen ALL pregnant women
– First prenatal visit
– High prevalence communities screen again at
28 weeks and then again at delivery
• No infant should ever be discharged from
the hospital without confirmation of
negative maternal serology
• Screen anyone who delivers a stillborn
infant after 20 weeks gestation
Appropriate treatment of
pregnant women infected with
syphilis
• Penicillin remains the treatment of choice
for pregnant women
– Up to 10% failure rates with other antibiotics
– Early stage syphilis 2 doses, one week apart
– Late stage disease 3 doses, one week apart
Penicillin Desensitization
Dose
Penicillin V
Suspension
Amount
Penicillin V Suspension
Cumulative Dose
Route
Units/mL
mL
Units
Units
1
1,000
0.1
100
100
P.O.
2
1,000
0.2
200
300
P.O.
3
1,000
0.4
400
700
P.O.
4
1,000
0.8
800
1,500
P.O.
5
1,000
1.6
1,600
3,100
P.O.
6
1,000
3.2
3,200
6,300
P.O.
7
1,000
6.4
6,400
12,700
P.O.
8
10,000
1.2
12,000
24,700
P.O.
9
10,000
2.4
24,000
48,700
P.O.
10
10,000
4.8
48,000
96,700
P.O.
11
80,000
1.0
80,000
176,700
P.O.
12
80,000
2.0
160,000
336,700
P.O.
13
80,000
4.0
320,000
656,700
P.O.
14
80,000
8.0
640,000
1,296,700
P.O.
Wait 30 minutes
15
2,400,000 Units Benzathine Penicillin G
Wendel, GD et al. N Engl J Med
1985: 312:1229-32
I.M.
Syphilis Therapy Efficacy by
Stage
100%
0
4
2
0
6
100%
94.7%
98%
100%
98.2%
Prim
(27)
Sec
(75)
EL
(102)
LL
(136)
Total
(340)
80%
60%
40%
20%
0%
Success
Failure
Alexander JA, et al. Obstet Gynecol
“He who knows Syphilis,
knows Medicine”
Sir William Osler(1849-1919)
Ricard Tennant Cooper (1912)
Wellcome Library, London
Cytomegalovirus
• Most common congenital viral infection in
the United States
– 0.2-2.5% incidence of congenital infection
• Herpesvirus family
– Ubiquitous dsDNA virus
– Latent phase with sporadic reactivation
• Preexisting maternal CMV decreases but does not
eliminate fetal infection (partial protection)
Cytomegalovirus
• Overall 58% of women aged 15-44 years
are seropositive (US based study)
– Up to 85% of women from lower
socioeconomic backgrounds are seropositive.
– 50-60% of women from higher income groups
are seropositive.
• Transmission may occur to a fetus of an
immune mother secondary to reactivation
or from re-infection with a new serotype.
– Non-primary infections more common in low
SEC compared to high SEC (3.6 vs. 1.7%)
United States CMV Rates
4 Million Live
Births
1% Transmission
rate
40,000 infants
10% Symptomatic
at birth
4,000 infants
90% Asymptomatic
at Birth
36,000 infants
Survivors with
Sequelae
3,600 infants
10% Fatal Infection
400 infants
5-17% Develop
Clinical CMV
~4,000 infants
CMV Transmission
• Transmission Route
– Horizontal : saliva, urine and blood, STD
– Vertical
• Transplacental (infects the placenta)
95%
– Placental cytotrophoblasts permissive to replication
• Peripartum
5%
– cervical shedding
– breast milk
• Ascending antepartum
– Amniocentesis is not a risk factor
Rare
CMV Transmission
• Transmission Rate
– Primary maternal infection
32-40%
• Highest up to 6 months after a primary infection
– Non-primary maternal infection
0.15-2%
– MAY be higher as gestation advances (primary
infections)
• Bodeus et al 2010 J Clin Virol 524 seroconversions
– 35% first trimester
– 44% second trimester
– 73% third trimester
CMV Transmission
• Transmission Rate
– Feldman et al Am J Ob/Gyn 2011
• 508 women seroconversion
– 12 months to 8 weeks prior to pregnancy 0%
– 8 weeks prior to 6 weeks after conception 4.6%
– First trimester
34.8%
– Second trimester
42%
– Third trimester
58.6%
– Overall
23%
– Seroconversion during pregnancy
39.9%
– Periconception (3 weeks either side)16.4%
Epidemiology
• Fetal Transmission
– First and early second trimester exposure
often associated with the most severe
sequelae i.e. microcephaly
– Late pregnancy exposure associated with
functional sequelae i.e. thrombocytopenia and
hepatitis
Congenital CMV Infection
• 5 - 20% symptomatic at birth
– “Congenital CMV”
• SGA, microcephaly, ventriculomegaly,
chorioretinitis, hepatitis, splenomegaly, TCP,
petechiae
– 5% mortality
Congenital CMV Infection
• 5-20% symptomatic at birth
– 50-60% long-term neurologic sequelae
•
•
•
•
•
Sensorineural hearing loss
Retinitis
Seizures
Mental retardation
Developmental delay
• Symptomatic disease at birth and severe
sequelae are most common with primary
infection acquired in the first half of
pregnancy
Maternal screening not
recommended
• No vaccine available to prevent infection in
seronegative women
• Hard to tell timing, primary vs. non-primary
so counseling difficult
• No evidence that antiviral therapy prevents
or mitigates disease in the fetus
• Fetal infection can be detected but no way
to determine sequelae risk
Treatment and Prevention
• No antepartum antiviral therapy recommended
for the immunocompetent woman
– No good data that is improves maternal outcome or
decreases transmission to the fetus
• CMV hyperimmune globulin may lower risk of
congenital disease if given antepartum (Nigro
2005)
– 157 women diagnosed with primary CMV
• Therapy offered to women with evidence of AF infection by
PCR or culture – high dose IVIg multiple doses if “needed”
• If no amniocentesis, stratified into prevention group and got
monthly lower dose IVIg
Treatment and Prevention
• CMV hyperimmune globulin may lower risk of
congenital disease if given antepartum (Nigro
2005)
–
–
–
–
–
Therapy group, 1 of 31 women had infected infant
No intervention group, 7 of 14 women had infected infant
Prevention group, 6 of 37 women had infected infant
No adverse events
Subsequent case control of 64 additional kids noted a
decrease in CMV sequelae in infants born to mothers
receiving IVIg
– CRAPPY study design – Network study in process
Treatment Trials
• Hyperimmunoglobulin
– 3 prospective observational trials
• IG given to pregnant women with primary CMV
decreased transmission and disease severity
– Congenital Human CMV Infection Prevention
(CHIP) trial
• 124 pregnant women 5-26 weeks gestation with
recent primary CMV randomized to
hyperimmunoglobulin or placebo every 4 weeks
until 36 weeks or detection CMV in AF
– Congenital infection the same (30 vs 44%)
– Symptoms at bith also similar (30 vs 24%)
– More complications in hyperimmunoglobulin group
HIV and AIDS
• 1970s reports of a “wasting disease” in
Africa
• 1981 the first cases were reported in
California and New York among the MSM
and then the injection drug use population
• 1984 the HIV was identified (HTLV-III or
LAV)
• 1985 HIV test for blood supply screening
Survival of vertically infected children worldwide
Perinatal Transmission
• Antiretroviral Therapy
• 1994 076 Protocol
– 24% to 8 % transmission rate
– All CD4 counts > 200
– No prior therapy
Antepartum
Zidovudine 300 mg BID
or 200 mg TID
Intrapartum
Zidovudine 2 mg/kg loading
1mg/kg/hr until delivery
Neonatal
Zidovudine 2 mg/kg every 6 hours
for 6 weeks
Malaria and Obstetrics
• Global estimated malaria case incidence
rate fell by 30% between 2000 and 2013
and mortality rates fell by 47%
• 198 million cases (124-283 million) worldwide
• Malaria remains an important direct cause of
maternal and fetal complications
–
–
–
–
–
PTL
Miscarriage
Stillbirth and neonatal death
Low birthweight
Congenital infection
Malaria and Obstetrics
• Pregnant women are less likely to clear the
parasites, leading to higher mortality and morbidity
rates.
– Pregnant women are 3 times more likely to develop
severe disease
• Malaria parasites sequester and replicate in the
placenta
Malaria and Obstetrics
• Intermittent preventative treatment in pregnancy
(IPTp) has been adopted in 34 of the 45 countries
with ongoing transmission in Africa (sulfadoxinepyrimethamine at each of 4 antenatal visits)
– 25% of pregnant women have acute infection in
pregnancy
• Uncomplicated malaria treatment in pregnancy
– Chloroquine as per non-pregnancy guidelines
• Can use hydroxychloroquine
– If chloroquine-resistance, use mefloquine or a
combination of quinine/clindamycin
• Can also use atovaquone-proguanil or artemetherlumefantrine
Influenza Virology – Type A
• Subtyped based on
surface glycoproteins
– 16 hemagglutinin (HA) and
9 neuraminidase (NA)
• Infects multiple other
species and can jump
between them
– Birds, pigs, horses, seals,
dogs
– Host preference
Birds reservoir for new
subtypes
Risk of Acute Respiratory Influenza-like
Illness Increases as Gestation
Advances
Timing of Influenza Exposure
Odds Ratio (95% CI)
Relative to Non-Pregnant
First trimester
1.12 (0.79-1.59)
Second trimester
1.30 (0.97-1.73)
Third trimester
1.84 (1.31-2.59)
Postpartum
2.28 (1.42-3.68)
Lindsay et al., Am J Epidemiol 163:838-48, 2006
Influenza and Pregnancy
• Well established increase in morbidity and
mortality with both seasonal and pandemic
influenza strains
• Vaccination is an effective was to
decrease both maternal and neonatal
morbidity
– Immunization studies performed
both in the United States and
internationally
• 1/3 of the world’s population infected
with TB
– 2011 9 million people developed
tuberculosis
– 1.4 million TB-related deaths
TB and Pregnancy
• Fetal effects if the mother has untreated TB
– Low birth weight and congenital or neonatal TB
– Significant issue worldwide though rare here in
the United States
• Much of the worldwide focus on decreasing
maternal and neonatal mortality has focused
on tuberculosis, helminths and malaria
– These diseases are affecting global health
policy with regards to the care of the pregnant
woman
Human Genomics and
Infectious Diseases
One of the greatest feats in medical history
The mapping was completed in April, 2003
The Human Microbiome
• As humans have evolved, so have the millions of
microorganisms that populate the human body
– Digestive and metabolic functions
• 40% host’s energy intake
– Development and adaptation of the host immune
response
• The human as a “superorganism”, combining our
genome with the microbiome
– In the future, this thinking will help guide therapeutic
strategies, not just targeting the individual but also the
microbiome
Braundmeier and colleagues, 2015
The Microbiome and Pregnancy
A New Paridigm
• We are now characterizing the microbiome and how
it changes in response to pregnancy (Human
Microbiome and the MetaHIT Projects)
– The vaginal and cervical microbiome shift during
pregnancy
• Reduction in microbial richness and diversity with a predominance
of Lactobacillus species
– Improve immune system function for protection of the fetus from the maternal
immune response and to protect against pathogen invasion
– The gut microbiome shifts, resulting in an impact on host
metabolism
Aagaard and colleagues 2012
The Microbiome and Pregnancy
A New Paridigm
• Placenta and amniotic fluid microbiomes, both in
healthy and abnormal pregnancies
– Bacterial species colonizing the placenta are involved in
nutrition transport to the fetus e.g. metabolizes cofactors
and vitamins
• These microbes are transmitted to the fetus during
gestation to populate the “naïve” fetal tissues
– Affected by mode of delivery and breastfeeding
– Aid in metabolism and immune protection at birth
Braundmeier and colleagues, 2015
The Microbiome and Pregnancy
Pathologic Implications
• Bacterial vaginosis
• Preterm birth with and without BV
– Altered vaginal microbiome with racial differences
• Failure of IVF
• Early pregnancy loss
• Pelvic inflammatory diseases and STDs
This leaves the field wide open for new therapeutic approaches
in obstetrics
Braundmeier and colleagues, 2015