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Infections in Pregnancy and
Neonates
Fiona Cooke & Hamid Jalal Department of Medical Microbiology
and Virology, Addenbrooke’s Hospital
Overview
• Definitions
• Maternal Factors
• Foetal factors
• Neonatal Factors
• Infection: Screening and
Diagnosis
• Cases
Recent changes in Epidemiology and
management of infection of foetus and newborn
• Increase in: – Viability of very low birth weight infants
– Multiple births
• Improved Diagnostics: – molecular e.g. PCR, MALDI-TOF Mass spectrometry
• Prevention: – Intrapartum prophylaxis against GBS
– ARV for prevention of HIV transmission
• Spread of multi-drug resistant pathogens in nurseries: – MRSA, ESBL, Pseudomonas aeruginosa
Definitions
• Congenital : Conception to birth
• Abortion: Death of fetus up to 20 weeks of gestation
• Intra Uterine Death: Death of fetus between 21 and 37 weeks of gestation
• Peri-natal : 28th week of gestation to 7 days after delivery
• Stillbirth: Death of fetus after 37 weeks of gestation
• Neonate: A baby up to 28 days of life
• Infant: A child under the age of 1 year
• Labour: The process of expulsion of the fetus and the placenta from the uterus.
Maternal Factors Compromised cellular immunity
• Modest – e.g. severity of malaria in pregnancy
Specific systems at enhanced risk of infection
• urinary tract and uterus
Risk of infection of the products of conception:
• overwhelming – e.g. life threatening septic abortion – large volume infected material + heavy microbial load
• less severe e.g. Q fever – failure of foetal eradication of infection → prolonged maternal ill health
Post delivery ‘surgical’ infection
• episiotomy, Caesarean wound, retained products – Genital tract colonisation by high grade pathogens
• e.g. Group A or B ß-haemolytic Streptococci
Chronic Infections in the mother
• Tuberculosis, HIV, syphilis, malaria, viral hepatitis….
Foetal Factors
Immunocompromised cellular and humoral immunity
• profound (1st trimester) to modest (at term)
Risk of:
• Ascending infections from vaginal flora
• Trans-placental infection :
– Severe consequences
• abortion, premature delivery with infection
• e.g. listeriosis
– Less severe infection but interference with organogenesis
• →congenital malformation
• e.g. rubella
Important causes of trans-placental infection
Viral:
– rubella
– parvovirus
– CMV (very rarely: VZV, HIV)
Bacterial:
– Listeria monocytogenes,
– Treponema pallidum
– Chlamydophila psittaci
– Coxiella burnetii
– Borrelia burgdorferi
– Mycobacterium tuberculosis
Protozoal:
– Toxoplasma gondii
– Plasmodium spp.
– Trypanosomiasis
Symptoms and signs of infection vague and non-specific
↓
Delayed diagnosis
↓
Rapid progression to septicaemia
Widespread dissemination of infection
e.g. to lungs, bones, CNS
↓
Heavy antibiotic use with toxicity
Selection pressure for resistant bacteria and fungi
Managing Neonatal Infection:
Pitfalls
Screening and Diagnosis
• Screening: • An active process to identify the individuals suffering with an
infection or increased risk of disease, with the aim of preventive and therapeutic interventions.
• Antenatal Screening in the UK: – Booking antenatal clinic visit
– HIV, HBV, rubella and syphilis
– MSU
• Screening is not routinely offered for the following: – Hepatitis C, Toxoplasmosis, Cytomegalovirus, HSV,
Group B Streptococcus, Chickenpox, Parvovirus
Prevention
• Avoiding potential hazards – NICE clinical guideline 62 March 2008
http://www.nice.org.uk/nicemedia/pdf/CG062PublicInfo.pdf
– Avoid contact with chicken pox, Parvovirus if non-immune
– Raw meat, unpasteurised dairy products, soft cheese cold meats/pate
– Kittens, cat faeces
• Vaccination – Influenza
• Antibiotic prophylaxis – GBS: Intrapartum Penicillin
– UTI and asymptomatic bacteriuria: antibiotics
– HIV: Anti-retroviral Rx of mother and newborn
Laboratory Diagnosis of
Infections
Specimens Techniques
Mother Blood, body
fluids, swabs,
placenta
Serology, PCR,
culture
Fetus Amniotic fluid,
fetal blood
PCR or culture
Neonate Blood, body
fluids, swabs
Serology, PCR,
culture
Case 1
• 24 -year-old woman.
• 22 weeks pregnant.
• Fever and malaise for 3 weeks.
• What investigations would you do?
– MSU Negative
– Blood cultures Negative
– CMV IgG negative IgM positive.
– Toxoplasma IgG negative.
– Rubella IgG positive Rubella IgM negative.
– Parvovirus IgM negative
– Parvovirus IgG positive
• What is the risk to the baby?
• Can you treat congenital CMV?
• How can we diagnose CMV in the neonate?
Ganciclovir has been tried, does have some effect, but is not
recommended because of toxicity (it rots rats’ gonads!). Do not
use ganciclovir in pregnancy.
- Culture/PCR of urine.
- IgG/IgM seroconversion in mother.
- Only a minority of babies will have IgM at birth.
- They will have mother’s IgG level at birth.
CMV risk to foetus.
40% transmission to baby transplacentally of these
1% severe/fatal infection
10% symptomatic at birth
90% asymptomatic – of which approximately 20% will have
some sequelae
Primary CMV infection
Serology screen –
CMV IgM Toxo IgG, rubella IgM, parvo IgM.
?UTI, ?Listeria, ?Endocarditis – MSU, Blood cultures
Case 2.
• The urine from a healthy 26 year old primi-gravida was tested routinely at booking with the following results:
Normal values
WBC <5 (<5 x 106/l)
RBC <5 (<5 x 106/l)
Squamous cells <1 (<1 x 106/l)
Casts ) )
Renal cells ) Nil ) Nil
Organisms ) )
• Culture:
105 organisms/ml of Escherichia coli
Resistant to amoxicillin
Susceptible to co-amoxiclav, trimethoprim, cephalexin
• What does this result indicate?
• Why are the pregnant predisposed to this problem?
• Why is asymptomatic bacteriuria in pregnancy important?
• How should the patient be treated?
The patient has an asymptomatic bacteriuria
It occurs in 4% of pregnancies. Present at booking in
80-90% (some test once again later in pregnancy),
persists long term during pregnancy.
Principally due to defective hydro-kinetic defences -
delayed and incomplete clearing of urine.
The ureters are flaccid possibly due to progesterone; urine
clearance is inhibited by pressure on the urinary tract by
the gravid uterus.
Elevated oestrogen levels are also associated with more
rapid growth of E. coli in animal models of pyelonephritis
The renal medulla is also relatively hyperosmolar with
consequent impaired leucocyte and complement activity.
Associated with
•Pyelonephritis (<30%)
•Mid-trimester abortion
•Pre-term delivery
•Intrauterine growth retardation
With an oral antibiotic considered safe in pregnancy.
These are the Beta-lactams (although experience with the newer
agents is more limited, e.g. co-amoxiclav is “probably safe”) and
nitrofurantoin (but see below)
Cephalexin would be appropriate, but for 7 days rather than the 3 day
course given for ‘simple (uncomplicated) cystitis’ as there is an
underlying abnormality predisposing to more serious infection, delayed
clearance and relapse.
A follow-up urine should be taken 5-7 days after completing the course,
and monthly thereafter as relapsing/recurrent infection after treatment
is seen in one third of cases. These patients should be retreated as
before (?try another antibiotic) and long-term antibiotic prophylaxis
(nitrofurantoin) considered if the problem persists.
Case 3
• 24-year-old woman
• 14 weeks pregnant
• Her 3-year-old boy developed chickenpox 2 days ago.
– Is this a problem?
• What should you do?
• She has not had chickenpox before.
– What should you do?
• VZV IgG negative - Not immune
• What action should be taken?
• Will ZIG prevent infection?
• What if she develops chickenpox?
- Yes, chickenpox can cause congenital damage in the child. If
infection in the mother <20 weeks pregnant
- 1-2% risk Ask her if she has had chickenpox before. If she has, she
should be immune, and her baby should not be at risk (99%
certain).
Not necessarily, but will reduce the risk of congenital infection
(can use aciclovir prophylaxis – 2 weeks zoster dose in
pregnancy – but it is NOT licenced for this!)
If severe chickenpox, treat with iv aciclovir (especially if
pneumonia or encephalitis)
- If moderately ill, can use oral aciclovir
- Aciclovir does not cause damage to babies in utero
Give her ZIG (1000mg IM)
(ZIG is human zoster immunoglobulin)
- Take 10ml clotted blood sample and have it tested for VZV IgG
Case 4.
• 25 year old primigravida presents in the 30th week of pregnancy
H/O
• fever and abdominal pain x 1/7
• previous day noticed a little watery vaginal discharge.
O/E
• tenderness over the uterus,
• Per Vaginal discharge of foul amniotic fluid
• FBC: peripheral neutrophil leucocytosis.
• What is the likely diagnosis?
• What is the likely cause?
• What complications may follow?
• How should she be managed
Intra-uterine infection: anatomically a chorioamnionitis -
infection of foetal membranes
+/- amniotic fluid. Affects 0.9% pregnancies.
Given the history, an ascending infection with vaginal flora,
probably mixed:
E. coli, Streptococci (including Group B), obligate
anaerobes, occasionally Staphylococcus aureus
Intrauterine infection may also be secondary to bacteraemia
(e.g. Listeria monocytogenes) but this is rare
Endomyometritis (19%),
C-Section wound infection (15%),
Bacteraemia/septicaemia (4%),
Spontaneous abortion/preterm labour [<37th week] (almost
certain)
Neonatal infection (3%).
Cultures of amniotic fluid (including Listeria selective plate –
routine in our lab), blood cultures
Vaginal delivery (if possible) ASAP,
Broad spectrum intravenous antibiotics e.g. ceftriaxone +
metronidazole (poor Listeria coverage probably unimportant in
this case) or penicillin + gentamicin + metronidazole
Patients with less severe symptoms could receive oral
co-amoxiclav, which is also suitable as oral follow-on therapy.
Case 5
• 30 year old Para 1 Gravida 2
• 10th week of pregnancy
H/O
• fever x 4/7 (no other symptoms including rash or vaginal discharge)
• Developed abdominal pains and contractions this morning
• Recently returned from a trip to France : no dietary precautions
O/E
• an oral temperature of 38oC
• CVS: hypotension and tachycardia
• PA: marked tenderness over the uterus
• PV: broken membranes with a fully dilated cervix
• Shortly thereafter she aborted a foetus with no signs of life.
• Cultures of blood and placenta were taken
• Treated with parenteral penicillin + gentamicin + metronidazole
• Condition steadily improved thereafter
Case 5 • What is the likely diagnosis?
• What is the likely cause?
• A microbiologist contacts you 24 hours after admission to inform you that the blood and placenta cultures are positive: both have yielded a small Gram-positive rod in pure culture. What is the organism likely to be?
• Was the antibiotic treatment appropriate?
• How did the patient acquire this infection?
• How may the diagnosis be established in the early ‘flu-like’ stages of maternal infection?
• Which other groups of patients are prone to develop this infection?
• Is there any risk to other babies when neonates are nursed on the open ward?
This is a septic abortion.
From the history, an acute bacterial intrauterine infection is
likely.
As in the previous case, a spontaneous ascending infection
may have been responsible,
(an induced abortion would have to be considered, but is
unlikely) but a transplacental infection may also have
occurred from a bacteraemia
Listeria monocytogenes
Yes – penicillin is appropriate and there is evidence for synergy
with gentamicin. It could be stopped as soon as she improves
clinically. The metronidazole is not active against the Listeria but
could be continued until she is afebrile in case of retained
products or local superinfection.
The organism was probably acquired from food (ultimate source likely
to be farm animal gut)
DOH advice, 1989:
Pregnant women should avoid ‘high risk foods’:
•Avoid soft cheeses & pate
•Observe "best by" dates
•Wash salads & raw veg
•Thoroughly cook poultry & meat - care with microwave ovens
•Reheat chilled food till 'piping hot'
•Throw away left-over reheated food
The reported incidence of this infection has fallen dramatically in this
country since pregnant women were routinely offered this advice
Pregnant women should also avoid parturient animals
- risk of acquiring Listeria / Chlamydophila / Coxiella
This is difficult. The DOH has advised blood cultures in any febrile 'flu-like'
illness with fever >38oC not resolving in 48 hours, with 5 days oral
amoxycillin or erythromycin if listeriosis is suspected. Vaginal swabs are
unhelpful (as bacteraemic spread, not an ascending infection; also frequent
false-positives) as is serology. The immunocompromised (the DOH recommends these should be
offered the same dietary advice); the newborn (q.v.) and elderly
(septicaemia, meningitis), both with a high mortality
Yes. Cross infection has occurred in nurseries from infected neonates and such
babies should be isolated.
Affected neonates may be heavily colonised after delivery and also and shed the
organism in urine. The mother may shed the organism from the vagina for a 7-10
days after delivery. Both can present a hazard to other newborns, who are highly
susceptible to Listeriosis. ‘Blood and Faeces’ Isolation is therefore appropriate for
both mother and baby. By contrast, there is very little risk from other infected
adults to other adults, who are generally immune. Routine isolation is therefore
unnecessary in this context.
Case 6
• A 5 day old baby develops
bilateral conjunctivitis.
• What are the likely infecting
organisms and how may they
be acquired?
• How may a diagnosis be
established?
• How should these infections
be treated?
Chlamydophila trachomatis - topical tetracycline.
Note the high association of chlamydial conjunctivitis with development of
chlamydial pneumonia (see below). Therefore, consider systemic erythromycin as
well. Treat parents, since organism acquired from mother.
N. Gonorrhoeae - systemic cefotaxime (penicillin used less as risk of resistance),
saline irrigation and topical gentamicin eye ointment. Isolate for 24hrs. Treat parents
and contact trace.
Other bacteria - topical antibiotics eg neomycin, gentamicin or chloramphenicol
(also used as empirical therapy).
Pyogenic bacteria - Swab in transport medium immediately to laboratory for
Gram stain and culture including selective media for N. gonorrhoeae.
C. trachomatis - conjunctival scrapings examined by direct IF/ELISA for
chlamydial antigen, or cultured in McCoy cells.
From maternal genital tract:
Chlamydophila trachomatis (cervical infection), commonly presents 5-14
days after delivery
N. gonorrhoeae, Group B beta-haemolytic Streptococcus – presents 2-5
days after birth
From cross-infection (>5 days after birth): S. aureus, coliforms,
Pseudomonas spp
Case 7
• 24 hours after delivery at 34 weeks a nurse expresses concern at a 2 week premature neonate’s condition, which has deteriorated acutely.
• There is no fever, but there is respiratory distress, hypotension and floppiness. There are no other abnormalities detected on examination.
• No intravascular lines are present and the baby has been breast feeding.
• The chest x-ray is normal. Urgent laboratory investigations reveal a raised CRP and neutrophil count.
Case 7 • What is the likely diagnosis?
• How should you investigate the possibility of infection in this case?
• What are the likely bacterial pathogens and what is their source?
• What empirical antibiotic therapy would you prescribe?
• After a further 24 hours the laboratory informs you that Gram-positive cocci in chains are growing in the blood culture. What is their likely identity?
• Which factors are known to predispose neonates to infection with this organism?
• Can anything be done to prevent infection with these organisms?
Penicillin (Gram-positive bacteria: Streptococci , Listeria, also N. meningitidis) plus:
gentamicin (Gram-negative bacteria: E. coli, coliforms, Pseudomonas)
or ceftriaxone - replacing gentamicin, as higher CSF levels in neonatal meningitis and
Pseudomonas is rare.
Obligate anaerobes are rare in the absence of an obvious predisposing cause (e.g gut
abnormality such a necrotising enterocolitis), hence metronidazole not routine.
Infection with penicillin-resistant organisms (e.g. coagulase-positive and negative
Staphylococci) is unlikely in the absence of invasive devices. Gentamicin would in any
event cover many of these. Vancomycin might be used on the Neonatal Intensive
Care Unit instead of penicillin if a ‘long line’ was in situ
Group B beta–haemolytic streptococci
Prematurity, low birth weight, prolonged rupture of membranes, maternal
vaginal colonisation (and heaviness of colonisation), maternal intrapartum fever,
colonisation with a virulent strain, and lack of protective maternal antibody.
The obstetricians should be informed of this finding as the organism – should the
mother also be, or become febrile, infection with this organism, originating in the
genital tract, would be the likely cause.
This is difficult. Around 30% of women in developed countries are colonised
genito-rectally with the bacterium at the time of delivery. The majority (>99%) of
colonised babies do not become infected.
Selective administration of intra-partum ampicillin to colonised mothers who are
in premature labour, or have PROM > 18hrs, or who have intrapartum fever of
>37.5oC has been demonstrated to reduce neonatal infection
There is no GBS vaccine.
Group B beta haemolytic Streptococci and E. coli account for the majority
Other organisms include:- Listeria monocytogenes, also Group A/C/G
Streptococci , "viridans" Streptococci , S. pneumoniae, Haemophilus spp.
Usually only one organism is invasive (blood/CNS/bone etc.).
In early-onset (first five days after birth) these organisms are most likely acquired
from the mother's genital tract. This is the reason for taking the surface swabs –
to look for widespread heavy growth of pathogens (acquired from infected
amniotic fluid in large numbers, and predictive of heavy intrauterine exposure
and invasive disease).
Perform a ‘septic screen’
1. Blood cultures
2. CSF microscopy and culture (meningitis complicates 20-30% of cases
of septicaemia)
3. Urine microscopy and culture
4. In first 48 hours: surface swabs (nose, throat, umbilicus, external auditory
canal, gastric aspirate).
Sepsis, very likely septicaemia
Diagnosis of sepsis in neonates is challenging as they can
be severely ill with only subtle signs of sepsis. Only one
third of septicaemic neonates have a fever. 15% are
hypothermic or show temperature instability, the rest are
normothermic. The classical signs of meningitis (neck
stiffness, decreased consciousness, bulging fontanelle)
are often absent.
References
• http://www.rcog.org.uk/womens-health/clinical-guidance → Infection and Pregnancy
• Infection and Pregnancy
– A Maclean, L Regan, D Carrington RCOG Press; 2001
• Protocols for Infectious Disease in Obstetrics and Gynecology
– P Mead D Hager Wiley-Blackwell; 2000