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Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology and Virology, Addenbrooke’s Hospital
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Page 1: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

Infections in Pregnancy and

Neonates

Fiona Cooke & Hamid Jalal Department of Medical Microbiology

and Virology, Addenbrooke’s Hospital

Page 2: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

Overview

• Definitions

• Maternal Factors

• Foetal factors

• Neonatal Factors

• Infection: Screening and

Diagnosis

• Cases

Page 3: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 4: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 5: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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….

Page 6: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 7: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 8: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 9: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 10: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 11: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 12: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 13: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 14: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 15: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 16: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 17: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 18: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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

Page 19: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 20: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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.

Page 21: Infections in Pregnancy and Neonates - alancam.com in Pregnancy and Neonate… · Infections in Pregnancy and Neonates Fiona Cooke & Hamid Jalal Department of Medical Microbiology

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