Infections in pregnancy

Cuddly cats, toxoplasma and pregnancy

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DCF 1.0
DCF 1.0

A recent case of severe toxoplasma infection in pregnancy at one of my institutions reinforces the need for preconception and early pregnancy hygiene advice.

What is toxoplasma infection?

Toxoplasmosis is an infection caused by the parasite Toxoplasma gondii. The parasite may be found in raw and cured meat, raw eggs, unpasteurised milk and cat faeces. It can also be found in soil contaminated with cat faeces. This means cat owners need to be careful when they handle kitty litter and should wear gloves when they garden in areas where the soil may be contaminated.

Clinical consequences of toxoplasma infection

Outside of pregnancy, toxoplasmosis results in a mild flu-like illness or a subclinical infection with no symptoms.

However, toxoplasma infection acquired in the period from three months prior to conception and during pregnancy, is more significant.  The parasite can cross the placenta and infect the developing baby who has an immature immune system. The consequences can be serious and include miscarriage, brain damage, blindness and death.

Why the timing of the infection is important

The timing of the infection in pregnancy influences the risk of the baby acquiring the infection. It also impacts on the severity of the sequelae of the infection in the baby.

In early pregnancy, less than 5% of babies are infected. This is because the placenta is too immature for transplacental infection.

However, in late pregnancy, 65% of babies can acquire the infection, as the placenta is mature and rates of transplacental infection are higher.

Even though infection caught late in pregnancy is more likely to result in fetal infection, the consequences of the infection are usually less severe.

In contrast,  infection caught by the mother early in her pregnancy results in a lower fetal infection rate but has far more significant consequences for her baby.

Most of the advice on toxoplasma in pregnancy comes from a few landmark research papers. It is worth looking at the findings from these papers to help guide pregnancy advice and management.

 

 

Landmark research papers

1. Pregnancy outcomes

The first landmark paper on toxoplasma in pregnancy was published in the New England Journal of Medicine in 1974 (1).

The researchers reported on the pregnancy outcomes of two groups of women. One group had evidence of toxoplasmosis prior to pregnancy and the other group acquired toxoplasmosis during pregnancy.

The key findings were:

  • Mothers who acquired toxoplasmosis prior to pregnancy did not infect their baby. No babies in this group had toxoplasmosis.

However;

  • In the 77 women who acquired toxoplasma infection during pregnancy:
    • 11 women miscarried;
    • 7 women suffered fetal death in utero and delivered a stillborn baby;
    • 2 newborns died soon after delivery;
    • 7 babies had severe effects of congenital toxoplasmosis and had cerebral and ocular complications;
    • 11 babies had  only mild illness requiring treatment:
    • 39 babies had subclinical illness with no long term problems.
  • Severe outcomes were only detected when the maternal toxoplasma infection occured during the first two trimesters (up to 27 weeks pregnancy).
  • Acquiring the toxoplasma infection in the third trimester resulted in subclinical infection or in no fetal infection.

2. Risk factors

The largest published research paper on risk factors comes from France (2), which has one of the highest rates of toxoplasma infection in pregnancy in the world. The authors reported that there were approximately 4900 cases of primary Toxoplasma infection in pregnant women in France each year.

Since 1992, France has had a policy that all pregnant women at risk of Toxoplasma infection undergo monthly serological testing. This research paper reported on 80 pregnant women who seroconverted to Toxoplasma in pregnancy and compared their risk factors against 80 pregnant women who had repeatedly negative tests.

After performing a multivariate statistical analysis to ensure differences between the two groups of women were accounted for, they found the risk factors for Toxoplasma infection were:

  • Poor hand hygiene increased risk by almost 10 fold (OR=9.9; 95%CI: 0.8-125);
  • Consumption of undercooked beef increased risk by almost 6 fold (OR=5.5; 95%CI: 1.1-27);
  • Having a pet cat increased risk by almost 5 fold (OR=4.5; 95%CI: 1.0-19.9);
  • Frequent consumption of raw vegetables outside the home increased risk by 3 fold (OR=3.1; 95%CI: 1.2-7.7);
  • Consumption of undercooked lamb increased risk by 3 fold (OR=3.1; 95%CI: 0.85-14).

The researchers noted that when women were provided with documentary advice on how to prevent toxoplasma infection, they had a lower risk of infection. They concluded that all  pregnant women should be given information on their eating habits, hand hygiene and cats in order to reduce the risk of acquiring toxoplasma infection in pregnancy.

3. Treatment of toxoplasma infection in pregnancy

The third landmark paper addressed the treatment of toxoplasma infection in pregnancy (3).

This treatment study was conducted across 5 major centres that specialised in the management of toxoplasma infection in pregnancy. The aim of the study was to determine if prenatal antibiotic therapy could reduce the rate of mother to baby transmission of Toxoplasma gondii and reduce the risk of severe consequences in infected babies as measured when they were one year old.

The study followed 144 women and considered key factors such as the gestational age at which the infection was acquired, the administration of antibiotic therapy, duration of antibiotic therapy, and time lapse between infection and the start of antibiotic therapy.

The authors reported that 64 of the 144 infected women (44%) gave birth to a congenitally infected infant.

After performing a multivariate analysis they concluded that the rate of transmission from the mother to the baby was not affected by the administration of antibiotics. The only factor that affected the rate of transmission was the gestational age at which the mother developed the infection in pregnancy (P < .0001).

However, antibiotic administration significantly reduced the risk of serious sequelae in the babies (P = 0.026, odds ratio 0.30, 95% confidence interval 0.104-0.863).

Of particular note, severe sequelae were significantly reduced when the mother was administered antibiotics (P = .007, odds ratio 0.14, 95% confidence interval 0.036-0.584). The sooner antibiotics were given after the infection, the less frequently sequelae were seen (P = 0.021).

The results were consistent with the earlier New England Journal of Medicine paper which also reported that treatment of infected mothers with the antibiotic Spiramycin reduced the impact of fetal infection (1).

What is the current pregnancy advice for preventing toxoplasmosis in pregnancy?

In Australia, the risk of toxoplasma infection is low. Therefore routine screening for the infection is not performed.

The main method to prevent infection is through education on strategies to reduce the risk of becoming infected.

The Australian Government’s Pregnancy, Birth and Baby website outlines strategies to reduce the risk of infection (4). These are:

  • Wear gloves when gardening, particularly when handling soil;
  • Wash your hands thoroughly after handling soil, using soap and hot water;
  • Do not eat raw or undercooked meat;
  • Cook all red meat until no trace of pinkness remains and the juices run clear;
  • Do not eat cured meats (e.g. Parma ham, salami);
  • Do not taste meat before it is fully cooked;
  • Wash your hands thoroughly after handling raw meat;
  • Wash all kitchenware thoroughly after preparing raw meat;
  • Always wash fruit and vegetables before cooking and eating;
  • Avoid drinking unpasteurised goat’s milk or eating products that are made from it;
  • Do not handle or adopt stray cats;
  • Keep animals, especially cats, away from areas that you prepare/store food;
  • Wash your hands and other exposed body parts with soap and running water after touching animals, their enclosures or food containers;
  • Avoid cat faeces in cat litter or soil – wear gloves if you are changing a cat’s litter tray and wash your hands thoroughly afterwards. If you are pregnant or immune deficient, ask someone else to change it for you and empty the litter tray daily;
  • Feed your cat dried or canned cat food rather than raw meat;
  • Cover children’s outdoor sand boxes to prevent cats using them as litter boxes;
  • Avoid contact with sheep and newborn lambs during the lambing season.

Management if infection is suspected

If a pregnant woman is concerned that she may have acquired toxoplasmosis in pregnancy, she should immediately see her doctor or midwife to discuss her concerns and be referred for an antibody test.

If the test demonstrates the presence of IgG antibodies, she can usually be reassured that she has already had the infection and is immune.

If the test demonstrates IgM antibodies, or no antibodies but the clinical suspicion of infection is high, the pregnancy should be managed by an obstetrician with expertise in this area.

Many cases are not detected until an ultrasound examination is performed and is noted to be abnormal.

Once maternal infection is diagnosed, or an ultrasound examination is suspicious of features of toxoplasma infection in the fetus, a tertiary level ultrasound, blood tests and amniocentesis to diagnose fetal infection are indicated. Antibiotic therapy needs to be commenced as soon as possible to reduce the impact of the fetal infection.

All cases should be managed in a tertiary obstetric hospital and advice and management will be individualised to each woman.

Babies should be enrolled in a follow up service to ensure any sequelae are diagnosed and managed as soon as possible.

Summary

Toxoplasma infection in pregnancy resulting in severe consequences for the baby is rare. However it can be prevented with good hygiene practices and managed with expert interventions by specialist teams.

The most important message is to be aware of good hand hygiene practices.

References

  1. Dismounts G, Couvreur J. Congenital Toxoplasmosis — A Prospective Study of 378 Pregnancies.N Engl J Med 1974; 290:1110-1116May 16, 1974. DOI: 10.1056/NEJM197405162902003
  2. Baril L, Ancelle T, Goulet V, Thulliez P, Tirard-Fleury V, Carme B. Risk Factors for Toxoplasma Infection in Pregnancy: A Case-Control Study in France. 
    Scandinavian Journal of Infectious Diseases 1999; 31(3): 305-309. 
    doi.org/10.1080/00365549950163626

  3. Foulon W, Villein I, Stray-Pedersen B, et al. Treatment of toxoplasmosis during pregnancy: A multicenter study of impact on fetal transmission and children’s sequelae at age 1 year. Am J Obstet Gynecol 1999; 180(2): 410-415.

    4. Department of health. Toxoplasmosis. Pregnancy, Birth and Baby. Australian Government 2016. Accessed on 31 December 2016 at http://www.pregnancybirthbaby.org.au/toxoplasmosis

Causes and consequences of too many antibiotics in pregnancy

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Antibiotics in pregnancy

I was recently checking audited hospital files from one of my research trials and noticed the majority of  women had been prescribed an antibiotic in pregnancy. The commonest indication was for prophylaxis against wound infection in women about to have a caesarean section. The second commonest indication was to prevent neonatal group B streptococcal infection in women with vaginal colonisation.

However, many other women had been prescribed antibiotics for urinary tract, vaginal and respiratory infections.

Yet the audit demonstrated that many of the mid stream urine samples and vaginal swabs collected from these women were ultimately normal. The respiratory infections documented in the notes were almost universally viral, and not bacterial.

It seems antibiotics in pregnancy are being overprescribed.

Overprescription of antibiotics in pregnancy

No drug or medication should be taken in pregnancy unless benefit outweighs the risk of harm.

A course of antibiotics prescribed for a viral chest infection or for urinary symptoms when no infection is present, is not harmless. Many patients and obstetric clinical staff mistakenly think it is “safer” to use antibiotics when in doubt.

However, there is a risk of real harm from the overprescription of antibiotics – harm to the mother, baby, and wider community.

Harm to the mother

Every time antibiotics are prescribed, they kill bacteria. However, they kill both harmful and beneficial bacteria.

In pregnancy, the flora of vagina stabilises (1). This stabilisation is associated with improved outcomes in pregnancy.

The use of antibiotics disrupts normal vaginal flora. This is because beneficial bacteria die and this creates an opportunity for pathogenic bacteria to colonise and infect the vagina.  The presence of pathogenic vaginal bacteria in pregnancy has  been linked to many adverse outcomes including preterm birth and fetal death in utero (2,3,4,5).

Colonisation by pathogenic bacteria is not the only risk. Other micro-organisms, such as fungi, can colonise or infect the vagina following a course of antibiotics. One commonly observed complication is post antibiotic vaginal Candidal infection. This can cause symptoms of itch, soreness and vaginal discharge.

Harm to the baby

As a baby is born, it passes through the vagina and acquires microorganisms from the mother’s reproductive tract. When the mother’s vaginal flora is healthy and stabilised, the baby’s microflora in the gastrointestinal tract will also be healthy and stabilise.

However, pathogenic bacteria in the maternal genital tract can be directly transmitted to the baby, causing serious newborn infection.

Even relatively minor pathogens such as Candida can still cause postnatal problems.  Vaginal Candidal infection can result in neonatal oral Candidal infection, and Candidal infection of the maternal nipples. The end result can be breastfeeding and overall feeding difficulties.

Harm to the community

The biggest harm arising from the overprescription of antibiotics comes from the development of resistance.

The Clinical Senate of Western Australia recently hosted a policy debate to develop recommendations to prevent the development and transmission of “Superbugs”. These are bacteria that are resistant to many antibiotics (6).

The World Health Organisation’s 2014 report on global surveillance of antimicrobial resistance reported that antibiotic resistance is no longer a prediction for the future; it is a reality. This year, several bacteria have been identified that are resistant to every known antibiotic.

This is a ticking time bomb for humanity.

Without urgent, coordinated action, the world is heading towards a post-antibiotic era in which common infections and minor injuries, which have been treatable for decades, can once again kill.

Impact of infections and antibiotic resistance

According to the National Health and Medical Research Council (NMHRC) and Australian Commission on Safety and Quality in Healthcare (NSQHS), infection is the most common complication affecting hospital patients, affecting 200,000 patients per year (7). At least half of healthcare associated infections are preventable. Successful infection control to minimise the risk of transmission requires a range of strategies across all levels of the healthcare system and a collaborative approach for successful implementation.

Excess length of stay due to a surgical site infection is between 3.5 and 23 hospital bed days, depending on the type of infection. The total national number of bed days due to surgical site infections for a one year period was estimated to be 206,527 bed days (8). If there was optimal use of antimicrobials and containment of antimicrobial resistance, $300 million of the Australian national healthcare budget could be redirected to more effective use every year (9).

 

What are Superbugs?

Dr Paul Armstrong, Director, Communicable Diseases Control Directorate, Public Health Division, Department of Health WA recently defined Superbugs as being multi-resistant organisms (MROs), resistant to a number of antibiotics. MROs arose from natural selection, that is, evolutionary pressure that selected resistant organisms following exposure to antibiotics within human medicine, veterinary medicine and agriculture.

Dr Armstrong stated the pressure on bacteria to develop resistance occurred in both hospitals (especially large tertiary hospitals) where the sickest patients are cared for and where the need for powerful antibiotics is greatest, and in the community.

Antibiotic resistance organisms are, to some extent, a natural process. However, overuse and misuse of antibiotics accelerates the emergence of drug-resistant strains, so that a drug that was previously effective to treat a particular microorganism is rendered ineffective.

Cost of Superbugs

Dr Armstrong told the Clinical Senate of Western Australia that the USA Centers for Disease Control and Prevention (CDC) estimated that $20 billion in direct costs was associated with antimicrobial resistance each year.

There is a direct cost on the health system due to increased costs of antibiotics, special equipment, prolonged length of stay, increased staff time and tying up of resources.

Some bacteria now had no antibiotics effective against them.

Origins of Superbugs

There are three major sources of Superbugs.

The first is  environmental contamination with antibiotics. This is is a particular problem in developing countries that manufacture pharmaceuticals and where the use of antibiotics in agriculture is not adequately regulated. In some regions, environmental contamination is strong high, multi resistance organisms have been found in the water supply.

The second key driver is unnecessary prescribing of antibiotics. This is a severe problem in the developing world where people are able to access and purchase antibiotics over the counter. However, developed countries also carry some of the blame. It has been estimated that nearly ¾ of all antibiotics in clinical medicine in Australia may have been inappropriately prescribed. This overprescription arises jointly from pressure from patients who overestimate the benefits of antibiotics and also from clinicians who underestimate their harm.

Globalisation was is a third important factor in the emergence and spread of Superbugs. Food imported from countries with higher resistance levels create risk. International travel and medical tourism also drive risk.  Individuals who travel overseas to areas of high antibiotic environmental contamination return to Australia  with infections that are resistant to antibiotics.

What are the solutions to combat Superbugs?

The WA Clinical Senate came up with some solutions to slow the spread of Superbugs. If you are interested in reading the full report and recommendations click here.

However, the two principles are

(a) Prevent antimicrobial resistance from developing in the first place; and

(b) Determine how to manage MROs or Superbugs when they arise.

Strategies for prevention include

  • Good infection control practices;
  • Vaccines;
  • Thorough cleaning practices;
  • Good surveillance systems;
  • Guidelines on appropriate antibiotics use;
  • Screening programs for patients who have been hospitalised within Australia or abroad;
  • Agricultural controls and regulation;
  • Prescription regulation.

At the end of the day, it is  timely to recall the message of the World Health Organization

“Preserve the miracle of antibiotics – “No action today, no cure tomorrow”.

References

  1. Kaakoush NO, Mendz GL, Quinlivan JA. New techniques to characterize the vaginal microbiome in pregnancy. AIMS Microbiology 2016, 2(1);55-68.
  2. Mendz GL, Kaakoush NO, Quinlivan JA Bacterial aetiological agents of intra-amniotic infections and preterm birth in pregnant women. Frontiers in Cellular Infection and Microbiology. 2013, 3: 58. doi: 10.3389/fcimb.2013.00058
  3. Kaakoush N, Quinlivan J, Mendz G. Bacteroides and Hafnia Infections Associated With Chorioamnionitis and Preterm Birth. Journal of Clinical and Gynecological Obstetrics. 06/2014; 3(2):76-79.
  4. Quinlivan JA, Kaakoush NO, Mendz GL. Acinetobacter Species Associated with Spontaneous Preterm Birth and Histological Chorioamnionitis. British Journal of Medicine & Medical Research, 2014; 4(33): 5293-5297.
  5. Mendz GL, Petersen R, Quinlivan JA, Kaakoush NO. Potential involvement of Campylobacter curvus and Haemophilus parainfluenzae in preterm birth. BMJ Case Reports 2014: published online 1 October 2014, doi:10.1136/bcr-2014-205282.
  6. Quinlivan JA, Weeramanthri T, Geelhoed G. Superbugs Executive Summary and recommendations for action from the Clinical Senate of Western Australia. Health Department of Western Australia 2016 March debate.
  7. NHMRC. NHMRC Australian guidelines for the prevention and control of infection in healthcare. canberra NHMRC 2010; 260.
  8. Graves N, Halton K, Robertos L. Costs of health care associated infection. In: Cruickshank M, Fergusson J (ed) Reducing harm to patients from health care associated infection: The role of surveillance. Sydney Australia Commission on Safety and Quality in Health Care 2008, 307-335.
  9. Australia Commission on Safety and Quality in Health Care. Windows into safety and quality in healthcare 2009. Sydney Australia Commission on Safety and Quality in Health Care 2009.