Question 3.1

College Answer

a) Applying SIRS criteria to pregnancy may be problematic as there is:
1. Leukocytosis
2. Body temperature is raised during pregnancy and labour
3. Tachycardia and tachypnoea are seen during normal labour

b)
1. Pyelonephritis
2. Chorioamnionits
3. Septic abortion
4. Episiotomy infections
5. Necrotising fasciitis
6. Septic thrombophlebitis
7. Aspiration pneumonia

c)
1. Gram negative more common than Gram positive agents
2. E.Coli
3. Group B Streptococcus
4. Can also be polymicrobial – E.coli, Klebsiella

d)
1. Tetracyclines
2. Chloramphenicol
3. Aminoglycosides
4. Metronidazole
5. Sulphonamides
6. Trimethoprim
7. Fluoroquinolones
8. Some macrolides
9. Nitrofurantoin
10. Isoniazid

Note: Some antibiotics in the above list are relatively rather than absolutely contra-indicated. The list is not exclusive and candidates giving other valid choices were given credit.

Discussion

a) Outline briefly the difficulties associated with the diagnosis of sepsis during late pregnancy and labour.

Problems of the obsolete definition of sepsis and SIRS:

• Neutrophilia is normal in pregnancy
• Inflammatory markers are normally slightly elevated
• The patient is normally slightly tachycardic, and may be slightly hypotensive, with a decreased SVRI. The circulation is normally hyperdynamic. They appear to be in early stages of vasodilated shock at the best of times.
• Tachypnoea is normal in pregnancy and labour (chronic respiratory alkalosis)
• The whole process of labour tends to obscure the findings one would normally associate with sepsis.
• Then, suddenly, they collapse (as they tend to compensate right up until the last minute, and then drop everything, given their increased susceptibility to lipopolysaccharide)

Other problems (stolen from the LITFL entry on this topic)

• Pneumonia may masquerade as the normal shortness of breath in pregnancy
• Abdominal pain due to visceral pathology may masquerade as contractions (or - more  confusingly - may co-present with labour)
• Appendicitis may be more difficult to diagnose, as the gravid uterus gets in the way of palpation.
• Nausea, vomiting, constipation - all of these may be routine for the pregnant woman, and a bowel obstruction may present disastrously late (eg. this case report by Khan et al, 2012).
• Abdominal pathology may be impossible to image, as everybody is going to freak out about the radiation exposure associated with a CT abdo/pelvis. This is in fact quite irrational, as the risks to a late-term foetus are quite small  (Chen et al, 2008). Instead, people should think about the foetal risk associated with remaining inside the septic abdomen of a critically ill mother whose source control is compromised by indecision about imaging. (In case anybody is interested, the dose from such a CT will total about 5 rads, which maxes out the recommended safe total foetal cumulative dose of 5-10 rads).
• Urinary sepsis may be asymptomatic (urinary frequency is pretty normal)

b) List the leading causes of sepsis in pregnant patients.

• Chorioamnionitis
• Urinary tract infections
• Pyelonephritis
• Endometritis
• Septic abortion

also...

• Episiotomy infections
• Necrotising fasciitis of the ceasarian wound
• Septic thrombophlebitis - especially pelvic vein thrombophlebitis
• Aspiration pneumonia

Acute pyelonephritis Retained products of conception Septic abortion Conservative management of placenta accreta or percreta Neglected chorioamnionitis or endomyometritis Uterine microabscess or necrotizing myometritis Gas gangrene Pelvic abscess Unrecognized or inadequately treated necrotizing fasciitis Abdominal incision Episiotomy Perineal laceration

Bacterial pneumonia Bacterial examples Staphylococcus Pneumococcus Mycoplasma Legionella Viral pneumonia Influenza H1N1 Herpes Varicella Intraperitoneal etiology (nonobstetric) Ruptured appendix or acute appendicitis Bowel infarction Acute cholecystitis Necrotizing pancreatitis

c) What are the common pathogens encountered in pregnancy-related sepsis?

Oh's Manual quotes the following bugs:

• Gram-negatives
• Streptococci (especially Group A, i.e. S.pyogenes)
• Bacteroides

To this, the Sanford Guide adds a few:

• Enterobacteriaceae
• Chlamydia trachomatis
• Ureaplasma urealyticum

(these are specific to chorioamnionitis and septic abortion)

d) List two antibiotics contra-indicated during pregnancy.

 The full list:

Antibiotics which are contraindicated in pregnancy or lactation, and Why

Contraindicated antibiotics	Why
Aminoglycosides in high doses	Increased uptake by neonatal kidney leads to increased nephrotoxicity (but apparently gentamicin is still relativey safe)
Streptomycin	8th cranial nerve damage
Sulfonamides	Kernicterus in the newborn due to displacement of bilirubin off albumin, particularly if used shortly before birth. The specific culprit is sulfamethoxazole. Trimpethoprim appears to be relatively safer.
Tetracyclines	Tetracyclines have nightmarish dental and bony effects.  In fact, these drugs are contraindicated from 16th week of gestation all the way until the 7th year of extrauterine life.
Quinolones	Quinolones cause birth defects (though it seems fluoroquinolones are safe, and it was really mainly nalidixic acid that was the culprit).
Rifampicin	Seems to be somewhat teratogenic, mainly in animal studies (spina bifida and impaired osteogenesis seem to be the major consequences)- but in humans one may overlook this if rifampicin is strongly indicated (eg. treatment of lifethreatening tuberculosis)
Fusidic acid	Like sulfonamides, causes displacement of bilirubin by competing with it for albumin binding
Chloramphenicol	This "Grey baby syndrome" is the consequence of disrupted mitochondrial function, when chloramphenicol metabolites interfere with the electron transport chain. Foetal failure to properly metabolise chloraphenicol by glucourinidation seems to be to blame.
Azole antifungals	Teratigenic and embryotoxic. The specific dangerous ones are ketoconazole  fluconazole and voriconazole, earning a D classification.
Echinocandins	Hard to discuss humans in the absence of real data, but in animals using normal treatment doses caspofungin and anidulafungin cause skeletal abnormalities, reduction of litter size, ossification and rib malformations.
Flucytosine	Embryotoxic and in fact abortificant in the first trimester, which is hardly surprising given that its main metabolite is 5-fluorouracil
Albendazole	Teratogenic and embryotoxic. If the pregnant lady has some sort of hideous helminthic parasitosis which cannot wait until after delivery, ivermectin is probably a safer alternative
Foscarnet	Seems to be teratogenic in animals, but if your CV infection is so severe and resistant that you've failed primary therapy, the chances are that your foetus is already significantly damaged by congenital CMV.

The college answer for Question 3.1 from the first paper of 2014 also lists nitrofurantoin, isoniazid and macrolides as drugs which are relatively contraindicated. This in fact, is not true:

Oh's Intensive Care manual:

Chapter 64   (pp. 684) General  obstetric  emergencies by Winnie  TP  Wan  and  Tony  Gin

Chapter 65   (pp. 692) Severe  pre-existing  disease  in  pregnancy by Jeremy  P  Campbell  and  Steve  M  Yentis

Fernandez-Perez, Evans R., et al. "Sepsis during pregnancy." Critical care medicine 33.10 (2005): S286-S293.

Barton, John R., and Baha M. Sibai. "Severe sepsis and septic shock in pregnancy." Obstetrics & Gynecology 120.3 (2012): 689-706.

van Dillen, Jeroen, et al. "Maternal sepsis: epidemiology, etiology and outcome." Current opinion in infectious diseases 23.3 (2010): 249-254.

Khan, Muhammad R., and Sameer ur Rehman. "Sigmoid volvulus in pregnancy and puerperium: a surgical and obstetric catastrophe. Report of a case and review of the world literature." World Journal of Emergency Surgery 7.1 (2012): 1.

Demers, P., et al. "Effects of tetracyclines on skeletal growth and dentition. A report by the Nutrition Committee of the Canadian Paediatric Society."Canadian Medical Association Journal 99.17 (1968): 849.

Bar-Oz, Benjamin, et al. "The safety of quinolones—a meta-analysis of pregnancy outcomes." European Journal of Obstetrics & Gynecology and Reproductive Biology 143.2 (2009): 75-78.

Erić, Mirela, and Ana Sabo. "Teratogenicity of antibacterial agents." Collegium antropologicum 32.3 (2008): 919-925.

Chen, Morie M., et al. "Guidelines for computed tomography and magnetic resonance imaging use during pregnancy and lactation." Obstetrics & Gynecology 112.2, Part 1 (2008): 333-340.

Mylonas, Ioannis. "Antibiotic chemotherapy during pregnancy and lactation period: aspects for consideration." Archives of gynecology and obstetrics 283.1 (2011): 7-18.

Pilmis, Benoît, et al. "Antifungal drugs during pregnancy: an updated review." Journal of Antimicrobial Chemotherapy (2014): dku355.

David, S. Ben, et al. "The safety of nitrofurantoin during the first trimester of pregnancy: meta‐analysis." Fundamental & clinical pharmacology 9.5 (1995): 503-507.

Lin, Kueiyu Joshua, et al. "Safety of macrolides during pregnancy." American journal of obstetrics and gynecology 208.3 (2013): 221-e1.

Bar-Oz, Benjamin, et al. "Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study." European Journal of Obstetrics & Gynecology and Reproductive Biology 141.1 (2008): 31-34.

Ormerod, P. "Tuberculosis in pregnancy and the puerperium." Thorax 56.6 (2001): 494-499.