TXA’s post-partum fragility

Warning: An American on TXA.

The WOMAN trial was an international randomized double-blind placebo controlled trial across 193 hospitals in 21 countries looking at TXA use for morbidity and mortality for post-partum hemorrhage.

First off, this was a massive undertaking as this was an enormous trial – about 10,000 patients in each treatment arm, with fantastic follow up- only 31 of about 20,060 total patients were lost to follow up. If the treating provider was unclear as to the utility of TXA for post-partum hemorrhage control, the patient was randomized 1:1 to placebo or 1g of TXA, and if the bleeding continued after 30 min or stopped and restarted within 24 hours of the first dose, a second dose (1g TXA) or placebo was given. Baseline characteristics were quite similar between the placebo and TXA arms.

So since social media is clamoring, and since this is published in the Lancet, there must be a mortality benefit, right?

This is where I point out three things:

1) there was no difference in mortality (2.3% vs 2.6% – favoring placebo)

2) TXA had 0.4% fewer patients who experienced death due to post-partum hemorrhage

3) this was accompanied by a p value of 0.045, and a fragility index of…..

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A study of 20,000+ patients, and a p-value of 0.045, and a fragility index of zero.  And again, the most patient-centered outcome possible- mortality – favored placebo.

TXA is not the magic bullet in this instance.  There is a weak signal of benefit if you are proceeding to laparotomy for bleeding – particularly for caesaean delivery (1.5% vs 2.4% mortality benefit, fragility index of 4), but that is an exploratory analysis needing further review, otherwise, this is a flimsy trial.  While TXA remains inexpensive, it is worth a go- particularly in low-resource areas after laparotomy (provided TXA is still inexpensive there), but by no means does a clinician not giving it deserve to be chided – the evidence is incredibly fragile and not worthy of social media’s  “life-saving” claims – at least for post-partum hemorrhage.

Improving Outcomes, Improving Throughput, Mythbusting

Pregnancy & Pyelonephritis…

You are seeing a twenty-something female, who presents for back pain & abdominal pressure x 3 days, and “felt warm” today.  You quickly diagnosis her with pyelonephritis, complicated by her new diagnosis of pregnancy.  After an ultrasound confirms viability and estimates a 15 week old fetus, you now have to decide treatment and disposition.  A 2014 review of pyelonephritis in pregnancy (from 1993-2010 in the Kaiser Permanente system) found pyelonephritis was more likely to occur in the African American or Hispanic population, those under 18 years old, less educated, nulliparous, those who initiated prenatal care late, and smoked during pregnancy.  Septicemia was quite low (1.9% vs 0.03%), as was acute pulmonary insufficiency (0.5% vs 0.04%) and acute renal dysfunction (0.4% vs 0.03%).  Spontaneous preterm birth (10.3% vs 7.9%) was somewhat higher in the pyelonephritis group, though most of the preterm births occurred between 33-36 weeks.

So then how do we treat these patients?

Let’s look at a few studies:
Study #1
179 women <24 weeks gestation randomized to 1) IV ampicillin & IV gentamicin 2) IV cefazolin or 3) IM ceftriaxone.  After one afebrile day, patients were then provided 10 days of keflex.  The three arms were similar in age, parity, temperature, gestational age, and initial WBC.  There was no statistically significant differences in LOS, hours to defervescence, resolution of CVA tenderness, or birth outcomes among the three treatment arms.  Positive blood cultures were found 8.4% of the time.

Study #2:
RCT of women <24 weeks pregnant with pyelonephritis were randomized to either: three daily 2 gram IV doses of cefazolin (88 patients) or a single daily IV dose of 1 gram ceftriaxone along with two additional doses of normal saline solution (90 patients).  All infusions were given on an 8-hour schedule.  Treatment continued until the patient became afebrile and were discharged on antibiotics based on culture & sensitivity.   Patient demographics and presenting signs and symptoms were similar in both groups.  There were no differences noted between the two treatment arms in regards to morbidity, LOS, treatment failure, or febrile days.

Study #3
RCT of women <24 weeks pregnant with pyelonephritis comparing 60 inpatients treated with IV cefazolin until afebrile for 48 hours vs 60 outpatients received two injections of IM ceftriaxone, both followed by a 10-day course of cephalexin.  Both groups were similar with respect to age, parity, temperature, estimated gestational age, initial WBC, and incidence of bacteremia.  Three patients in each group had recurrent pyelonephritis.  Six inpatients were switched to gentamicin: two because of a worsening clinical picture and four due to  a prolonged febrile course; no outpatients required a change in antibiotic.

Study #4
Ninety pregnant women admitted with a diagnosis of pyelonephritis and randomized to either 500 mg of oral cephalexin every 6 hours or to intravenous cephalothin 1 gram every 6 hours.  There was no difference between the oral and IV groups concerning predefined criteria for successful therapy (91.4% versus 92.9% successful therapy, respectively).  No characteristic available at presentation predicted bacteremia or ultimate failure of therapy.

Conclusions? IV cefazolin, IV ampicillin / IV gentamicin, and IM / IV ceftriaxone are all equivalent to each other in the patient population for study one & two.  Study three suggests that IM ceftriaxone x 2 doses (once in the ED, another the following day at an infusion center or in the ED) is equivalent to IV cefazolin for the treatment of pyelonephritis in pregnancy <24 weeks, and as we’ve stated in the past, IV vs PO antibiotics are likely equivalent as study 4 suggests.
Septicemia in pregnancy is quite low at 2%, but if you think your pregnant patient is truly ill, then feel free to keep them in observation, as patients likely improve with a day or so of antibiotics anyway.  However, be confident that if patients are going to fail therapy, the difference between an oral medication and its IV counterpart is minimal at best.  The risk of spontaneous preterm birth goes up to about 10% from 8%, but choice of antibiotic does not seem to affect this.  Bottom line, if the patient looks well, and feels well, they can probably go home if they are agreeable to return for any decline (or failure to improve).