Category: Obstetrics

Progesterone for First-Trimester Bleeding

Emergency Department evaluation for patients with first-trimester bleeding is fairly straightforward. Most of the time, an ultrasound identifies an unremarkable intrauterine pregnancy and patients are provided with expectant management and best wishes. However, there is some evidence progesterone supplementation – in this trial, an intravaginal progesterone supplement – may help implantation and prevent pregnancy loss. This, the Progesterone in Spontaneous Miscarriage (PRISM) trial, is the first, large, high-quality investigation of this intervention.

Over the course of two years, 12,862 women with bleeding before 12 weeks of pregnancy were screened, and 4,153 enrolled across 48 hospitals in the United Kingdom. Enrolled patients were randomized to either 400mg intravaginal micronized progesterone twice daily through 16 weeks of pregnancy, or identical placebo. The primary outcome was live birth after at least 34 weeks, with secondary outcomes being other early pregnancy milestones, as well.

Per the authors, and hewing fast to their frequentist analysis, this is a negative trial. The primary outcome occurred in 75% of the progesterone cohort and 72% of placebo, a relative rate of 1.03 (1.00 to 1.07) and a p-value of 0.08. The authors conclusion: “treatment with progesterone did not result in significant improvement in the incidence of live births among women with vaginal bleeding during the first 12 weeks of pregnancy.”

Maybe?

It is always curious to look at the statistical analysis portion of these articles and consider the decisions leading to the inability to detect a difference. In this trial they state their choice of sample size was driven by the “minimally important absolute difference of 5 percentage points between the progesterone group and the placebo group in the incidence of live births after at least 34 weeks of gestation (65% vs. 60%)”. If we had a medication for use in sepsis that was inexpensive and readily available, would we require a 5% difference in mortality for its use? Anti-hypertensives, taken for five years, prevent heart attack, stroke, and all-cause mortality with numbers-needed-to-treat swimming right around a 1% difference – and these are taken in massive numbers at the population level. Without delving into any sort of personhood argument, a lost pregnancy is effectively a mortality benefit – and, despite the massive scale required, it might have rather been more appropriate to choose a smaller “minimally important absolute difference.”

If the observed difference of 2 to 3% were to be confirmed, these are NNTs in the 33-50 range to prevent pregnancy loss. While this would not be rank as a profoundly effective intervention, we are rather talking about producing an actual new human being. No harms were detected, although a trial such as this would be expected to be even further from powered to detect very rare events such as congenital deformities. I would expect the debate regarding this to continue, and I wouldn’t be surprised if you found some groups encouraging its use or initiation in the ED.

“A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy”
https://www.nejm.org/doi/full/10.1056/NEJMoa1813730

The Swiss, Ruling out PE in Pregnancy

Evaluating the average Joe/Jane for pulmonary embolism is rather straightforward – but let’s not go back into that morass of practice variation and low-value over-diagnosis. This is an a study looking at how to diagnose PE during pregnancy, which is fraught with its own unique issues.

Firstly, obviously, CTPA ought to be avoided whenever possible – and moreso when there is a chance of fetal exposure. When the benefits outweigh the risks, of course, it is reasonable to proceed. Then, use of D-dimer as a tool to inform the posterior probability of PE is challenged by its steady increase in pregnancy.  This combination of issues results in general uncertainty with regard to the approach.

This is their algorithm:

Over the course of eight years, at 11 centers, these authors included 395 patients in their study – 357 of whom were evaluated per-protocol. Only a handful were assessed as “high” risk, while the bulk underwent D-dimer testing with a test threshold of 500 µg/L on the Vidas assay. The D-dimer was virtually useless, with only 46 of 392 being excluded from further evaluation. Then, the bilateral lower extremity ultrasound was basically useless, with only 7 positives out of 349 performed – resulting in 342 CTPAs. There were 19 positive CTPA, and then two of the inconclusive CTPA were ultimately diagnosed with PE by V/Q scanning.

What a mess. For those keeping score at home, that’s 7.1% yield for their evaluation of PE, and all their extra hoops prevented little radiation exposure. From a diagnostic evaluation standpoint, of course, their protocol was entirely adequate with regard to missed PE – unsurprising because most patients received all the tests in their algorithm.

The ugliest observation here is their prevalence of 7.1% is actually far lower than the prevalence observed in the non-pregnant population in Europe. Step one in fixing this approach: just apply the same gestalt to this population as the remainder of ED presentations. Then, let’s adopt the YEARS protocol, at a minimum, and consider adopting trimester-adjusted cut-offs for D-dimer. The miss rate will not be zero – but, incorporating appropriate clinical judgment, the net harms from untreated PE will be balanced by the benefit of avoided radiation, anticoagulation, and over-diagnosis.

“Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study”
http://annals.org/aim/article-abstract/2708166/diagnosis-pulmonary-embolism-during-pregnancy-multicenter-prospective-management-outcome-study

Just Stand There! Bacterial Vaginosis Edition

There has long been considered to be a causative association between bacterial vaginosis and preterm delivery – with increasing risk of delivery when BV is identified earlier in pregnancy. Clearly, of course, early antibiotic treatment would eradicate the pathology and improve pregnancy outcomes. It just makes sense.

But, no.

In this large, multicenter trial performed in France, 84,530 pregnant women were screened before 14 weeks gestation, resulting in 5,630 diagnoses of BV. Patients deemed “low-risk” for preterm delivery were treated with one of regimens of clindamycin or placebo, while those few deemed “high-risk” were excluded from placebo randomization. The primary outcome was late miscarriage or early preterm birth, a range of preterm delivery spanning 16-32 weeks gestation.

Approximately 2/5ths of those approached for enrollment declined to participate, leaving 2,869 for randomization into one of the three low-risk arms. There were no important baseline differences between the three cohorts. The results: no difference. About 1% of each group met the primary outcome, and there were no signals of even a small magnitude of benefit to treatment with clindamycin in the low-risk cohorts. Adverse events, of course, clearly favored placebo – as befitting clindamycin’s known propensity for gastrointestinal effects, but no effects on fetal outcomes were apparent.

This is not specifically relevant to Emergency Medicine other than to demonstrate the need to rigorously test even what seems obvious. Widespread screening and aggressive, proactive treatment – even when all signs point to an expected positive result – represented low-value, and potentially harmful care.

“Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31617-9/fulltext

Useful Pregnancy-Related Guidance

So, I might be alone here, but in my canvassing the interesting literature this morning, I stumbled across this Clinical Expert Series in Obstetrics & Gynecology and thought: “This is great! I wish we’d (myself and my wife) had this four years ago!”

It’s a concise summary of the evidence (mostly lack thereof) and recommendations for things pregnant women “should and should not routinely do during pregnancy.” There’s so much nonsense floating around on the internet, and so many dark wombat burrows full of sinister imaginings, I almost feel this would be a good document to hand out to pregnant patients with adequate levels of health literacy.

A few highlights:

  • Prenatal vitamins are unlikely to be harmful, but potentially unnecessary for women already consuming balanced diets.
  • Alcohol consumption up to 7-9 drinks per week does not appear to be harmful, but no specific threshold for safety is known.
  • Up to 300 mg/d of caffeine is probably safe.
  • Examples of good fish are anchovies, Atlantic herring, Atlantic mackerel, mussels, oysters, wild salmon, sardines, snapper, and trout.
  • Appropriately prepared sushi is unlikely to give you a tapeworm.
  • “Pregnant women should avoid foods that are being recalled for possible Listeria contamination.”
  • Using toxic insect repellent is probably safer than the risk of insect-borne illness, where appropriate.

… and many more!  Useful!

“Dos and Don’ts in Pregnancy – Truths and Myths”
https://www.ncbi.nlm.nih.gov/pubmed/29528917

The End of the “Emergency” Pelvic Exam

Enthusiasm, as measured by time-to-provider, for performing a pelvic examination in the Emergency Department is low. The logistics of a comfortable, adequate examination can be time consuming and detract from patient throughput. The yield of such examination is thought to be poor – enough so many providers, even absent sufficient evidence, choose to forgo the examination whenever reasonable, and depend on symptoms or advanced imaging to complete the evaluation.

This study aims to determine the acceptableness of the practice of forgoing the pelvic examination in a subset of vaginal complaints, those presenting with vaginal bleeding or abdominal pain in early pregnancy. From an ED standpoint, the typical most worrisome consideration is an ectopic pregnancy, with other diagnostic considerations important, but less salient. These authors developed a protocol in which women of fewer than 16 weeks gestation could be randomized to assessment with pelvic examination omitted or not. Their primary outcome was a composite pregnancy morbidity and utilization outcome at 30 days, with the trial designed to evaluate statistical equivalence between the two strategies.

Unfortunately, we have to give this trial a grade of “incomplete” for its ability to answer the research question – not the least because they under-enrolled their study cohort by over 500 patients. Of a planned enrollment of 720, they were only able to capture 202 due to slow enrollment due to a variety of factors. Furthermore, even if they had met their enrollment, I’m uncertain whether their composite outcome – chosen, almost certainly, to reduce the sample size needed to detect already rare outcomes – is clinically meaningful. Some elements of their composite morbidity outcome – unscheduled ED visits, hospital admissions, procedures relating to pregnancy – are of uncertain relationship to the decision to provide or withhold a pelvic examination at the time of first encounter. The most relevant of their composite is undoubtedly the identification of an alternative symptom source, but, again, this would require additional enrollment to detect a difference in such an infrequent outcome. Of the 202 patients included, 2 of 100 in the pelvic examination cohort had an alternative source for symptoms identified, but these are not specifically commented upon in the text.

Secondary outcomes relating to ED throughput and patient satisfaction favored the cohort omitting the pelvic examination, only ED length of stay suggests a potentially meaningful difference of approximately 20 minutes (not reaching statistical significance). Patient perceptions and concerns over embarrassment were not consistent across measures and assessment and probably not reliable.

Generally speaking, this study probably provides evidence supporting a strategy in which pelvic examinations are omitted, but this evidence is quite weak. The clinical significance of the information gleaned from a pelvic examination is unlikely to be of substantial clinical interested except in rare cases, and I would suggest the next steps in observational research to be to evaluate the clinical features of patients whose diagnosis or plan of care is changed by the pelvic examination.

“Is the Pelvic Examination Still Crucial in Patients Presenting to the Emergency Department With Vaginal Bleeding or Abdominal Pain When an Intrauterine Pregnancy Is Identified on Ultrasonography? A Randomized Controlled Trial”
http://www.annemergmed.com/article/S0196-0644(17)31387-2/fulltext

 

Tranexamic Acid & The WOMAN Trial

Tranexamic acid is popular for the treatment of freckles and nosebleeds – oh, and major bleeding in the setting of trauma. But, originally, the drug was developed for use in controlling hemorrhage in obstetrics and gynecology. Finally, then, we have a trial examining its use for its intended purpose.

Comprising 20,060 patients with clinically significant post-partum hemorrhage across 193 hospitals in 21 countries, the WOMAN trial is – inconveniently – negative as originally designed. The initial study design called for 15,000 patients and a composite endpoint of hysterectomy or death within six weeks of childbirth. However, as the study progressed, it was clear the standard practice in the settings involved indicated the intervention was going to have no effect on hysterectomy rates, and the trial was then expanded to examine the effect on mortality.

So, then, with their expanded sample size, does TXA save lives, as reported profusely throughout the lay media?

Nope.

Mortality within 6 weeks was 2.3% in the TXA cohort and 2.6% with placebo a relative risk of 0.88 (0.74-1.05).

There is, however, some layered complexity in these outcomes. Broken down by cause of death, deaths due to bleeding were 1.5% in the TXA cohort compared with 1.9% with placebo, reaching “statistical significance” with a p-value of 0.045. Then, if you further unpack these results, it seems even within the TXA cohort there is probably a time-to-treatment effect similar to CRASH-2.  Mortality was 1.2% in those receiving their TXA within 3 hours compared with 1.7% treated with placebo. In those treated beyond 3 hours, there was no difference in outcomes – and much higher mortality, regardless (2.6% vs. 2.5%).

So, what should we take away from these data? Is TXA more than just a treatment for freckles, or are these authors and the lay media exaggerating secondary outcomes in the setting of an overall negative trial? As usual, the answer is a little bit of both. The magnitude of the treatment effect, considering the size of this trial, is very, very small. That said, death is a quite meaningful clinical outcome, TXA is fairly inexpensive, and no specific harms were detected in this trial. Therefore, in the settings in which this trial was conducted – Nigeria, Pakistan, Sudan, Albania, etc. – this is likely an important treatment for post-partum hemorrhage.

In more robust clinical settings where additional resources are typically available to support the resuscitation of women suffering bleeding complications from childbirth, the effect size on mortality is likely even much smaller. There may be clinically important effects regarding hysterectomy, hemostasis, and reduction in transfusion utilization, but I again suspect they will be very small and difficult to quantify without a similarly large trial. Then, as the NNT increases for clinically important outcomes, even the very rare harms of a treatment become relevant – and failure of this trial to detect harms may simply be a limit of its statistical power.

Ultimately, as the mortality benefit decreases, the range of acceptable practice variation for protocols incorporating TXA increases.  This is an important trial – but, as typically, not quite as breathlessly so.

“Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial”
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)30638-4/abstract

Tylenol & Case of the Flawed Fetus

If you’re like most folks advising pregnant patients on pain and fever control, you’ve advised against ibuprofen and recommended acetaminophen. It is, after all, considered to be generally safe throughout pregnancy, in contrast to the alternatives.

I’m afraid I do not know precisely what to make of this study, but it is the latest in a context of several other studies linking maternal acetaminophen use during pregnancy with behavioral issues in young children. These authors link surveys of pregnant women performed over a decade ago with follow-up surveys of their children, with specific emphasis on identifying potential cofounders for their observed association.

The ultimate conclusion is fairly clear from just the title, with the subtitle of “Evidence Against Confounding”. An association is clearly observed between those they identify with likely or confirmed usage of acetaminophen and increased behavioral and attention difficulties in childhood. However, the evidence against confounding is rather incomplete. There are small differences in maternal psychiatric illness, maternal smoking, and maternal alcohol use favoring normally behaved children – and, while these authors attempt to control for these factors, this still introduces some element of statistical tomfoolery. There are also several non-genetic and non-prenatal risk factors for ADHD, and these authors are able only to collect a handful of these – absent completely any observations of the home environment of the children evaluated. Finally, no dose-response relationship is ultimately measured, as well.

I would, of course, ultimately advise minimal medication exposure in pregnancy, regardless. If pain control is necessary, it is not clear this risk – if true – is specifically of greater magnitude than those associated with alternative analgesia. For, this does not yet change practice.

“Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood”

http://archpedi.jamanetwork.com/article.aspx?articleid=2543281

Gestational Age and D-Dimer Levels

In general, the utility of D-dimer for the evaluation of venous thromboembolism declines with gestational age.  The typical cut-offs for the 95th percentile, depending on your assay, become less and less relevant as pregnancy progresses.  Wouldn’t it be nice, perhaps, if we had reliable data?

So, well, here’s something:

One glaring hole in this data is the broad inclusion criteria of “healthy” women.  No testing was specifically performed to exclude asymptomatic venous thromboembolism, so the possibility exists of inclusion of small, subsegmental pulmonary emboli, or of non-occlusive lower extremity deep venous thrombosis.  The effect on this data would be to increase the 95% percentile, and to widen the 95th percentile confidence interval.

Jeff Kline has proposed gradually increasing cut-offs of 750, 1000, and 1250 ng/mL for the first, second, and third trimester, respectively (based on a standard cut-off of 500 ng/mL).  This sample is much larger than the one cited by Kline in his “PE in pregnancy” algorithm, but his appear to be reasonable, sensitive cut-offs.  By far, the most important aspect of evaluating pulmonary embolism in pregnancy is simply to communicate the uncertainty, and to inform and share decision-making with the patient along the way.

“Gestation-specific D-dimer reference ranges: a cross-sectional study”
http://www.ncbi.nlm.nih.gov/pubmed/24828148

Ondansetron vs. Metoclopramide in Hyperemesis

I hate to say it, but this is one of the first randomized trials I’ve stumbled across from Obstetrics and Gynecology – so, even though it’s not terribly profound, I felt compelled to cover it.

This is a double-blind, randomized trial of women admitted to observation with hyperemesis gravidarum.  They received either 4mg of ondansetron or 10mg of metoclopramide every 8 hours for 24 hours, and patient were tracked for vomiting episodes and self-reported nausea.  With regard to these co-primary outcomes, there was no difference between study drugs – most had full resolution, and most in each group had 2 episodes of vomiting or fewer.  However, secondary outcomes and adverse effects – drowsiness, xerostomia, and persistent ketonuria – favored ondansetron.

The authors therefore conclude ondansetron ought probably be favored – all else being equal.  But, for these authors, all else is not equal – ondansetron is markedly more expensive.  Therefore, the ultimate conclusion of these authors is rather in favor of metoclopramide, considering their similar efficacy.

Of other interesting note, one patient, despite admission and supportive care, had 23 episodes of vomiting during the study period.  Oy.

“Ondansetron Compared With Metoclopramide for Hyperemesis Gravidarum
A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/24807340

The Curious Story of Diclegis

For no particular reason, I’ve recently become familiarized with the story of Diclegis (Diclectin in this study, and in Canada).  For use in pregnancy-induced nausea and vomiting, Diclegis is a delayed-release combination formulation of 10mg each of doxylamine and pyridoxine.  It was approved by the FDA in April of 2013, and has rapidly become first-line therapy.

The surprising bit – this is precisely the same drug our mothers took in pregnancy.  It was introduced in the 1950s as Bendectin, and it was estimated as many as 30% of pregnant women took this combination pill in the 1970s.  However, in the early 1980s, the manufacturer was the target of innumerable lawsuits alleging fetal malformation – and in 1983, voluntarily withdrew the drug from the market.  This choice was made solely due to the costs of defending against litigation, and not a reflection of the safety of the drug.  The physicians who had published data suggesting fetal risk were eventually discredited, and even the FDA noted in 1999 that Bendectin was not withdrawn for reasons of safety or effectiveness.

So – now it’s back, and, unsurprisingly, it works better than placebo.  This manufacturer-sponsored, double-blind, placebo-controlled trial demonstrated improvement with Diclectin in almost every measure.  And, 48% of Diclegis users asked for compassionate use of the study drug following conclusion of the study (although, so did 32% of placebo).  I’ve also discovered my new favorite disease-severity scoring system: the PUQE Score.

The downside: it costs ~$160 for 30 pills.

A brief perusal of the internet shows doxylamine, a sedating, first-generation antihistamine costs as low as 3 cents per tablet.  Pyridoxine, vitamin B6, costs as little as 6 cents per tablet.  Diclectin costs ~$5 per tablet.  You could pay for Diclegis – after all, it is a special “delayed-release” formulation where doxlyamine reaches peak concentration 6 hours after ingestion.  Or, you could do what obstetricians have been telling their patients to do for the last several decades: make your own equivalent dosing from the component medications at a fraction of the cost.

It certainly seems prudent to try the cheaper option, first.

“Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/20843504