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The Bendectin Controversy Redux?

When I read that a new study had shown that antihistamines were harmful for patients with morning sickness, I cringed and thought “Here we go again.”

Hyperemesis gravidarum (HG) is a serious complication of pregnancy. Simple morning sickness is more common and less serious. When I started out in medicine, we routinely treated morning sickness with Bendectin. It was a safe and effective remedy, a combination of the antihistamine doxylamine and a B vitamin, pyridoxine. Unfortunately the manufacturer, Merrill Dow Pharmaceuticals, was bombarded with numerous lawsuits claiming that Bendectin caused birth defects. There was a clear scientific consensus that the evidence did not show that Bendectin caused birth defects and there was plentiful evidence of its safety. The lawyers prevailed over the science, and in 1983, Dow voluntarily took Bendectin off the market to avoid further litigation expenses. After the drug’s withdrawal, the rate of birth defects did not decrease, but the rate of hospitalization for hyperemesis gravidarum doubled.

This was frustrating to those of us treating morning sickness, because it denied us a remedy that we knew was safe and left us with only less safe options for a potentially life-threatening condition. Some of us found a way to do an end run. We advised patients to buy doxlyamine (sold over-the-counter as the sleep aid Unisom), and to take it with pyridoxine, effectively reconstituting what we could no longer get as a single pill.

The Daubert Standard

One good thing came of the litigation against Dow. The controversy led to a landmark U.S. Supreme Court decision, Daubert v. Merrill Dow Pharmaceuticals in 1993, which set a new standard for rules for admission of expert testimony, including scientific evidence. Under Daubert, the trial judge assumes a gatekeeper responsibility. The judge decides whether an expert’s testimony is based on a reliable foundation of scientific knowledge and can exclude evidence not based on good science. Daubert is now embodied in Rule 702 of the Federal Rules of Evidence:

A witness who is qualified as an expert by knowledge, skill, experience, training, or education may testify in the form of an opinion or otherwise if:

(a) The expert’s scientific, technical, or other specialized knowledge will help the trier of fact to understand the evidence or to determine a fact in issue;

(b) The testimony is based on sufficient facts or data;

(c) The testimony is the product of reliable principles and methods; and

(d) The expert has reliably applied the principles and methods to the facts of the case

The Daubert standard is now the law in federal court and over half the states. While the original intent of Daubert and the rules of evidence the Supreme Court interpreted in that case was to liberalize the introduction of expert testimony, the general consensus is that Rule 702 has kept a good deal of junk science out of the courtroom. This is demonstrated by the history of the Daubert case itself.

The Dauberts had two children with serious congenital defects that they blamed on Bendectin. In the trial court, an expert for the defense testified that  extensive published scientific studies had found no evidence that Bendectin was a risk factor for congenital anomalies, and there was widespread acceptance that it was not. The plaintiffs responded with the testimony of eight experts who disagreed, based on animal studies, chemical structure analyses, and the unpublished “reanalysis” of data from human statistical studies. Their star witness, Dr. William McBride, was the lead author of a study allegedly showing that Bendectin caused birth defects. When the paper was published, his co-authors protested about discrepancies, and he was eventually found guilty of falsifying data and of scientific fraud, and was struck off the register (no longer allowed to practice medicine).

The appellate court ruled (as summarized here) that:

The Plaintiffs’ experts did not conduct their research independent of the litigation and the theories have not been published in scientific journals or reviewed by peers, though there has been ample time to do so because the theories and litigation has been around for a decade…The Plaintiffs cannot show causation directly and attempt to show it through circumstantial evidence provided by their experts. The testimony cannot establish that the defects were not caused by an independent cause, since limb reduction defects occur in the babies of mothers who did not take the drug. The Plaintiffs’ experts cannot say that the drug more than doubled their risk of the defect, only that there was a statistical relationship between the drug and the birth defect.

New evidence against antihistamines?

A new study published in the European Journal of Obstetrics and Gynecology and Reproductive Biology, is titled “Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum.” The lead author is Marlena Fejzo, a respected researcher in the field. It is a case control study with 254 patients with hyperemesis serious enough to require intravenous fluids and/or total parenteral nutrition/nasogastric feeding tube, and 308 control patients. Subjects submitted their medical records and completed an online survey. A large number of demographic characteristics, pre-existing conditions, pregnancy symptoms and treatments, and maternal and fetal outcomes were included.

Objective: The stated purpose of the study was to determine the frequency of adverse perinatal outcomes in women with hyperemesis gravidarum and to identify prognostic factors.

Results: Several demographic characteristics were found to be associated with HG: gestational hypertension, immune problems, anxiety, bipolar disorder, and depression. Carrying a female fetus increased the risk of HG. None of the factors that were significantly different in women with HG were associated with adverse outcomes except for gestational hypertension. Onset of nausea and vomiting at 3-4 weeks gestation was associated with poorer outcome; onset of symptoms at 1-2 weeks and >4 weeks was not.

Adverse fetal outcomes (AFOs): Women with HG were more likely to report lower birth weight and prematurity. The overall rate of adverse fetal outcomes was 16.93% compared to 4.55% in controls. There was no significant difference in the rate of birth defects, perinatal mortality, or weight below the 10th percentile.

Medications/treatments: They explored the effect of treatments by comparing 43 HG subjects with an adverse fetal outcome (AFO) to 211 subjects with no AFO. They looked at 36 different medications and treatments.  Acupuncture was associated with significantly fewer AFOs (but it was also reported to be ineffective in relieving symptoms).  A statistically significant correlation was found between AFOs and Solumedrol, Phenergan, and some (but not all) antihistamines. For most of the 36 treatments there was no statistically significant correlation with AFO. I was puzzled to see dimenhydinate listed as one of the antihistamines associated with AFO but also listed among the anti-motion sickness medications that were not associated with AFO. Bendectin was in the list of antihistamines correlated with AFO, and they noted a “trend towards adverse outcome” with Bendectin itself, but noted that there were not enough subjects to reach statistical significance. In other words, this study did not show that Bendectin caused adverse fetal outcomes.

What about effectiveness? The only treatments self-reported as effective by more than 50% of patients were cannabis, intravenous fluids, methylprednisolone, and ondansetron (Zofran), and there was no significant association between self-reported medication effectiveness and outcome for any medication including the medications associated with poor outcome.

Problems with the study

Here are a few of the things that bothered me about this study:

  • The title may indicate bias. They could have called it “Frequency of adverse perinatal outcomes and prognostic factors in women with hyperemesis gravidarum” which would have been more in line with the stated objectives of the study, but they chose to emphasize antihistamines in the title. Maybe I’m just quibbling, and I admit this is a hot-button issue for me because of what happened with Bendectin.
  • The discussion at the end expressed more concern about the use of antihistamines than I felt was warranted. Again, that could be bias on my part.
  • They examined 36 different treatments. When you look at that many factors, you are almost guaranteed to find some spurious correlations. They did not do any statistical corrections for multiple endpoints.
  • The numbers were far too small to reach reliable conclusions for most treatments. They only looked at 43 subjects with HG and AFOs, and the numbers of subjects using each treatment were small.
  • Some of the numbers in the table struck me as odd. For example, for Motilium, there was a total of only 2 patients who got the treatment, presumably one in the AFO group and one in the no-AFO group. They nevertheless calculated a p value of 0.3105%. They calculated p values for several other treatments that were only used by 4-6 subjects total. Is it legitimate to calculate p values based on such small numbers?  I don’t know, but it certainly isn’t very meaningful. And calculating out to 4 decimal places for a sample of 2 is beyond silly.
  • There are other studies that support the safety of antihistamines. One study even found that they protected against fetal malformations.
  • Data were based on patient recall, which is potentially unreliable.
  • Early symptoms were associated with more AFOs. I wondered whether patients with early symptoms were more likely to try antihistamines.

What Should We Make of this Study?

The mom/baby websites are already warning against antihistamines for morning sickness. A typical one says:

Poor outcomes were associated with early start of symptoms and treatment with methylprednisolone, promethazine and other antihistamines; Benadryl, Gravol, Unisom, Vistaril/Atarax and Diclectin/Bendectin, independent of effectiveness.

That’s inaccurate. The association they found was for a group of many antihistamines lumped together, and when they examined Bendectin separately, they did not find a significant association.

Should we change our practices based on this study? I think not. Better studies will be required before we can conclude that antihistamines are harmful.

In June, 2013, Bendectin (doxylamine/pyridoxine) returned to the US market under the new brand name Diclegis. We already had good evidence that Bendectin was safe, and this new study failed to find a significant association between Bendectin and adverse fetal outcomes. I see no reason to avoid the new formulation.

Note: Thanks to Jann Bellamy, JD for her assistance with the Daubert section.

Corrections: The Daubert case involved one Daubert child and a child from another family. McBride was not a witness in the original case, but his now-discredited study was relied on by other witnesses.

 

Posted in: Legal, Obstetrics & gynecology, Pharmaceuticals

Leave a Comment (20) ↓

20 thoughts on “The Bendectin Controversy Redux?

  1. Alexander Huszagh says:

    “When you look at that many factors, you are almost guaranteed to find some spurious correlations. They did not do any statistical corrections for multiple endpoints.”

    “Some of the numbers in the table struck me as odd. For example, for Motilium, there was a total of only 2 patients who got the treatment, presumably one in the AFO group and one in the no-AFO group. They nevertheless calculated a p value of 0.3105%. They calculated p values for several other treatments that were only used by 4-6 subjects total. Is it legitimate to calculate p values based on such small numbers? I don’t know, but it certainly isn’t very meaningful. And calculating out to 4 decimal places for a sample of 2 is beyond silly.”

    As much of a respected researcher Marlena Fejzo may be, both these quotes signal red flags. We would expect likely 2 spurious correlations with 36 tests at a p<.05, which would be amplified with the small sample sizes below advisable levels for proper statistical analysis.

  2. Pharmacist-in-Exile says:

    Thank you Harriet for leaving me a “personal” comment on the Bendectine/antihistamine story. The reintroduction of doxylamine+pyridoxine in the US caused a bit of a stir even here in Sweden due to the misunderstandings about what happened when it was pulled from the market (and in relation to an ongoing, heavily biased toward emotion, discussion about Pandemrix-vaccination and OTC-diklofenac CVD-risks).
    And I do agree with your first “bother” with the current study. There is to much emphasis on publicity, which includes non-scientific avenues of reporting, so there are so often titles and abstracts that are inflating (or, sadly, even inventing) the importance of the results. I see a trend where press-releases are being used in the debate instead of the studies themselves – what can we do to steer away from this (but at the same time avoid the “expertise” trap of demanding a PhD-level pre-knowledge of understanding published research)?

  3. Emma says:

    Diclectin has been widely used in Canada for I think decades now. I know I took it with both of my pregnancies. And lots of it – it kept me out of the hospital, without it I had a severe case of hyperemesis. Taking it enabled me to keep food down and manage those miserable early months of pregnancy.

  4. Young CC Prof says:

    Pregnant lady reading this while “fighting the good fight” over breakfast. Highly entertaining, actually.

    You’re right about the statistics being nonsense. You can’t analyze half a dozen factors on a sample of 43, that’s just common sense. (Or Stats 101, whatever.)

    One other thing about the study confuses me. Morning sickness can’t start in weeks 1 and 2, because you’re not actually pregnant until at least 2 weeks 6 days, which is the earliest possible implantation date. Were they using a different method of dating pregnancies, like from conception rather than LMP? Or did some of these women have preexisting digestive issues?

    1. elburto says:

      That was my thought too. LMP is the standard for dating pregnancy, and it seems like that’s another thing that this researcher is making up as they go That was my thought too. LMP is the standard for dating pregnancy, and it seems like that’s another thing that this researcher is making up as they go along.

      This “research” is not only worthless, it is obviously biased and dangerously alarmist.

      How many women and foetuses will now be put at risk due to HG because they’re scared to use the standard accepted treatment?

      1. elburto says:

        Not sure what happened there, there was no extra text when I pressed ‘submit’!

        Weird.

      2. Young CC Prof says:

        Pregnancy is such a time for fear bombardment. The fact is, there are plenty of reasonable, real things to be afraid of, even if most of them aren’t terribly likely. What I can’t stand are the people who want to keep inventing terror, the folks who turn a hint of a potential risk (not confirmed, evidence shaky and estimated effect size small) into big scary headlines.

  5. Kevin Dugan says:

    Why is this even mentioned?

    “Acupuncture was associated with significantly fewer AFOs (but it was also reported to be ineffective in relieving symptoms). ”

    It seems to me there would be too many potential confounding factors at work to make a declarative statement like this. Does the affluence necessary to afford acupuncture influencing other factors like diet ,exercise and overall health? How many patients used acupuncture? How often?

    Was this controlled against pseudo-acupuncture? Or just getting a massage by someone kindly three times a week?

    Did they also investigate Cupping? Ear candles? Anti-toxin foot pads? Homeopathic antinausia treatments?

    1. Harriet Hall says:

      Why did I mention acupuncture? Because the study mentioned it and it is a topic of interest to SBM readers. Acupuncture was only one of the 36 treatments used among 43 patients, and too few patients used it to draw any conclusions. I agree that the study authors were wrong to make a declarative statement like this. No, they didn’t do any acupuncture controls. They were not studying acupuncture itself, but merely comparing outcomes and efficacy reports of patients with and without HG who used acupuncture. And none of the other treatments you list were included in the 36 treatments they listed.

      1. Janet Camp says:

        I thought he was asking why the acupuncture bit was included in the study, itself, and I wondered the same thing, as it seems to just be inserted with no data or raison d’être.

        1. Harriet Hall says:

          Clarification: Acupuncture was listed as one of the 36 treatments, and effectiveness was reported for the different treatments. I just chose to pick it out as an item of interest from among the 36.

          1. Janet Camp says:

            Yes, I figured you just included it out of interest, but one wonders why the study includes it :-) Thanks for clarification.

      2. Kevin Dugan says:

        My apologies for being unclear Dr Hall. Ms Camp is correct. I was nonplussed by the inclusion of the statement in the study itself.

        I count myself one of those SBM enthusiasts, and really appreciate the light SBM sheds on pseudo-medical therapies. I commonly point people here (or quackwatch) when someone in my cyber-circle post credulous mis-information about cures and therapies.

        Thanks and keep up the great work!

        1. pacopicopiedra says:

          Someone should recalculate the results using the acupuncture group as a control group. Maybe it’ll make more sense.

  6. Jeremy Praay says:

    Excellent post! I am quite familiar with the Daubert standard, although I still believe it could be better, as well as the Frye standard, which seems even worse. But I was not so familiar with the case underlying the court’s decision.

  7. I got through my first pregnancy with Tigan (trimethobenzamide) although still continued to vomit a few times a day, by my second Zofran was used. What a lifesaver! With both pregnancies the N/V didn’t go away until sometime in the 8th month when hypertension/preeclampsia set in. I was always sensitive, as I believe, to the hormones in oral contraceptives, they also made me nauseated. Preeclampsia and gestational diabetes (2nd pregnancy also) are thought to be associated with pregnancy hormones. Perhaps, causation could be determined. But, It would be nice to see, realistic help. Acupuncture? Of course not. Seabands?, no! Cannabis?! Really?

  8. Jason Daubert says:

    Hellow SBM-folks!

    I have been a lurker and fan of Dr. Novella for a long time. I’ve been re-familiarizing myself with this issue as it affected me personally — I am Jason Daubert, the primary plaintiff in the Daubert v Merrell Dow case.

    I wanted to comment to correct two inaccuracies in this post:

    * The Daubert case was brought by my parents and the parents of another child, not two children from the same parents.

    * We did not use Dr. McBride as one of our witnesses when we filed our case. Here is a listing of the experts we planned to call: http://homepages.law.asu.edu/~kayed/talks/se-bassv-98/soundness/experts.htm

    This second inaccuracy seems to be common (it has made it to Wikipedia and I have seen it in quite a few of the other articles I have found recently).

    Dr. Hall, I most assuredly do not have the scientific background to evaluate the studies on my own (my background is in computer technology, not medicine), but I still have one concern about the re-introduction of the drug. I would love to discuss it further if you have the time.

    1. Harriet Hall says:

      I stand corrected. I will add a note to my article reflecting this.

  9. WilliamLawrenceUtridge says:

    John, what is your concern?

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