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Bendectin History

Bendectin: The Genesis

Bendectin was developed in the mid-1950s by the Wm. S. Merrell Company of Cincinnati, Ohio, from pharmaceutical ingredients that had been individually marketed for many years. It was indicated specifically for nausea and vomiting of pregnancy. The product was approved by the FDA in 1956.1

The original drug formulation contained three ingredients: doxylamine succinate (an antihistamine), which has antinauseant and antiemetic properties, pyridoxine hydrochloride (Vitamin B6) and dicyclomine hydrochloride (an antispasmodic).2

In 1975, the efficacy of each ingredient of multi-ingredient medications marketed between 1938 and 1962 had to be re-evaluated to ascertain that the drugs meet the efficacy requirement contained in the amended Food, Drug, and Cosmetic Act. Consequently Bendectin was submitted to this retrospective review - known as the DESI process (Drug Effectiveness Study Implementation) - which was conducted by the National Academy of Sciences and the FDA).17 Following an 8-way study, Bendectin was reformulated in 1976 to contain only the two active ingredients (doxylamine, pyridoxine) that demonstrated efficacy to treat NVP. Therefore the third ingredient, (dicyclomine, for which no benefits were observed), was removed from the original formulation.3

Bendectin became the leading treatment for nausea and vomiting of pregnancy (NVP) in the USA and in many other parts of the world under different trade names: as Debendox in the UK and Australia, as Lenotan in Germany and Switzerland as well as in other countries of Europe, South America and Africa. The product maintained its status as the only antinauseant and antiemetic for NVP through 27 years and was used by more than 33 million pregnant women worldwide. In the 1980 annual National Ambulatory Medical Care Survey (NAMCS), Bendectin accounted for 82 percent of 584,452 antiemetic prescriptions used to treat NVP in the U.S.2  The delayed-release combination of doxylamine and pyridoxine is currently available in Canada under the brand name of Diclectin®, where it is manufactured by Duchesnay Inc..4 The Canadian family-owned company has continued studying the safety and effectiveness aspects of the doxylamine-pyridoxine combination through surveillance programs and studies, including child neurodevelopment outcomes.32 

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Bendectin: The Litigation

Bendectin's legal saga started in the USA in the late 1970s with the first allegations regarding possible teratogenicity with Bendectin. The first case that received wide publicity was the Mekdeci case, which alleged that Bendectin resulted in a birth defect called Poland syndrome (a deficit in the pectoralis muscle) was filed in 1977.1 

Some studies had emerged in the late 1970s and early 1980s, which associated Bendectin to some specific malformations.5,6,7,8 Following an article published in the National Enquirer (1979)9 which stated  that Bendectin could cause birth defects, many women wanted to abort their pregnancies. Following this article, the FDA issued a FDA talk paper on Bendectin, which was helpful to physicians and patients by stating that "the current physicians labelling for the drug reflects the FDA's evaluation that there is no adequate evidence linking Bendectin with an increased risk of birth defects."10 A series of lawsuits involving the safety of Bendectin in pregnancy followed throughout the 1980s, which again attracted widespread media and public attention.3  

 A number of large epidemiological studies, many of which were reviewed in a 1983 article11 and in two meta-analyses12,15 have exonerated Bendectin and found no measurable teratogenic effect.

 In September 1980, the FDA convened a panel of independent experts to review the available scientific information and address the confusion and concern caused by the court cases involving Bendectin. The committee concluded that the existing data did not show an association between Bendectin and human birth defects.13 Subsequently, the FDA and other regulatory agencies (Canada, UK, Germany, Switzerland) continued to monitor the scientific evidence on Bendectin.13

Although the FDA panel concluded that there were no association between Bendectin and birth defects13, and despite that no known association between the use of Bendectin and birth defects was established in any of the legal cases, Merrell Dow Pharmaceuticals ceased production of Bendectin worldwide in 1983, as their soaring legal and liability insurance costs eclipsed sales.14 The drug remained approved by the FDA and continues to be used in Canada under the trade name Diclectin®.

In addition to the FDA, other national health agencies responsible for drug safety (Canada, UK, Australia, Germany and Switzerland) had reviewed the scientific evidence on Bendectin safety and had issued public statements indicating that the evidence did not demonstrate a connection between the use of Bendectin during pregnancy and birth defects. Subsequent to the 1980 FDA panel meeting, the FDA continued to monitor the scientific evidence of Bendectin.

In 1989, the cases in the US Federal court system (750 separate cases with 1,100 claimants) were consolidated by the Judicial Panel on Multidistrict Litigation into one action (MDL-486) with Merrell Dow as the defendant in the Federal Court in Cincinnati, Ohio. Following unsuccessful settlement discussions, the case went to the jury which ruled in the company's favor. The verdict was upheld on two appeals.16 In spite of the lack of scientific evidence showing that Bendectin could be teratogenic, a number of other cases followed.1

In the late 1980s, following scientific fraud complaints against Dr. William Griffith McBride, he was convicted of scientific fraud and ultimately struck in 1993 from the Australian Register of medical practitioners for deliberately falsifying data.17  Dr. McBride is the Australian obstetrician and gynaecologist who took the stand in the 1980s as an expert witness in several highly publicized U.S. cases and raised doubt about the safety of Bendectin based on the “Debendox experiment” he claimed to have performed but which later was proven to be false.17 

The seminal U.S. Supreme court case involving Bendectin is Daubert v. Merrell Dow, 509 U.S. 579 (1993).18 Daubert established a standard for admissibility of scientific testimony in courts of law in the U.S. In that case, plaintiffs alleged that Bendectin - which had been manufactured by Merrell Dow Pharmaceuticals, Inc. - caused limb reduction birth defects. Plaintiffs' experts, through what was ultimately deemed to be "junk science", failed to present any study in support of plaintiffs' theory that Bendectin could cause malformations in human fetuses.18  Dr. McBride had been on of the plaintiffs' expert witnesses.19 The Daubert decision is known well by lawyers and legal scholars, because it became a landmark case and it changed the standards for determining the admissibility of expert testimony and scientific evidence in the U.S. federal court civil system cases.18 

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Bendectin: Following Discontinuation

Two separate meta-analyses were published by Einarson et al in 198812 and by McKeigue et al in199415, which included over 200,000 pregnancies (exposed and control groups). Neither analysis observed an increased risk for major malformations. Separate analyses were conducted for specific defects, with no increased risks observed for these defects. These studies, as a group, showed no difference in the risk of birth defects among those infants whose mothers had taken Bendectin during the first trimester of pregnancy and those infants whose mothers had not.26 The naturally occurring rate of birth defects for all pregnancies, that is the risk of having a child with a birth defect even in the absence of a teratogen exposure is approximately 1-3%. This underlying risk may be increased due to maternal age, medical or family history, or exposures to certain drugs, chemicals or levels of radiation known to cause birth defects. Published data show that Bendectin use in pregnancy does not increase a woman's baseline risk of having a child with a major malformation.2,4,12,15,22

In the publication entitled Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk (1999) - the gold standard reference for drugs used to treat disorders during pregnancy - Briggs, Freeman and Yaffe concluded that "the preponderance of data supports the assessment that the fixed combination of doxylamine/pyridoxine is safe in human pregnancy, including in the first trimester."23 Therefore, the  doxylamine/pyridoxine combination was elevated to the safest Drug Category in the Briggs Risk Scale "Level A".

As a result of the discontinuation of Bendectin, which was the only approved drug for nausea and vomiting of pregnancy, hospital admissions for vomiting in pregnancy doubled during the five-year period 1980-85 (which was the time period when Bendectin use declined and then ultimately ceased in the Unites States), birth-defect rates remain constant.(click here to view graph)24 NAMCS data showed a nearly 90 percent drop in antiemetic use for NVP compared to 1980 figures, leaving American women deprived of a safe and effective pharmacological option for their NVP symptoms.2 An estimate of excess hospital costs attendant to these admissions over the years 1983–87 in the United States was $73 million.14 Comparison studies have failed to detect any significant reduction in the incidence of birth defects since Bendectin became unavailable in 1983. In an epidemiolgical assessment of the safety and efficacy of Bendectin, the author showed the time-trend of NVP, hospitalizations, limb reduction deformities and Bendectin usage (1974-94).24

In 1999, the FDA determined that Bendectin was not withdrawn from the market for reasons of safety or effectiveness. Accordingly, the product was listed by the agency in the "Discontinued Drug Product List" section of the Orange Book.25

A US conference on Understanding and Treating Nausea and Vomiting of Pregnancy was held in Bethesda, Maryland in November 2000. The meeting was requested and supported by the National Institute of Child Health and Human Development (NICHD) and the Office of Rare Diseases Research, National Institutes of Health (NIH). The conference organizers were T. Murphy Goodwin, MD of the University of Southern California, Roberto Romero, MD, Chief of the Perinatal Research Branch of the NICHD, Jennifer Niebyl, MD, of the University of Iowa and Charlotte Catz, MD, of the NICHD. The goal was to identify gaps in knowledge about the mechanism of disease and opportunities for therapeutic intervention that may help women and their families cope with the problem of NVP. In his presentation, Frank Miller, MD, from Lexington, KY and at the time President of ACOG, opened his presentation with the following comment: "One cannot practice obstetrics for any length of time and not be impressed that nausea and vomiting is a real disease."26

In 2001, The US Association of Professors of Gynecology and Obstetrics (APGO) published its first Educational Module on Nausea and Vomiting of Pregnancy (NVP). The combination doxylamine-pyridoxine is shown as the drug of choice for the treatment of Nausea and Vomiting of Pregnancy. The same year, the Organization of Teratology Information Specialists (OTIS) published its first Fact Sheet on the management and treatment of Nausea and Vomiting of Pregnancy (NVP)27

In December 2010, a group of American and Canadian researchers reported on the effectiveness of the delayed-release formulation of doxylamine and vitamin B6 for morning sickness (Diclectin®). The study, which was published in the American Journal of Obstetrics and Gynecology, was carried out in 3 university centers in the US: Pittsburgh, Texas (Galveston), and Georgetown (Washington DC). All three centers belong to the Obstetric-Fetal Pharmacology Research Unit (OPRU) Network of the National Institute of Child Health and Human Development (NICHD). The study concluded that the delayed release formulation of doxylamine succinate and pyridoxine hydrochloride (Diclectin®) is effective and well tolerated in treating nausea and vomiting of pregnancy.34

When Merrel Dow stopped the sales of Bendectin worldwide in 1983, the Canadian generic version, Diclectin (containing doxylamine and pyridoxine), remained on the market as the only approved treatment of nausea and vomiting of pregnancy.  After Bendectin was no longer available, statistical data showed in the US and in Canada an increase of hospitalization for Excessive Nausea and Vomiting of Pregnancy (EVP) and a corresponding decrease in EVP with the increase in Diclectin sales. Click here to view graph.33

On April 8, 2013 the US Food and Drug Administration (FDA) approved doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 10mg/10mg to treat nausea and vomiting pregnancy in women who have not improved with change in diet or other non-medicine treatments.

 

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Bendectin Historical Timeline

  • 1956
  • Bendectin is approved by the Food and Drug Administration (FDA) for the treatment of nausea and vomiting of pregnancy (NVP).1
  • The original drug formulation contains dicyclomine hydrochloride, doxylamine succinate and pyridoxine hydrochloride (Vitamin B6).2
  • 1960
  • Bendectin sales grow steadily. Within the decade, it becomes the leading treatment for NVP in the US.2
  • 1969
  • The first allegations questioning Bendectin's safety use are filed.1
  • 1975
  • Following a FDA restrospective review of the efficacy of each multi-ingredient medications marketed between 1938 and 1962 (known as the DESI process), an 8-way study was performed and Bendectin was reformulated in 1976. Dicyclomine hydrochloride, for which no benefits were observed, was removed from the formulation.3
  • 1978
  • Bendectin is licensed as a two-ingredient product containing doxylamine and pyridoxine.3
  • Late 1970s-80s
  • Lawsuits and certain media begin to allege that Bendectin is a significant human teratogen.2
  • The first case that received wide publicity was the Mekdeci case, which alleged that Bendectin resulted in a birth defect called Poland syndrome (a deficit in the pectoralis muscle) was filed in 1977.1
  • Bendectin accounted for 82 percent of 584,452 antiemetic prescriptions used to treat NVP in the U.S.2 
  • Some epidemiological data associated Bendectin to some specific malformations5,6,7,8, raising doubt about the safety of Bendectin.
  • An article published in the National Enquirer (1979) stated that Bendectin could cause birth defects.9
  • Following the Bendectin article in the National Enquirer, the FDA issued a Talk Paper on Bendectin stating that there is no adequate evidence linking Bendectin with an increased risk of birth defects.10 
  • A number of large epidemiological studies were published, many of which were reviewed in a 1983 article11 and in two meta-analyses in 1988 and 1994.12,15 These analyses exonerated Bendectin and found no measurable teratogenic effect.
  • The FDA convened a panel of independent experts to review the available scientific information and address the confusion and concern caused by the court cases involving Bendectin. The committee concluded that the existing data did not show an association between Bendectin and human birth defects.13
  • 1981
  • NAMCS data showed a nearly 30 percent reduction in antiemetic use for NVP, essentially due to the decreased use of Bendectin.2
  • 1983
  • Despite no known association with birth defects, Merrell Dow Pharmaceuticals ceased production of Bendectin worldwide in 1983, as their soaring legal and liability insurance costs eclipsed sales.14
  • Product discontinuation left a therapeutic gap for nausea and vomiting of pregnancy. Doctors either stopped treating their patients for this complication or resorted to medications that were inadequately studied for this indication.2
  • In Canada Diclectin ( containing doxylamine and pyridoxine) manufactured by Duchesnay Inc. remained on the market.
  • 1985
  • NAMCS data showed with no Bendectin use a nearly 90 percent drop in antiemetic use for NVP compared to 1980 data.2
  • For the five-year period 1980-85 in which Bendectin use declined and then ceased, birth-defect rates remained constant and hospitalizations for NVP doubled.14
  • 1988
  • A meta-analysis (asystematic method of evaluating epidemiological studies to quantify the impact of a treatment) was published using Bendectin as an illustrative example. Results from the meta-analysis corroborated previous reports and scientific literature concluding that Bendectin was not associated with teratogen outcomes.12
  • 1989
  • The largest mass tort litigation brought against Merrell Dow drew to a close. The suit incorporated 750 cases involving 1,100 claimants. Following unsuccessful settlement discussions, the jury ruled in the company's favor and the verdict was upheld on two appeals.16 The presiding judge and the jury were heavily influenced by exhibits showing no change in limb-malformation incidence following the market withdrawal of Bendectin.16
  • 1993
  • Following scientific fraud complaints, which started in the late 1980s, Dr. William Griffith McBride, who had given depositions as an expert witness in several US district courts of justice against the manufacturer of Bendectin, was convicted of scientific fraud  and ultimately struck from the Australian Register of medical practitioners in 1993 for deliberately falsifying data, having been proven to fabricate and published false and misleading evidence against Bendectin/Debendox.17
  • Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993) is a United States Supreme Court case determining the standard for admitting expert testimony in federal courts. This judgment has generally been successful in excluding "junk science" or "pseudoscience", as well as experimental or new techniques and research that  might otherwise have been expected to be deemed admissible. Dr. McBride had been one of the Plaintiffs' expert witnesses.18,19
  • 1994
  • A meta-analysis comprising data from more than 11 studies showed no difference in the risk of birth defects between those infants whose mothers had taken Bendectin during the first trimester of pregnancy and those infants whose mothers had not.15
  • 1995
  • A review in Reproductive Toxicology Review reported that the epidemiologic and experimental data indicated that the clinical use of Bendectin does not increase the risk of birth defects in populations of exposed pregnant women. Cohort studies include more than 120,000 non-exposed and more than 13,000 exposed pregnant women.4
  • The Society of Gynaecologists of Canada (SOGC) released the first Canadian guidelines on the management of nausea of vomiting of pregnancy.20
  • 1998

  • The First International Conference on Nausea and Vomiting of Pregnancy held in Toronto, Ontario, called for increased attention to this medical condition and its potentially serious complications.21

  • A review article on Drugs in Pregnancy in the New England Journal of Medicine presented Diclectin as the drug of choice for the treatment of NVP (Table 5 – Selected drugs that can be used during pregnancy, according to condition).30
  • 1999
  • FDA published a notice in the Federal Register stating that Bendectin had not been withdrawn from the market for safety or health reasons.25
  • The fixed combination of doxylamine-pyridoxine was elevated to the safest Drug Category in the Risk Scale [Level A] in "Brigg's publication entitled Drugs inPregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. The authors concluded that the combination is safe in human pregnancy, including the 1st trimester.23
  • 2000
  • A US conference on Understanding Nausea and Vomiting of Pregnancy was held in Bethesda, Maryland, requested and supported by the National Institute of Child Health and Human Development (NICHD). The goal was to identify gaps in knowledge about the mechanism of disease and opportunities for therapeutic intervention that might help women and their families cope with the problem of NVP.26
  • After Bendectin was no longer available, statistical data showed an increase of hospitalization for Excessive Nausea and Vomiting of Pregnancy (EVP) and a corresponding decrease in EVP with the increase in Diclectin sales in Canada. Click here to view graph.33
  • 2001
  • The US Association of Professors of Gynecology and Obstetrics (APGO) published its first Educational module on Nausea and Vomiting of Pregnancy (NVP). The combination doxylamine-pridoxine is shown as the drug of choice for the treatment of Nausea and Vomiting of Pregnancy.
  • The US Organization of Teratology Information Specialists (OTIS) published its first Fact Sheet on the management and treatment Nausea and Vomiting of Pregnancy.27
  • 2002
  • Motherisk at the Hospital of Sick Children in Toronto, Canada, published its first Nausea and vomiting of pregnancy evidence-based treatment algorithm.29
  • The Society of Obstetricians and Gynaecologists of Canada (SOGC) updated its Canadian guidelines on the management of nausea of vomiting of pregnancy.28
  • 2004
  • Clinical Management Guidelines on Nausea and Vomiting of Pregnancy were published by the American Congress of Obstetricians and Gynecologists (ACOG) recommending vitamine B6 and doxylamine as first choice treatment for Nausea and Vomiting of Pregnancy.30
  • 2007
  • Motherisk at the Hospital of Sick Children in Toronto, Canada released an updated algorithm - Treatment of nausea and vomiting in pregnancy.31
  • 2009
  • Publication of the Canadian study on long-term neurodevelopment of children exposed to Maternal Nausea and Vomiting of Pregnancy and Diclectin.32
  • 2010
  • Publication of the study Effectiveness of delayed-release doxylamine and pyridoxine (Diclectin) for nausea and vomiting of pregnancy: a randomized placebo controlled trial. The study was carried out in 3 university centers in the US: Pittsburgh, Texas (Galveston), and Georgetown (Washington DC). All three centers belong to the National Institute of Child and Human Development from the Obstetric Pharmacology Unit Network.34
  • 2013
  • On April 8, 2013 the US Food and Drug Administration (FDA) approved doxylamine succinate and pyridoxine hydrochloride delayed-release tablets 10mg/10mg to treat nausea and vomiting of pregnancy in women who have not improved with change in diet or other non-medicine treatments.
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References

  1. Hale RW, Niebyl J. Bendectin: how a safe and effective drug was removed from the market by our legal system. ACOG Clinical Review. Sep-Oct 2012.
  2. Kutcher JS, Engle A, Firth J, Lamm SH. Bendectin and birth defects II: Ecological analyses. Birth Defects Res A ClinMol Teratol. 2003;67:88-97.
  3. Ornstein M, Einarson A, Koren G. Bendectin/Diclectin for morning sickness: A Canadian follow-up of an American Tragedy. Reprod Toxicol. 1995;9(1):1-6.
  4. Brent RL. Bendectin: Review of the medical literature of a comprehensively studied human nonteratogen and the most prevalent tortogen-litigen. Reprod
    Toxicol. 1995 Jul-Aug;9(4):337-49.
  5. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol. 1979;109;433-9.
  6. Eskenazi B, Bracken MB. Bendectin (Debendox) as a risk factor for pyloric stenosis. Am J Obstet Gynecol. 1982;144:919-24
  7. Golding J, Vivian S, Baldwin JA. Maternal anti-nauseants and cleft of lip and palate. Human Toxicol. 1983:2:63-73.
  8. Aselton P, Jick H, Chentow SJ, Perera DR, Hunter JR, Rothman KJ. Pyloric stenosis and maternal Bendectin
    exposure. Am J. Epidemiol. 1984;120:251-6.
  9. Experts reveal drug causing deformed babies. National Enquirer. Oct 9, 1979.
  10. FDA Talk Paper, Bendectin, T79-49. Oct 1, 1979.
  11. Holmes LB, Teratogen Update: Bendectin Teratology 83;27:277-81.
  12. Einarson TR, Leeder JS, Koren G. A Method for Meta-Analysis of Epidemiological Studies. Drug
    Intell Clin Pharm. 1988 Oct;22(10):813-24.
  13. FDA Federal Register. 1980;80740-43.
  14. Brent R. Medical, social, and legal implications of treating nausea and vomiting of pregnancy. Am J Obstet Gynecol. 2002 May;186(5);S262-6.
  15. McKeigue PM, Lamm SH, Linn S, Kutcher JS. Bendectin and Birth Defects: I. A Meta Analysis of the Epidemiologic Studies. Teratology. 1994;50:27-37.
  16. Foster K, Huber P. Judging Science: Scientific Knowledge and the Federal Courts. The MIT Press. 1999:3.
  17. Fortin CA, Lalonde AB. The Bendectin Affair (of Legal and General Interest). Journal SOGC. 1995 Jan;17(1).
  18. Dixon L, Gill B. Changes in the standards for admitting expert evidence in federal civil cases since the Daubert decision. RAND Institute for Civil Justice. 2002.
  19. Milliken R. Thalidomide doctor guilty of medical fraud: William McBride, who exposed the danger of one anti-nausea drug, has been disgraced by experiments with another, writes Robert Milliken in Sydney. The Independent. Feb 20, 1993.
  20. SOGC Clinical Practice Guidelines for the management of nausea and vomiting in pregnancy. Society of Obstetricians & Gynaecologists of Canada. Nov 1995.
  21. Koren G, Bishai R. Nausea and Vomiting of Pregnancy - State of the Art 2000. Motherisk, Hospital for Sick Children, Toronto, 2000.
  22. Koren G, Pastuszak A, Ito S. Drugs in Pregnancy. N Engl J Med. 1998;338:1128-37.
  23. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, Sixth Ed, Lippincott Williams & Wilkins. 2002;446-553.
  24. Lamm SH, Epidemiological Assessment of the Safety and Efficacy of Bendectin, published in Koren G, Bishai R. Nausea and Vomiting of Pregnancy: State of the Art 2000. Motherisk, Hospital for Sick Children, Toronto, 2000;100-3.
  25. Food and Drug Administration. Determination that Bendectin was not withdrawn from sale for reasons of safety or effectiveness. Fed Regist 1999;64:43190-1.
  26. Understanding and treating nausea and vomiting of pregnancy. Supplement to Am J Obstet Gynecol. 2002 May;186(5).
  27. Organization of Teratology Information Specialists (OTIS), Fact Sheet on Nausea and Vomiting of Pregnancy, 2001..
  28. SOGC Clinical Practice Guidelines. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Can. 2002;24(10):817-23.
  29. Motherisk Treatment algorithm for nausea and vomiting of pregnancy. Can Fam Phys. 2002;48:268.
  30. The American College of Obstetricians and Gynecologists. Nausea and vomiting of pregnancy. ACOG Practice Bulletin No. 52. 2004;103(4):803-15.
  31. Motherisk Treatment of nausea and vomiting in pregnancy; An updated algorithm. Can Fam Phys. 2007;53:2110.
  32. Nulman I, Rovet J, Barrera M, Knittel-Keren D, Feldman BM, Koren G. Long-term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and Diclectin. J Pediatr. 2009 Jul;155(1):45-50, 50.e1-2.
  33. Neutel CI. Variation in rates of hospitalization for excessive vomiting in pregnancy by Bendectin/Diclectin use in Canada. Nausea and Vomiting of Pregnancy : State of the Art 2000, Toronto, The Motherisk Program, 2000;54.
  34. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial.Am J Obstet Gynecol. 2010 Dec;203(6):571.e1-7. doi: 10.1016/j.ajog.2010.07.030. Epub 2010 Sep 16.