The Mother of All FDA Fails

The FDA has never required drug safety assessment for fetal germline impact, even though FDA staff understand that gestational exposures can adversely affect developing germ cells. We must end this catastrophic omission, while also granting all Americans access to their own prenatal medical records.

Suspension of Approval Urged for New Morning Sickness Drug, Diclegis, Pending Assessment of Fetal Germline Impacts


Hylton V. Joffe, M.D., M.M.Sc., Director
Audrey Gassman, M.D., Deputry Director
Margaret Kober, Chief, Project Management Staff
Jennifer Mercier, Chief, Project Management Staff
Food and Drug Administration
Center for Drug Evaluation and Research

Division of Reproductive and Urologic Products
5901-B Ammendale Road

Beltsville, MD 20705-1266

Phone: (301) 796-2130

Fax: (301) 796-9897

Via Fax, U.S. Mail and email to hylton.joffe@fda.hhs.gov

April 11. 2013

Re: Request to suspend approval for Diclegis pending fetal germline impact assessment, and to issue additional warnings for Diclegis and all other prenatal drugs regarding potential for fetal germ cell perturbation


Dear Dr. Joffe, Dr. Gassman, Ms. Kober and Ms. Mercier:

I am writing to urgently request that the FDA take immediate steps to suspend approval for the prenatal drug Diclegis pending appropriate safety testing for impacts to fetal germ cells, the precursor cells to the baby’s egg or sperm. In addition, I urge the FDA to take immediate steps to issue warnings regarding potential germline impact of all prenatally administered drugs.

While testing of Diclegis revealed no increase in obvious somatic birth defects caused by fetal exposure to the drug, neither the FDA nor the drugmaker has made any attempts to ascertain whether fetal exposure to the compound may perturb the epigenetic programming of the vulnerable fetal germ cells, the tissues which are most vulnerable during early embryonic development, and are of course the most important in the child’s body, assuming that child desires to reproduce upon reaching maturity.

Any molecular disturbance of the germ cells would constitute a severe, yet hidden, birth defect of the exposed child, as it would likely result in subtle or severe developmental abnormalities in the grandchildren of the women taking the drug.

As FDA staff are no doubt aware, the delicate process of fetal germline reprogramming occurs during weeks 6-18 of human gestation, precisely the time period of morning sickness experienced by most pregnant women. During this period the germ cells are specified and migrate along the genital ridge to the rapidly developing fetal gonads.  During this time, the germ cells are demethylated and remethylated in a manner controlled in large part by the exogenous molecular signaling environment present in the womb.

Indeed, it is likely that morning sickness — wherein a pregnant woman becomes exceedingly sensitive to her environment — evolved as a mechanism to protect the exposed and sensitive germline from potentially harmful exposures. Yet, administration of Diclegis is expressly targeted at this known window of epigenetic susceptibility, and may wreak unknown and unmitigatable havoc on the germ cell programming.

Animal models have repeatedly demonstrated fetal germline vulnerabilities and adulteration caused by both acute and low-level exposures to exogenous compounds, resulting in multigenerational impairments. These perturbations may have any number of pathological outcomes, including abnormal neurodevelopment and behavior of the grandchild offspring. See, for example, Crews, Epigenetic transgenerational inheritance of altered stress responses, Proc Natl Acad Sci USA. 2012 doi: 10.1073/pnas.1118514109; Hunt, Bisphenol A alters early oogenesis and follicle formation in the fetal ovary of the rhesus monkey, PNAS (2012); Rissman, Gestational Exposure to Bisphenol A Produces Transgenerational Changes in Behaviors and Gene Expression, Endocrinology 1195 (2012); Skinner, Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior, PLoS ONE 3(11): e3745 (2008); Gore, Transgenerational neuroendocrine disruption of reproduction, Nature Reviews Endocrinology 7, 197-207 (2011). Indeed, in the past several years, this susceptibility of early mammalian germ cells to chemical manipulation and damage has become textbook knowledge. It is reckless in the extreme for the FDA to continue to ignore this well accepted dimension of profound risk.

The role of germline epimutation in today’s epidemics of autism and other mysterious neurodevelopmental abnormality is seen as urgent among leading scientists, see, eg, DeMarini, Declaring the Existence of Human Germ-Cell Mutagens, Environmental and Molecular Mutagenesis 53:166^172 (2012), Michael Demartini, Yauk et al 2013, Harnessing genomics to identify environmental determinants of heritable disease, Mutat Res. 2013 January; 752(1): 6–9, and Autism Epigenetics Summary Statement, http://autismepigenetics.org/wp/wp-content/uploads/2012/11/SummaryThemesPDF13.pdf, and must also ring the alarm bells within the walls of the FDA. By controlling drug approval and prenatal drug risk information, the FDA serves as the sole gatekeeper for protecting the fetus and its germline from dangerous drug exposures, yet to date has never taken a single step to review the probable germ cell impacts of any of the many drugs prescribed to and taken by pregnant women.

Antihistamine CNS depressants such as Diclegis can reasonably expected to interfere with the fine-tuned molecular programming of the germ cells owing to the disruption of normal receptor activity. Per the dosing instructions, 10mg of the antihistamine may be taken up to 4 times daily, for 40 mg daily, for likely 90 days, for a total of 3600 mg of foreseeable antihistamine drug exposure, not including the B6 component, and not including synergistic, cumulative effects of other drugs taken by the patient, which may include fertility treatment hormones, antidepressant drugs, antihypertensives, diabetes drugs, PPIs and others. What is the effect of this massive quantity of evolutionarily novel xenobiotic chemicals on human germ cell development? Given what evolutionary biology now teaches us about the epigenetic susceptibilities of the early germline, it is shocking that the FDA has never even asked the question.

The FDA must demand that this germline and multigenerational testing for epigenetic and other impacts occurs before even a single prescription is written in the United States. The public can no longer sit idly while the FDA ignores what could easily be a massive, if unintended, assault on future generations. The blind spot regarding fetal germline vulnerability must end; pregnant women and their partners have the right to know all, not just some, of the risks involved in ingesting pharmaceutical drugs, particularly to the developmental integrity of their descendants.

With gratitude for your kind and prompt consideration,

Jill Escher
Escher Fund for Autism

21 comments:

  1. I am extremely thankful for the research you have done, the questions you are raising and your effort to inform the public specially pregnant women and their families. I am 11 week pregnant with my second child now and have been suffering from severe nausea and vomiting for the past few weeks, just like I experienced with my first child. I rarely take drugs and am very sceptical about medication, but have in to Diclegis after my OB coordinator easily presctibed and insisted I use help! I googled about this only FDA approved medication and didn't come up to your article the first time and since all I could find was positive and the physiological and physical effects of severe morning sickness couldn't teay help much with making the right decision I started taking Diclegis! I felt great for the first 3 days and then extremely tired for days. I would wake up at 12 noon, eat something and go back to bed until 7 pm, get up, eat and go back to sleep until the next day 12 pm!!! This scared me very much but I couldn't even think right to stop the medication despite my husband and my mothers' suggestion! Until one night( about a week after taking the medication) I felt so drowsy and drugged as if I was on heavy medication like Morphine! I couldn't talk, couldn't walk and felt like I couldn't breathe! My husband who was witnessing this says I was experiencing hyperventilation. I remember I was trying to breathe and all I felt was dying! It was horrible! I stopped the medication immediately that night. Have gone back to severe vomiting and I'm not sure if this was the effect of the drug but I'm thankful someone like you is trying so hard to prove that this drug might not be the easy answer to morning sickness as FDA has approved! All I'm hoping is my baby is okay and has not suffered from this scary drug. I have such an amazing healthy first child and all I want is the same. I didn't use any medication the first time and my first child is extremely intelligent, has never been sick in 29 months of her life even with a simple cold and I can't help but think it's maybe because of my healthy diet and no medication first time. I am extreme scared until this baby is born if he/ she is fine. And this fear is not going to go away for all my life. Hank you again for your article and sorry for the long story! I really hope FDA will take this matter seriously. Regards,

    ReplyDelete
    Replies
    1. Hi Narges. . Have you given birth? How is your baby? I am 11 weeks pregnant and the doctor has prescribed the same drug.

      Delete
  2. I have taken in total 4 tablets... I decided to stop as I was sooo smashed... The side effects were so intense and I was sure the baby could well felt as bad as I did...
    I live in Australia and here the GP's are strongly pressuring you to take drugs for VNP. I had to insist not to take Zofran (even though this drug is very dangerous, here they prescibe it very easily and pretend it is safe!!) so they 'offered' (I should say forced) me this drug instead. I have to pretend that I take it to have them off my back ... I'd rather be sick and do my best to drink and eat as much as I can than to endanger my baby love.

    ReplyDelete
  3. I really impressed after read this of some quality work and informative thoughts . I just wanna say thanks for the writer and wish you all the best for coming!.
    Zofran lawsuit faqs

    ReplyDelete
  4. If you want to know if you or a loved-one is indeed an alcoholic or drug addict -
    it's important that you know what the drug addiction signs and alcoholism symptoms are. Now I could give you a whole list of bulleted signs here,drug evaluation

    ReplyDelete

  5. Choosing the right alcohol or drug rehab center can make all the difference when it comes to entering long-term recovery from an addiction. This article provides ten questions to help you in your search for the right drug or alcohol rehab facility. [www.aacsatlanta.com] see more
    drug evaluation

    ReplyDelete


  6. In contrast to conventional opionion, anger management is rapidly become an acceptable resource for persons experiencing problems managing anger and stress in business and personal relationships. [www.aacsatlanta.com] please visitalcohol and drug assessment

    ReplyDelete
    Replies
    1. What does this have to do with the color of the fishes ?

      Delete
  7. Alcohol and drug counseling may be needed by virtually anyone in the course of life. The process is nothing to be ashamed of, and is in fact a positive step to take toward putting one's life back together.[www.aacsatlanta.com] please visitalcohol and drug assessment

    ReplyDelete

  8. If you want to know if you or a loved-one is indeed an alcoholic or drug addict -
    it's important that you know what the drug addiction signs and alcoholism symptoms are. Now I could give you a whole list of bulleted signs here,[www.aacsatlanta.com] please visitalcohol and drug assessment

    ReplyDelete


  9. Turning to anger management counseling can be a very wise step for anyone
    who needs to attain or sharpen the skills that are needed to handle emotions and build healthy relationships. Everyone gets angry from time to time.[www.aacsatlanta.com] please visitalcohol and drug evaluation

    ReplyDelete
  10. Australian Risk Services: We provide services for Risk Management Plan, Security Risk Management, Enterprise Risk Management, Risk Management Courses

    ReplyDelete
  11. Many thanks for the exciting blog posting! I really enjoyed reading it, you are a brilliant writer. I actually added your blog to my favorites and will look forward for more updates. Great Job, Keep it up..
    Zofran Lawsuit Help Center

    ReplyDelete
  12. Hi, Thanks for your great post, there are much nice information that I am sure a huge number of guys and gals don’t know.
    Alcohol Treatment Center

    ReplyDelete
  13. i see there are a lot of different visions of this problem! http://skywritingservice.com/blog/horrible-impact-of-drugs-on-your-health has some arguments concerning drugs impact on your health!

    ReplyDelete
  14. I love the blog cotent it is very helfull for us. Plant Safety Assessment professional from Australian Risk Services can be of particular assistance at this stage. Being now familiar with your workplace, they can provide details on the best controls and practices for your situation.

    ReplyDelete
  15. Wow, if the research becomes successful, a lot of people who suffer from morning sickness would have found a permanent solution to their problem. I am hoping that the author will keep s updated on the progress of the research. I will be recommending this site to medical students who access Dissertation Revising Help.

    ReplyDelete
  16. voodoo spell has amazed me as I have seen results from everything he has done for me, often quite fast. While I have been to other spell casters who I believe tried their best; voodoo spell simply is the best, being truly gifted and having written the book on it. In addition, his integrity truly sets him apart in the field as he has told me several times I did not need a spell when he just as easily could have said I did. He is a truly kind and generous person who took time out on a weekend recently to help with a difficult ongoing case for me which brought him no personal gain. His work resulted in an all out miracle with a man I have been in love with for two years. voodoo spell rocks!. i so much believe in this man here is the contact in case you have any problem, dr.abalaka@outlook.com, God bless

    ReplyDelete