The Primodos Story
Oral hormone pregnancy tests such as Primodos, containing ethinylestradiol and very high doses of norethisterone, were given to over a million women from 1958 to 1978, when Primodos was withdrawn from the market because of concerns about teratogenicity.
Oct 2018 we published Version 1 of a systematic review and meta-analysis on ‘Oral hormone pregnancy tests and the risks of congenital malformations’ (version 2 was accepted in Jan 2019)
Our systematic review showed that oral HPTs in pregnancy is associated with increased risks of congenital malformations. We found 16 case-control studies and 10 prospective cohort studies, together including 71 330 women, of whom 4,209 were exposed to HPTs.
Exposure was associated with an increased risk of all congenital malformations, as well as congenital heart, nervous system and musculoskeletal malformations, and the VACTERL syndrome (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb defects),
Sky News provides a backstory to the issues that led to our review and how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.
Here is what has been happening since our review was first published:
May 6th 2019: Minutes of the meeting and MHRA assessment report published on the UK Government’s website. An ad hoc Expert Group of the UK’s Commission on Human Medicines (CHM) has considered a systematic review and meta-analysis of studies on oral Hormone Pregnancy Tests published by Heneghan et al.
April 23rd: 2019 House of Commons Debate took place:
You can read the full text of the debate at Hansard:
Yasmin Qureshi MP: ‘Such is the depth of concern about this issue that there have already been three debates on the expert working group’s review—this is the fourth. Each and every time, Members from across the House have urged Ministers to consider our concerns about the methodology, the independence of the panel members and the conclusions of the report. On each and every occasion, however, our concerns have been dismissed.’
Twelve MPs spoke at the debate:
- Yasmin Qureshi (Bolton South East) (Lab)
- Gordon Marsden (Blackpool South) (Lab)
- Mr George Howarth (Knowsley) (Lab)
- Bill Grant (Ayr, Carrick and Cumnock) (Con)
- Emma Reynolds (Wolverhampton North East) (Lab)
- Sir Mike Penning (Hemel Hempstead) (Con)
- Hannah Bardell (Livingston) (SNP)
- Yvonne Fovargue (Makerfield) (Lab)
- Brendan O’Hara (Argyll and Bute) (SNP)
- Sir Edward Davey (Kingston and Surbiton) (LD)
- Jonathan Reynolds (Stalybridge and Hyde) (Lab/Co-op)
- Paula Sherriff (Dewsbury) (Lab)
and the response was provided by The Parliamentary Under-Secretary of State for Health and Social Care (Jackie Doyle-Price)
‘I turn finally to the data published by Professor Heneghan. Although this analysis does not contain any new data, it found the use of hormone pregnancy tests in pregnancy is associated with a small increased risk of certain congenital malformations. The Government have therefore asked for a completely new expert group to be convened in order to consider Professor Heneghan’s work, and for a review to be conducted in parallel with the European review. Those reviews are ongoing, and I look forward to receiving that advice.
I appreciate that I have not been able to satisfy all the representations made by hon. and right hon. Members this morning. As I said, the Government will continue to review evidence in this area. We are still considering the evidence from Professor Heneghan, and we look forward to implementing any recommendations that Baroness Cumberlege brings forward in this regard.‘
April 18th 2019: Expert Working Group report on hormone pregnancy tests briefing report prepared by the House of Commons Library for the upcoming debate
By Sarah Barber Nikki Sutherland. This pack prepared ahead of the debate to be held in Westminster Hall on 23 April 2019 at 11.30am on the Expert Working Group report on hormone pregnancy tests. The debate will be led by Yasmin Qureshi MP.
A new systematic review and meta-analysis of the research on hormone pregnancy tests was published in November 2018. This concluded that:[…] use of oral HPTs in pregnancy is associated with increased risks of congenital malformations. One of the authors of the study, Professor Carl Heneghan, raised concerns about the 2017 Expert Working group review in an interview
with Sky News. He said that there had been a failure to undertake a systematic review:
April 8th 2019: written questions asked by Lord Alton of Liverpool of the House of Lords to government ministers
(See here HL15086) To ask Her Majesty’s Government what assessment they have made, if any, of the accusations made by Professor Carl Heneghan of the University of Oxford and reported by Sky News on 5 April that a study on Primodos overseen by the Medical and Healthcare products Regulation Agency failed to properly assess the risks of that drug; and that meta-analysis results were left out of the final report.
(see here HL15087) To ask Her Majesty’s Government what assessment they have made, if any, of reports by Sky News on 5 April that UK regulators in the 1970s destroyed evidence that suggested an association between the use of Primodos and birth defects.
April 4th 2019: Sky News Jason Farrell covers the story ‘Primodos review criticised for ‘not assessing risks properly’
March 28th 2018: FOI request data published on CEBM and sent by email for For the attention of the MHRA, the IMMDS review team, the APPG Primodos and interested parties,
We present a pooled analysis of data that were included in the report of the UK’s Commission on Human Medicines independent Expert Working Group (EWG), based on data obtained through an FOI request. Table 2 shows the striking similarity of the results for the EWG review and the Heneghan et al review for congenital heart defects, any malformations, and urogenital malformations.
Table 2 in the report is a comparison of analyses of the data presented in the EWG report and those presented by Heneghan et al.
||EWG results 
||Heneghan et al results 
|Congenital heart defects
||OR = 1.91 (95% CI = 1.36 to 2.68; I2 = 22%; P = 0.0002)
||OR = 1.89 (95% CI = 1.32 to 2.72; I2 = 0%; P = 0.0006)
|EWG: any congenital malformation
Heneghan et al: all congenital malformations
|OR = 1.34 (95% CI = 1.13 to 1.60; I2 = 0%; P = 0.0008)
||(OR) = 1.40 (95% CI = 1.18 to 1.66; P < 0.0001; I2 = 0%).
Heneghan et al: urogenital
|OR = 2.22 (95% CI = 0.82 to 6.02; I2 = 0%; P = 0.12)
||OR = 2.63 (95% CI = 0.84 to 8.28; I2 = 0%; P = 0.10)
This finding further adds to strengthen our conclusions as both systematic reviews show that the use of oral HPTs in pregnancy is associated with increased risks of congenital malformations. A copy of this report is available at: https://www.cebm.net/update-ohpts/
March 18th 2019: C Heneghan and JK Aronson discussed the findings of the Heneghan et al systematic review “Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis” at a meeting of an ad hoc expert group convened by the Medicines and Healthcare products Regulatory Agency (MHRA) in London.
Update to the association between Oral Hormone Pregnancy Tests, including Primodos, and congenital anomalies
March 15th 2019: BMJ EBM blog post on ‘Assessing bias in studies of harms: a case study of Primodos and congenital malformations’ by Carl Heneghan
March 13th 2019: German Parliament meeting where Jeff Aronson presents the evidence from Heneghan et al systematic review and issues with the animal data.
March 5th 2019: we were sent the MHRA’s review of the Heneghan et al systematic review.  The questions raised about the review were:
- The selection of controls.
- The selection of confounding variables across studies.
- The analysis from studies that took account of a previous history of congenital malformations.
We posted our response on CEBM here
Feb 28th 2019: Lord Alton of Liverpool debated the Safety of Medicines and Medical Devices in the House of Lords
‘Meanwhile, a team at Oxford, led by Professor Carl Heneghan, the scientist responsible for identifying Thalidomide association, has discovered that pooled data show “a clear association” with several forms of malformation. Professor Neil Vargesson has carried out other work on zebrafish, which revealed anomalies that mirrored the adverse effects on victims of Primodos. Their studies were peer-reviewed and remain in the top percentile of scientific studies.’
Lord Alton brought up requests for the raw data from the EWG report:
I welcome that. However, the raw data that Professor Heneghan needs to complete his review has not been made available. The All-Party Parliamentary Group on Hormone Pregnancy Tests, chaired by Yasmin Qureshi MP, and of which I am vice-chairman, has sent a freedom of information request for the data, but to date has not received a response.
Jan 28th 2019: The Expert Working working Group on HPTs presented evidence to the IMMDS review where they were asked about the Heneghan et al review findings.
Jan 16th 2019: at the Houses of Parliament, Yasmin Qureshi MP, asked direct questions about the review findings at Prime Minister’s Questions
Theresa May said “ministers are aware of the new study that has come out” and it will be “looked at very carefully.”
“Now Professor Carl Heneghan at Oxford University has published a review of the scientific data that clearly shows Primodos did cause deformities.
“Will the prime minister ensure that any review that’s carried out is independent of the MHRA (Medicines and Healthcare products Regulatory Agency) because we have no faith in them?”
“Obviously it is an important issue.” responded the prime minister
Dec 2018: review findings were submitted to The Independent Medicines and Medical Devices Safety (IMMDS) Review Chaired by Baroness Julia Cumberlege, and presented on the 29th November, by Carl Heneghan to the review panel
Nov 28th 2018: Research findings presented to All Party Parliamentary Group on Hormone Pregnancy Tests at the UK Houses of Parliament on the link between Primodos and congenital malformation.
Nov 28th 2018: Sky news covered the review: A groundbreaking study from Oxford University has linked the pregnancy test drug Primodos to malformations in babies born to mothers who used the drug.’
Heneghan C, Aronson JK, Spencer E et al. Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis [version 2; peer review: 3 approved]. F1000Research 2019, 7:1725 (https://doi.org/10.12688/f1000research.16758.2)
The review is funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR) [ProjectNumber 390]. The views expressed are those of the author(s) and not necessarily those of the NIHR, the NHS or the Department of Health
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.