Inquiry into hormone pregnancy tests

1.1 Background

Drugs containing progestogens and oestrogens were taken as a form of pregnancy test in the NHS from the late 1950s until 1970s. Primodos was the most commonly used of these medications in the UK, others included Norlestrin and Amenorone. They were used in the NHS for both the investigation/treatment of menstrual irregularities and the diagnosis of early pregnancy (usually between five and ten weeks). It is the latter use which has proved controversial.

For diagnosing pregnancy, Primodos was usually given as two doses 12 hours apart. If the woman taking the tablets did not subsequently have an episode of bleeding the test was positive (i.e. she was pregnant).[1]

At the time hormone pregnancy tests were introduced, pregnancy was usually medically diagnosed later than it is today, without chemical tests, once it was obvious that there had been two or more missed periods and a pregnant uterus could be felt. Hormone pregnancy tests were thought to allow a relatively confident diagnosis of pregnancy.[2]

Studies in the UK and elsewhere from the late 1960s to early 1970s suggested a link between use of hormone pregnancy tests and a wide range of serious fetal abnormalities, including cleft lip and palate, limb reduction deformities and heart abnormalities.[3]

Although the evidence was not conclusive on this, the Committee on Safety of Medicines (CSM) (an independent advisory committee to the UK medicines licencing authority) published a letter in the British Medical Journal (BMJ) on 26 April 1975 that agreed with an earlier leading article[4], stating that:

[...] there is little justification for the continued use of withdrawal-type pregnancy tests when alternative methods are available.[5]

In June 1975, the CSM sent an alert letter to all doctors in the UK in which advised them of a possible association between hormonal pregnancy tests and an increased incidence of congenital abnormalities. It recommended that doctors should not normally prescribe these products as pregnancy tests[6]:

Following this, there were subsequent notifications from the CSM (November 1977), and a yellow warning notice was provided on the products’ containers from 1975 onwards to avoid use in pregnant patients. However, it has been reported that Primodos continued to be used with varying frequency as a pregnancy test within the NHS until withdrawal from the market by Schering in 1978.[7] [8]

The CSM’s letters on the safety of a number of hormonal preparations, including Primodos in 1975 and 1977 and other relevant documentation is available in House of Lords Deposited Papers online.[9]

1.2 Campaigns and legal cases

The Association for Children Damaged by Hormone Pregnancy Tests was formed in 1978 by Valerie Williams, the mother of a child with congenital abnormalities attributed to Primodos. With support from Jack Ashley MP and others, the Association achieved wide publicity for its aims of obtaining compensation and justice for its member families. Mr Ashley secured an Adjournment Debate on hormone pregnancy tests on 26 May 1978, calling for a public inquiry.[10]

In 1980, the Association initiated legal proceedings against Schering Chemicals Limited on behalf of two children with heart defects.[11],[12] The damage claims were discontinued on 2 July 1982 after the judge found there was insufficient evidence linking Primodos and the conditions.[13]

In early 2014, a new campaign called for an independent public inquiry into hormone pregnancy tests. This had been prompted by the discovery of documents from the 1960s that that reportedly show that studies suggested that the drugs caused miscarriages and abnormalities at that time.[14]

1.3 Review of the evidence regarding hormone pregnancy tests and congenital abnormalities

The MHRA conducted a review of the historical evidence on hormone pregnancy tests and birth defects in 2014. The review considered 36 studies and further unpublished data and reviews.

The review findings were published in March 2014. The MHRA reported that the studies reviewed were “inconsistent in their findings for an association between use of HPTs and congenital anomalies and are not considered sufficient to conclude that an association exists.” The authors expressed concerns about significant limitations with the studies used, mainly related to them being conducted over 20 years ago, when the standards for research were not as high as they are now. They also highlighted that a number of the subsequent evidence reviews expressed similar comments about poor quality of the data in the studies and that most concluded that the evidence does not support a causal association between hormonal pregnancy tests and congenital abnormalities.

The conclusion from the synopsis of the MHRA report is included below. This states that the evidence on this issue is mixed but having considered all the available published evidence, the MHRA positon remains that the data is not sufficient to show a causal link between the tests and the congenital abnormalities:

The body of evidence for an association between HPTs and congenital anomalies is mixed, with some studies finding a strong association, some finding a weak association and many others finding no association.

Although it is understandable to suspect that there may be an association between a medicine and a condition that develops after taking it, particularly when that medicine is taken during pregnancy, this may not necessarily be the case. The timing of exposure is critical and needs to occur during the period of gestation when the fetus is susceptible to the observed outcome. The association also needs to be plausible; in this case the observation of isolated but different anomalies in different studies is particularly difficult to interpret. If HPTs really were teratogenic, all studies should have observed increased numbers of all the observed that have been anomalies because women were exposed to HPTs at random times throughout gestation. In addition the scientific methodology needs to be sufficiently robust as to exclude false positive findings ie the possibility that other factors could have been responsible for the observed finding - this is not the case for the vast majority of studies.

Having carefully considered the available published evidence, our position therefore remains that the data are not sufficient to conclude that there is a causal association between the use of Primodos (or any HPT) and congenital abnormalities.[15]

1.4 Hormone pregnancy tests inquiry

In response to a Backbench Business Committee debate on oral hormone pregnancy tests in October 2014, the then Minister for Life Sciences, George Freeman confirmed that there would be an independent review of the papers and all the evidence.[16]

A call for evidence was published in March 2015. This stated that the Commission on Human Medicines (CHM) had endorsed a need for a review of the evidence relating to hormone pregnancy tests and had agreed the terms of reference for a panel of independent experts. The review would not be a political inquiry but would examine the evidence to see if there are grounds for accepting a link between the medication and the congenital abnormalities.

The CHM Human Medicines Regulations 2012 Advisory Bodies Annual Report 2015 contains further information on the Hormonal Pregnancy Tests Working Group:

Hormonal Pregnancy Tests Working Group

In 2015 the Commission convened an Expert Working Group (EWG) to review the available data on a possible association between Hormone Pregnancy tests (HPTs) and congenital anomalies. HPTs were used in the 1950’s-1970’s but licenses were withdrawn in the late 1970’s.

The EWG met first in October 2015 to consider the remit and work plan for the Group, and whether any additional expertise was required and noted a review of the social, medical and legal perspective from the time that HPTs were available, together with a chronology of events from 1958 to the present day. The Group agreed that its terms of reference should focus on the scientific evidence on the possible association between exposure in pregnancy to HPTs and adverse effects in pregnancy (including birth defects in the child, abortion and stillbirth), what lessons may be learned for improving existing regulatory systems in relation to medicines used in pregnancy, and whether the findings have any implications for currently licensed medicines.

A second meeting of the Group was held in December 2015 to consider the information from spontaneous case reports including Yellow Card data and testimonials from a number of individuals who consider they have been affected by HPTs. Further meetings to consider the basic science and epidemiological evidence are planned for 2016.[17]

In response to Parliamentary questions in January 2016, the Under-Secretary of State for Health, Lord Prior of Brampton, reported that the group conducting the inquiry had met twice in 2015, and a number of further meetings were planned for 2016. At the time of the answer the report of the group’s findings was expected before the end of the year (2016).[18]

[1] Dewhurst CJ, Current Practice: Obstetrics in general practice, British Medical Journal, 7 March 1964 Volume I, p 612

[2] Dewhurst CJ, Current Practice: Obstetrics in general practice, British Medical Journal, 7 March 1964 Volume I, p 612

[3] Gal I, Hormonal pregnancy tests and congenital malformations, British Medical Journal, 23 October 1976 pp 1014-5

[4] BMJ, Synthetic sex hormones and Infants, 30 Novermber 1974 pg 485

[5] Greenberg G et al, Hormonal Pregnancy Tests and Congenital Malformations, British Medical Journal, 26 April 1975, p 191-2

[6] PIMS Deposited Paper 26.10.10 UID 73935

[7] Brewer C, Continued use of hormonal pregnancy tests, British Medical Journal, 18 February 1978, p 437

[8] The Times, Pregnancy test drug ‘still prescribed after babies-at –risk warning, 17 April 1978

[9] House of Lords Deposited paper on the Committee on the Safety of Medicines and hormone pregnancy tests, 26 October 2010

[10] HC Deb 2 March 1978 c390-392W and HC Deb 26 May 1978 c2002-9

[11] Times, Group to sue firm over hormone pregnancy tests, 30 November 1978, p 5

[12] Times, Primodos actions to go ahead, June 10 1980, p 16

[13] Times, Claim dropped, 3 July 1982, p 3

[14] The Telegraph, 'Is this the forgotten thalidomide?', 12 May 2014

[15] MHRA, Assessment of historical evidence on Primodos and congenital malformations – a synopsis, March 2014

[16] HC Deb 23 October 2014, c1138

[17] MHRA, Human Medicines Regulations 2012 Advisory Bodies Annual Report 2015

[18] HL Deb 21 January 2016, c897