A historical argument for regulatory failure in the case of Primodos and other hormone pregnancy tests

Abstract

The drug Primodos and other hormone pregnancy tests (HPTs) remained on the British market for about a decade after they were first implicated, in 1967, as a possible cause of birth defects. In November 2017, an expert working group (EWG) set up by the Medicines and Healthcare Products Regulatory Agency (MHRA) concluded against such an association. However, it was explicitly ‘not within the remit of the EWG to make formal conclusions or recommendations on the historical system or regulatory failures’, a situation that has left many stakeholders dissatisfied. Placing the question of a teratogenicity to one side, this article takes a more contextual and comparative approach than was possible under the auspices of MHRA. It asks why an unnecessary and possibly even harmful drug was allowed to remain on the British market when a reliable and perfectly safe alternative existed: urine tests for pregnancy. Based on archival research in several countries, this article builds a historical argument for regulatory failure in the case of HPTs. It concludes that the independent review which campaigners are calling for would have the potential to not only bring them a form of closure, but would also shed light on pressing issues of more general significance regarding risk, regulation and communication between policy makers, medical experts and patients.

Early pregnancy maternal progesterone administration alters pituitary and testis function and steroid profile in male fetuses

“…Increased gestational exposure to estrogens is associated with developmental defects of the reproductive system in both male and female offspring, tumour development and subfertility in adult life 4 . Likewise, oral hormone pregnancy tests (HPTs), such as Primodos, containing ethinylestradiol and high doses of synthetic progesterone, available from 1958 to 1978, were first implicated in 1967 as a possible cause of birth defects 5 , 6 . Recent meta-analysis concluded that HPTs were associated with a 40% increased risk of congenital malformations 7 .…”

Cumberlege review exposes stubborn and dangerous flaws in healthcare

“…Hormone pregnancy tests, sodium valproate, and pelvic mesh have been the subject of regulatory action in the UK and elsewhere. The tests were withdrawn in 1979, 11 years after concerns first emerged 2. Sodium valproate, now also used as a psychiatric medication, is the subject of warnings and voluntary restrictions for women of childbearing age, although, as the report documents, it is surprisingly difficult to get this critical information to either patients or doctors 34.…”

Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis

“…Oral hormone pregnancy tests (HPTs), such as Primodos (known as Duogynon in Germany), were available as injections from 1950 and in tablet form in the UK from 1956 onwards, before the modern forms of urine pregnancy tests became available 1 . Oral HPTs contained ethinylestradiol and large doses of norethisterone (synthetic forms of estrogen and progesterone respectively), the latter in much larger amounts than those included in current combined oral contraceptives (see Table 1).…”

“…( Supplementary File 1) Warnings about HPTs in pregnancy first emerged in 1956: 4 accumulating concerns over an increased risk of malformations led to their withdrawal in a number of countries at different times. Norway cancelled the indication in pregnancy for HPTs in 1970; when the UK did so in 1978, the manufacturers of Primodos, Schering AG (taken over by Bayer AG in 2008), voluntarily stopped marketing the product; in Germany, Duogynon was taken off the market in 1981 1 .…”

“…Furthermore, not all HPTs contained norethisterone; different companies used other types of synthetic progesterone, and the same goes for ethinylestradiol.‘Oral hormone pregnancy tests (HPTs), such as Primodos (known as Duogynon in Germany), were used from 1958 to 1978, before urine pregnancy tests were available’ (p. 3). Contrary to popular belief, urine pregnancy tests were in fact widely though unevenly available between 1958 and 1978 and HPTs were never the dominant method of pregnancy testing. For a detailed timeline of pregnancy testing in the UK, please see Olszynko-Gryn et al (2018 2 ), esp. pp.…”