UK Government announces a Review into Primodos, Sodium Valproate, Vaginal Mesh

Baroness Cumberlege will lead an examination of the circumstances in all three health cases and consider whether there are grounds for wider inquiries

The UK Prime Minister has ordered a review of public health scandals involving the hormone-based pregnancy test drug Primodos, the use of vaginal mesh implants and the anti-epilepsy drug sodium valproate.

In the Commons, Jeremy Hunt has announced a review into public health scandals caused by failings in the regulation of vaginal mesh implants, anti-epilepsy drug sodium valproate and hormone-based pregnancy test drug Primodos.

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Controversial pregnancy test drug shows deformities in zebrafish embryos within hours of exposure

Primodos drug components can cause embryonic damage in a dose and time responsive manner

“This is a great stepping stone. It doesn’t give definitive answers, but it’s a start, so we can finally put to rest whether or not Primodos caused birth defects

Dr Vargesson says.

The components of a controversial drug, allegedly linked to birth defects in the 1960s and ’70s, caused deformations to fish embryos just hours after they received a dose in new studies by researchers at the University of Aberdeen.

Primodos was a hormone pregnancy test used by thousands of women in the UK between 1958 and 1978.

“The first step was to show the drug has caused problems in fish and hopefully that will lead to some funding for tests on mammals and other tissues to show exactly what is going on.”

Dr Vargesson says.

Research at the time suggested the drug could be linked to a higher risk of women giving birth to babies with abnormalities – a claim denied by Primodos’ manufacturer.

Although Primodos is no longer in use, its components (Norethisterone acetate and Ethinyl estradiol) are used in other medications today including treatments for endometriosis and contraceptives.

“This research helps the campaigners because they can see there has been some up-to-date science being done with modern techniques.”

Dr Vargesson says.

In November last year a UK Government expert working group (EWG) study found no ‘causal association’ between the drug and the abnormalities, stating that outdated methods used by scientists in the 1970s was partly responsible for a failure to find a connection.

Now a new study at the University of Aberdeen, published today in the Scientific Reports journal, has revealed more about the effects of Primodos’ components on the embryos of zebrafish

The paper outlines how after the components of Primodos were added to water around zebrafish embryos, their movement slowed down rapidly; developed changes to the heart within four hours; and within 24 hours displayed damage to tissues such as the fins, eyes and spinal cords.

“I would like to think the PM will take this on board and consider there might be an alternative decision to the one the Commission On Human Medicines made in the Westminster report.”

Dr Vargesson says.

More surprisingly, according to the researchers, the study showed that the drug accumulates in the zebrafish embryo over time. They suggest that if this also occurs in a mammalian species that even a seemingly low dose of the drug for the mother could result in much higher levels for the embryo.

This latest study was led by Dr Neil Vargesson from the University of Aberdeen, who has also published extensive research into thalidomide – a drug used in Germany in the 1950s to treat morning sickness but which caused thousands of babies worldwide to be born with malformed limbs.

“At the moment the scientific research into whether or not Primodos caused these birth defects is inconclusive.”

“What this study highlights is that there is a lot still to be learned about Primodos and more widely its components effects on mammals.”

“Our experiments with the zebrafish embryos shows quite clearly the effects the Primodos components have. This does not mean it would do the same in humans of course, we are a long way from saying that but we need to carry out more research into these components because they are still in drugs today and in some cases in much higher doses than those found in Primodos.”

“The assumption by some previously has been that the doses given to mothers was too low to cause any damage but our study shows that the levels of Primodos’ components accumulate in the embryos over time because they don’t have a fully functional liver that can break down the drug. This too is new information and if the same thing happens in mammals, these drugs could build up in the embryo to much higher levels than shown in the mother’s blood.”

Dr Vargesson explains.

More About Primodos

Primodos 2018 Study : Yasmin Qureshi MP Comments

New Primodos study found that pregnancy tests had potential to deform embryos

I was on Sky News earlier to discuss ground breaking new research from Aberdeen University that shows Hormone Pregnancy Test drug Primodos had the potential to deform embryos in the womb, something I have long been campaigning on. Victims and families have been denied answers and justice for over 40 years. The Prime Minister and Health Secretary must take note of this evidence and set up an Independent Inquiry that seeks to put families first.

Yasmin Qureshi MP
13 February 2018 on Facebook.

More About Primodos

Primodos Link to Embryo Damage – SkyNews Report

Hormone Pregnancy Test Drug Given to 1.5M Linked to Birth Defects, New Study

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos“, a newly published research produced by Dr Neil Vargesson from the Institute of Medical Sciences in Aberdeen University, shows that Primodos (hormone pregnancy test) drugs had the potential to deform embryos in the womb.

More About Primodos

Primodos drug components can cause embryonic damage in a dose and time responsive manner

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos

2018 Study Abstract

Primodos was a hormone pregnancy test used between 1958–1978 that has been implicated with causing a range of birth defects ever since. Though Primodos is no longer used, it’s components, Norethisterone acetate and Ethinyl estradiol, are used in other medications today including treatments for endometriosis and contraceptives. However, whether Primodos caused birth defects or not remains controversial, and has been little investigated.

Here we used the developing zebrafish embryo, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic and tissue development.

We show that Norethisterone acetate and Ethinyl estradiol cause embryonic damage in a dose and time responsive manner. The damage occurs rapidly after drug exposure, affecting multiple organ systems. Moreover, we found that the Norethisterone acetate and Ethinyl estradiol mixture can affect nerve outgrowth and blood vessel patterning directly and accumulates in the forming embryo for at least 24 hrs.

These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose and embryonic stage of development in the zebrafish. Further work in mammalian model species are now required to build on these findings and determine if placental embryos also are affected by synthetic sex hormones and their mechanisms of action. Image credit nature.

More About Primodos

2018 measures to avoid valproate exposure in pregnancy recommended by the European Medicines Agency

PRAC new restrictions on valproate use; pregnancy prevention programme to be put in place

The European Medicines Agency’s experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC) are recommending new measures to avoid exposure of babies to valproate medicines in the womb. Babies exposed are at risk of malformations and developmental problems.

Main measures recommended by the PRAC

Where licensed for migraine or bipolar disorder

  • In pregnancy – valproate must not be used.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of a new pregnancy prevention programme (see below) are met.

For epilepsy

  • In pregnancy – valproate must not be used. However it is recognised that for some women with epilepsy it may not be possible to stop valproate and they may have to continue treatment (with appropriate specialist care) in pregnancy.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of the new pregnancy prevention programme are met.

Drugs Packaging

  • The PRAC has also recommended that the outer packaging of all valproate medicines must include a visual warning about the risks in pregnancy. In addition to boxed text, this may include a symbol/pictogram, with the details to be adapted at national level.
  • A patient reminder card will also be attached to the outer package for pharmacists to discuss with the patient each time the medicine is dispensed.
  • Companies that market valproate should also provide updated educational materials in the form of guides for healthcare professionals and patients.

New valproate pregnancy prevention programme

Assessing patients for the potential of becoming pregnant, and involving the patient in evaluating her individual circumstances and supporting informed decision making, pregnancy tests before starting and during treatment as needed, counselling patients about the risks of valproate treatment, explaining the need for effective contraception throughout treatment, carrying out reviews of treatment by a specialist at least annually, introduction of a new risk acknowledgement form that patients and prescribers will go through at each such review to confirm that appropriate advice has been given and understood.

Read the full press release.

Prenatal exposure to fracking chemicals linked to abnormal mammary glands in adulthood

Exposure to chemicals used during fracking may cause pre-cancerous lesions in mice, MU study finds

Environmental scientists at the University of Missouri and the University of Massachusetts observed changes in mammary gland development of female mice exposed during early development to the chemicals used in unconventional oil and gas (UOG) extraction – including fracking – at levels environmentally relevant to humans.

The Prenatal exposure to unconventional oil and gas operation chemical mixtures altered mammary gland development in adult female mice authors believe theirs is the first study to show that mouse mammary gland tissues are sensitive to a mixture of 23 commonly used UOG chemicals, with dose-specific effects on tissue morphology, cell proliferation and induction of intraductal hyperplasias, an overgrowth of cells considered a marker for future breast cancer risk.

2018 Study Abstract

Unconventional oil and gas operations (UOG), which combine hydraulic fracturing (fracking) and directional drilling, involve the use of hundreds of chemicals including many with endocrine disrupting properties. Two previous studies examined mice exposed during early development to a 23-chemical mixture of UOG compounds (UOG-MIX) commonly used or produced in the process. Both male and female offspring exposed prenatally to one or more doses of UOG-MIX displayed alterations to endocrine organ function and serum hormone concentrations. We hypothesized that prenatal UOG-MIX exposures would similarly disrupt development of the mouse mammary gland. Female C57Bl/6 mice were exposed to approximately 3, 30, 300 or 3000 μg/kg/day UOG-MIX from gestational day 11 to birth. Although no effects were observed on the mammary glands of these females prior to puberty, in early adulthood, females exposed to 300 or 3000 μg/kg/day UOG-MIX developed more dense mammary epithelial ducts; females exposed to 3 μg/kg/day UOG-MIX had an altered ratio of apoptosis to proliferation in the mammary epithelium. Furthermore, adult females from all UOG-MIX-treated groups developed intraductal hyperplasia that resembled terminal end buds, i.e., highly proliferative structures typically seen at puberty. These results suggest that the mammary gland is sensitive to mixtures of chemicals used in unconventional oil and gas production, at exposure levels that are environmentally relevant. The impact of these findings on the long-term health of the mammary gland, including its lactational capacity and its risk of cancer, should be evaluated in future studies.

Ambient air pollution and the risk of pregnancy loss

A prospective cohort study, January 2018

2018 Study Abstract

Objective
To estimate the association of pregnancy loss with common air pollutant exposure. Ambient air pollution exposure has been linked to adverse pregnancy outcomes, but few studies have investigated its relationship with pregnancy loss.

Design
Prospective cohort study.

Setting
Not applicable.

Patient(s)
A total of 343 singleton pregnancies in a multisite prospective cohort study with detailed protocols for ovulation and pregnancy testing.

Intervention(s)
None.

Main Outcome Measure(s)
Timing of incident pregnancy loss (from ovulation).

Result(s)
The incidence of pregnancy loss was 28% (n = 98). Pollutant levels at women’s residences were estimated using modified Community Multiscale Air Quality models and averaged during the past 2 weeks (acute) and the whole pregnancy (chronic). Adjusted Cox proportional hazards models showed that an interquartile range increase in average whole pregnancy ozone (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.07–1.17) and particulate matter <2.5 μm (HR 1.13, 95% CI 1.03–1.24) concentrations were associated with faster time to pregnancy loss. Sulfate compounds also appeared to increase risk (HR 1.58, 95% CI 1.07–2.34). Last 2 weeks of exposures were not associated with loss.

Conclusion(s)
In a prospective cohort of couples trying to conceive, we found evidence that exposure to air pollution throughout pregnancy was associated with loss, but delineating specific periods of heightened vulnerability await larger preconception cohort studies with daily measured air quality.

Endometriosis linked to elevated risk of placenta previa in pregnancy

Association between surgically diagnosed endometriosis and adverse pregnancy outcomes

2018 Study Abstract

Objective
To examine the association between surgically diagnosed endometriosis and pregnancy outcomes in subsequent pregnancies.

Design
Retrospective cohort study of women who delivered a singleton live birth from 2003 to 2013 in Ottawa, Ontario, Canada.

Setting
Tertiary level academic center.

Patient(s)
Pregnant women with surgically diagnosed endometriosis were identified using International Classification of Diseases-10 codes from previous hospital admissions and were compared with pregnant women with no prior admission for endometriosis for the occurrences of adverse pregnancy outcomes.

Intervention(s)
Observational study.

Main Outcome Measure(s)
Gestational hypertension, preeclampsia, placenta previa, placental abruption, postpartum hemorrhage, preterm birth, low birth weight, small for gestational age, and neonatal intensive care unit admission.

Results
Among the 52,202 eligible mother-infant pairs, we identified 469 mothers with surgically diagnosed endometriosis from a previous hospital encounter. Compared with women without endometriosis, women with endometriosis were on average older and were more likely to be primiparous, have lower gravidity, have a history spontaneous abortion, conceive with assisted reproductive technology, and reside in areas with higher neighborhood income and lower proportion of immigrants. Women with endometriosis were found to have an elevated risk of placenta previa (relative risk [RR], 3.30; 95% confidence interval [CI], 1.65–5.40) and cesarean delivery (RR, 1.24; 95% CI, 1.10–1.40). After adjustment for potential confounding factors, women with endometriosis were found to have a significantly elevated risk of placenta previa compared with women without endometriosis (adjusted RR, 2.54; 95% CI, 1.39–4.64).

Conclusion(s)
This study identifies baseline demographic differences between women with and without endometriosis and suggests that women affected by endometriosis have an independently elevated risk of placenta previa in pregnancy.

Air Pollution May Shorten Telomeres in Newborns – A Sign of Increased Health Risks

Shorter telomere length in cord blood associated with prenatal air pollution exposure: Benefits of intervention

A study conducted before and after the 2004 closure of a coal-burning power plant in Tongliang, China, found children born before the closure had shorter telomeres than those conceived and born after the plant stopped polluting the air.

“An individual’s telomere length at birth is known to influence their risk for disease decades later during adulthood,”

Tang, professor of Environmental Health Sciences at the Mailman School.

2018 Study Highlights

  • Compared telomere length (TL) in babies born before and after a coal plant shutdown.
  • Prenatal exposure coal pollutants (PAH) estimated by cord PAH-DNA adducts.
  • Shorter TL previously associated with certain adverse health outcomes in adults.
  • PAH-DNA adducts in cord blood associated with shorter TL.
  • The second (post- intervention) cohort had significantly longer TL compared to the first.

Abstract

Background
To examine the molecular benefits of the government action to close the local coal burning power plant in Tongliang County, Chongqing Municipality, we compared biologic markers and health outcomes in two successive birth cohorts enrolled before and after the plant was shut down. In this city, polycyclic aromatic hydrocarbons (PAH) were primarily emitted by the coal burning facility. We previously reported that cord blood levels of PAH-DNA adducts (a biomarker of exposure) and various adverse health outcomes were reduced in the second cohort, whereas levels of brain-derived neurotrophic factor/BDNF (a protein involved in neuronal growth) were increased. Here we assessed telomere length (TL), which has been associated with risk of certain chronic diseases, early mortality, aging and cognitive decline in adults.

Objectives
The goals of the present study were to determine whether TL differed between the two cohorts and whether prenatal PAH exposure, estimated by PAH-DNA adducts in cord white blood cells of newborns in China, were predictive of shorter TL in cord blood, suggesting the potential accrual of risk of certain chronic diseases during the prenatal period. We explored relationships of TL with BDNF and neurodevelopmental outcomes, each previously associated with PAH-DNA adducts in these cohorts, as well as the potential mediating role of TL in the associations between adducts and neurodevelopmental outcomes.

Methods
We analyzed TL in cord blood of 255 newborns who also had data on PAH-DNA adducts, BDNF, and relevant covariates. Multiple regression analysis was carried out to test associations between adducts and TL and between TL and BDNF, adjusting for relevant covariates. In the subset with developmental quotient (DQ) scores from Gesell testing at age 2 (N = 210), we explored whether TL was a mediator of the relationship between PAH-DNA adducts and DQ scores by first examining the associations between cord adducts and DQ, cord adducts and TL, and TL and DQ, adjusting for the same covariates.

Results
As hypothesized, the mean TL was significantly higher in the second cohort compared to the first cohort. Overall, PAH-DNA cord adducts were significantly and inversely correlated with TL. Multiple regression analysis showed a significant association between adducts and TL, after adjusting for key covariates: β (effect size per standard deviation adducts) = −0.019, p = .003. The regression coefficient of TL on (Ln) BDNF was also significant (β = 0.167, p < .001). Exploratory analysis, regressing TL on Gesell developmental scores, showed generally inverse, but not significant associations. TL was not, therefore, deemed to be a potential mediator of the association between adducts and developmental scores at age two.

Conclusion
This study provides the first evidence that prenatal PAH exposure from coal burning may adversely affect TL, with potential implications for future risk of chronic diseases including cardiovascular disease. The improvement in TL in the second cohort and the observed correlation between increased TL and higher levels of BDNF indicate direct benefits to the health and development of children resulting from the government’s closure of the power plant.

“The new study adds to the evidence that closing this coal-burning power plant was beneficial to the health and future wellbeing of newborns there,”
“Moreover, we know that lowering exposure to air pollution anywhere will be beneficial to children’s health and long-term potential.”

Perera, Director of the Columbia Center for Children’s Environmental Health, Professor of Environmental Health Sciences at the Mailman School of Public Health.

Chongqing featured image credit wikipedia.