Mass screening success: England eliminates vertical transmission of hepatitis B
The WHO has certified England’s elimination of mother-to-child transmission of hepatitis B (via Susan Bewley). (Elimination is public health lingo for no cases in a geographic area; eradication is no cases globally.)
This is a great example of a mass screening for a low-prevalence problem that works — despite extreme rarity of the problem. Like HIV screening all pregnant women even in low-prevalence areas, this program works for two reasons: (1) Because uncertainty about test classifications (i.e., what’s a true or false positive or negative result) can be disambiguated by further testing/intervention. And (2) harms from those secondary screenings/interventions are negligible (i.e., are minimal and offset by net gains accruing to the same people who risk the possible harms).
Why the success? How does this screening program work? Tsitsi Muchayingeyi wrote for the UK National Screening Committee blog:
Babies born to women who test positive are offered timely hepatitis B vaccination, and hepatitis B immunoglobulin (HBIG) if appropriate, within 24 hours of birth to prevent them developing chronic hepatitis B. This is given as part of a selective neonatal immunisation programme with vaccines at birth, 4 weeks and 12 months. This is in addition to the vaccines at 8, 12 and 16 weeks that are part of the universal immunisation programme introduced in the UK in 2017… Babies born to mothers with hepatitis B infection have testing at 12 months of age to confirm vertical transmission has not occurred and to facilitate prompt referral for further management if it has… This success has been achieved thanks to the 3-pronged approach of antenatal screening, selective neonatal immunisation and routine childhood immunisation.
It is also a good demonstration that nationally managed screening is not just about testing, but an end to-end pathway that involves many different health professionals and services, often across different settings. No test on its own helps people.
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Withdrawal looks highly effective if done right
This is consistent with a wide range of long-standing cultural practices worldwide, and highlights the social and political dimensions of the current contraceptive discourse which medicalizes pregnancy prevention despite many women reporting adverse effects from hormonal contraception and IUDs (see, e.g., Julie Holland, Sarah Hill, Betsy Hartmann, and previous).
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HPV vaccines may increase miscarriage risk
A recent meta-analysis found:
receiving 2vHPV during the period from 45 days before last menstrual period (LMP) to LMP and 9vHPV during the period from 90 days before LMP to 45 days after LMP seemed to be related to an increased risk of spontaneous abortion (RR = 1.59, 95% CI: 1.04-2.45, RR = 2.04, 95% CI: 1.28-3.24). - (“Does HPV vaccination during periconceptional or gestational period increase the risk of adverse pregnancy outcomes?-An updated systematic review and meta-analysis based on timing of vaccination,” Zhang et al, Acta Obstet Gynecol Scand, Aug. 2024.
The authors interpreted these findings notably cautiously, writing: “In conclusion, the likelihood of an elevated risk of spontaneous abortion caused by HPV vaccination during the periconceptional or gestational period could not be completely ruled out.” It is rare that researchers interpret statistically significant findings this cautiously. Were the researchers afraid of contributing to anti-vaxx sentiment by trumpeting their findings more clearly?
Both confidence intervals suggest evidence of increased risk. For the 2vHPV vaccine, that risk increase is estimated at 4-145%. For the 9vHPV vaccine, it’s estimated at 28-224%. These are substantial possible risk increases.
These findings fit in a larger context of widespread safety concerns about HPV vaccines. Amid these concerns, public health organizations and governments pushed for vaccination on the basis of interpreting the available evidence to mean that aggregate benefits outweighed risks. Critics pushed back, with leading medical methodologist Peter Gøtzsche criticizing the European Medicines Agency for spinning away concerns about rare but serious neurological harms stemming from possible autoimmune reactions to the vaccine — and alleging bias and nontransparency in evaluating evidence in favor of the vaccine manufacturers amid conflict of interest policy violations.
Meanwhile, consensus position defenders called critics who questioned their interpretation of the evidence anti-vaxx, comparing lower HPV vaccine uptake resulting from safety concerns to the fallout of Wakefield’s MMR-autism fraud (“Inadvisable anti-vaccination sentiment: Human Papilloma Virus immunisation falsely under the microscope,” Head et al, npj Vaccines, Vol. 2, No. 6, March 2017). Critics (two of them veteran Cochrane researchers including Gøtzsche) then co-published criticisms of a Cochrane review of HPV vaccines, to which Cochrane responded. They also pointed out that painting critics like them as anti-vaxx when they called for open discussion of suspected harms of healthcare interventions undermines the possibility of improving vaccine safety and jeopardizes public trust (“Suspicions of possible vaccine harms must be scrutinised openly and independently to ensure confidence,” Jørgensen et al, npj Vaccines, Vol. 5, No. 55, July 2020).
Critics have continued to reiterate their concerns (“EMA’s mishandling of an investigation into suspected serious neurological harms of HPV vaccines,” Gøtzsche & Jørgensen, BMJ Evid Based Med, 2022 Feb;27(1):7-10):
Concern has been raised about whether HPV vaccines might cause serious neurological disorders including postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS). The European Medicines Agency (EMA) investigated the issue and declared in 2015 that there is no link between HPV vaccines and serious neurological adverse events. However, the certainty conveyed in EMA's official report is undermined by a leaked, confidential document that reveals important disagreements among the experts. Furthermore, in its assessments, EMA relied on the data the drug companies had provided to them even though it had been demonstrated that the companies had underreported possible neurological harms. Even though active comparators were used (aluminium adjuvants and other vaccines), our research group found significantly more serious neurological harms in the HPV vaccine groups than in the comparator groups in a systematic review based on clinical study reports in EMA's possession. We outline areas where we believe the basis for EMA's decision was flawed; highlight that the relationship between HPV vaccines and POTS remains uncertain; and suggest ways forward to resolve the uncertainty and debate.
Could HPV vaccine-associated neurological disorders and miscarriages share an autoimmune mechanism?
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Upholding the norm of corporate silence may have set back GLP-1 agonist research decades — and cost earlier researchers millions
The demonstration in 1990 by the Pfizer/MetaBio program that several days of GLP-1 infusion lowered blood glucose in diabetic subjects was critical to positioning GLP-1 as a therapy for diabetes. Remarkably, the team also presented data to our internal group, showing that GLP-1 slowed gastric emptying and reduced hunger. These observations were extensively discussed by our joint team, and both were indicators of the eventual efficacy of these agents against diabetes and obesity. Sadly, none of this definitive work was ever presented publicly or published, so its existence, until now, has been known only to those involved. The Pfizer approach, enshrined in the founding documents of the alliance, was to keep the findings confidential, and no one thought twice about this at the time. The role of publishing data was dramatically different in pharma than in the academic world in which the founders had lived — Harvard University Distinguished Service Professor and Higginson Professor of Physiology and Medicine at Harvard Medical School Jeffrey Flier, “Drug Development Failure: how GLP-1 development was abandoned in 1990,” Perspectives in Biology and Medicine, Vol. 67, No. 3 (Summer 2024): 325–336, p. 331).
Flier blames a corporate strategic error — chiefly, Pfizer killing the research program due to mistaken beliefs about injectables’ unmarketability. But his account could just as easily be interpreted as a cautionary tale about upholding corporate norms instead of open access ones.
What if researchers had leaked their findings to the press — or presented publicly or published in contravention of the founding documents? Might violating the norm of corporate silence have resulted in public pressure and shifting opinions, which might then have resulted in Ozemic-type drugs being developed for a consumer market 20 years sooner — advancing health for many and making astronomical profits for (a different) few?
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U.S. NTP teases meta-analysis on high fluoride and child IQ
Speaking of open access norms (or lack thereof), the U.S. National Toxicology Program appears to have gone on the press circuit before publication of their forthcoming dose-response meta-analysis on high fluoride and children’s IQ; see the AP article here.
This is odd. There’s no preprint or other advance copy. So people can’t read the results and evaluate the evidence themselves. Science doesn’t speak for itself; we need to see the observations, analyses, and interpretations.
The NTP webpage says the researchers “concluded [with moderate confidence] that higher levels of fluoride exposure, such as drinking water containing more than 1.5 milligrams of fluoride per liter, are associated with lower IQ in children.” It links to the “monograph” that’s a systematic review. Usually reviews and meta-analyses are packaged together, since the latter builds on the former. Maybe the researchers broke them up for length. Maybe they wanted a peer-reviewed publication out of the work — perhaps to posture for other jobs, or raise the profile or prestige of the findings. But then why do the press circuit without publishing a preprint?
Anyway, NTP’s review hints that the possible fluoride-child IQ effect is small (2-5 IQ points in previous analyses), it’s hard to distinguish prenatal and postnatal exposures and sex differences (but, as usual, boy fetuses may be particularly sensitive), and the posited mechanism involves fluoride impairing thyroid status through decreasing iodine uptake:
The current review has evaluated the fluoride literature with an eye toward potential thyroid effects because a large literature base has accumulated examining the interaction of fluoride with iodine uptake by the thyroid gland and consequential effects on synthesis of thyroid hormones, which are recognized to play significant roles in neurodevelopment in utero and during early childhood. This literature, along with a detailed proposed mechanism of action, was recently reviewed by Waugh (2019) (NTP review, footnote 2, p. 2 of the review/p. 22 of the PDF).
Prenatal and early gestational iodine supplementation’s beneficial effects on child cognitive development is already relatively well-established, as are the dangers of hypothyroidism — from heightened miscarriage risk to lower child IQ. (Although, a note of caution: Too much prenatal iodine supplementation can also cause neonatal hypothyroidism in what’s known as the acute Wolff-Chaikoff effect.)
So there’s a posited causal mechanism here that’s highly plausible. If you know a little bit about fluoride (highly unstable, bonds to whatever) and a little bit about iodine (taken up by the thyroid so the thyroid can work properly) — it makes sense that these things might not play well together. Per Waugh, fluoride inhibits sodium iodide symporter (NIS) — “crucial for the development of the central nervous system and disease prevention” — by upregulating the expression and activity of biomarkers that inhibit NIS expression. Those biomarkers are pro-inflammatory, while NIS helps stuff travel along delicate membranes; so it makes sense that upregulating pro-inflammatory biomarkers gums up the works: the immune system wants to clamp down on transport when there’s a threat. So water fluoridation may contribute to iodine deficiency and thus neurodevelopmental disorders along this pathway.
If this mechanism pans out, it’s not just fluoridated water moms have to worry about. Tea and coffee can also contain fluoride, with coffee appearing to be the safer choice. Apparently infant cereals and chocolate may also contain fluoride, with some chocolate milk in Brazil exceeding “the dose regarded as the threshold level for the development of dental fluorosis, without taking into account other sources of fluoride intake.” (Why Brazilian researchers apparently lead the world in quantifying the fluoride content of chocolate products that kids are likely to disproportionately consume is an open question.)
Even if this mechanism is wrong, researchers like leading environmental toxicologist Philippe Grandjean have long considered fluoride suspect as a developmental neurotoxicant. It’s not just IQ, but also ADHD and autism we have to worry about. We should be afraid of what we don’t know about what we don’t know about neurotoxicants, and maybe not go out of our way to put them in the water.
More broadly, this story also resonates with some other modern public health cautionary tales. By promoting a standardized intervention (water fluoridation) to prevent one set of harms (dental caries), some governments may have inadvertently caused another set of harms (lower child IQ). This structure parallels other relatively recent, standardized public health interventions like folic acid fortification in flour intended to prevent neural tube and other birth defects — but unintentionally causing cancers, too. Or “exclusive breastfeeding” promotion intended to bring back old infant feeding norms for everyone’s benefit (babies, mothers, societies) — but unintentionally causing common and preventable harm to newborns. The moral of the story?
To further evidence-based policy, we’d like to see accepted scientific evidentiary standards implemented in public health and beyond. That means:
Proponents bear the burden of proof to establish that new interventions will do more good than harm.
Independent reviewers evaluate the evidence of claimed costs and benefits.
Relevant data must be public, including information about its production, storage, analysis, and interpretation.
Programs are structured to yield better efficacy data.
Independent safety monitors keep assessing the evidence with an eye to that net benefit-cost balance as we inevitably learn more. Well-intentioned reformers cannot anticipate unintended consequences of the changes they seek. Someone else has to measure and assess them.
On one hand, this seems like a hard system to design. So much evidence-weighing. So many variables. Who decides when and how safety monitors should add a possible harm? How many adverse reports before we start systematically measuring it? How do we know which sorts of reports are related, and which are unrelated, to know how to analyze them? And how can we ensure safety monitors’ independence, when we’re all part of the psychosocial soup, and these assessments can have far-reaching implications?
On the other hand, fluoridation isn’t the global norm. It’s a U.S. norm. Most European countries, for example, don’t fluoridate their water. But, here in Germany, it’s still fluoridated on U.S. military bases like Ramstein. And, though it’s not only a U.S. norm, its prevalence pattern does seem to reflect U.S. alliance, with fluoridation more common in the UK, Ireland, Canada, Australia, and New Zealand.
In the end, America and its closest allies may be just a little bit dumber because of water fluoridation. This is ironic given fluoridation’s special place in American cultural history: Was it a Soviet plot after all?