Acella NP Thyroid recall: maternal risk inflated

Acella, the makers of NP Thyroid, issued a voluntary recall notice on May 22, 2020.

This is part 2 of a two-part series reviewing the drug recall notice’s statements and the science behind them. [Part 1: Acella NP Thyroid recall: Ethical yet low-risk]

We should applaud Acella for being so conscientious about the exact amounts of liothyronine (LT3) hormone in their product. They tested, they were honest, and they dutifully issued this voluntary recall. The FDA is sharing Acella’s announcement — It’s good for the reputation of desiccated thyroid pharmaceuticals to be conscientious and to prove that you’re being watchful. It shows that you’re worthy of trust.

However, the most significant problem is that Acella’s notice is misleading about the risk of LT3 “superpotency” to health outcomes in pregnancy. They warn that an increase in T3 intake may lead to “miscarriage and/or impairment to fetal development.” But in fact, science and policy attribute these maternity risks to low T4, not excess T3 intake.

I briefly explain in this post the risks of hyperthyroidism and hypothyroidism in pregnancy, and the basis of the fear of hypothyroxinemia (Low T4) in pregnancy.

A review of common thyroid hormone levels in DTE shows that T4-sufficient, truly euthyroid dosing of DTE can remove risk to the fetus. In addition, Dr. Evelyn Man’s series of scientific articles on this topic have long ago provided evidence that only DTE underdose causes risk, and that euthyroid DTE dosing with sufficient T4 removes risk.

In view of this research, therapy guidelines’ strong prohibitions against T3-inclusive therapy spreads misundersanding and pharmaceutical prejudice against DTE.

Finally, I apply these research findings to the NP Thyroid recall and what we can do. The risk of T4 underdose during pregnancy cannot be attributed to excess of T3 ingested from a DTE tablet. Instead, risk is the fault of

  • widespread ignorance of what underdose, euthyroidism, and mild overdose look like on DTE,
  • an uninformed doctor not prepared to monitor and interpret FT4 levels in pregnancy and
  • a blind policy that would assume that testing TSH should be good enough in a person dosing DTE, when the policymakers openly admit that a normal TSH can be ignorant of a low FT4.

The pathway to reducing risk is simple and clear, and I’ll provide some useful steps forward in the conclusion.

Thyrotoxicosis in pregnancy

Next question and answer:

Q: Isn’t thyrotoxicosis (excess thyroid hormone) harmful in pregnant Graves disease patients?

A: The risks of severe thyrotoxicosis in antibody-driven Graves disease are primarily to the mother’s body. Hyperthyroid hormone status, usually excess T4 and RT3, may induce an early birth, but not miscarriage. The fetus is at risk of excess only if TSAb antibody crosses the placenta to stimulate its developing thyroid gland.

Outside of true Graves’ hyperthyroidism, in which antibody attack forces the thyroid to secrete excess thyroid hormone, the risks of thyrotoxicosis (excess thyroid hormone) in pregnancy are rare and few.

High T4 and T3 in healthy pregnancy

In healthy pregnant women, Both T3 and T4 hormone may be elevated and TSH suppressed by mother nature herself.

In 2019, Moleti et al published a review article titled “Hyperthyroidism in the pregnant woman: Maternal and fetal aspects.”

Pregnancy increases the body’s demand for thyroid hormone, and as T4 and T3 rise, “thyrotropin [TSH] levels [fall] below the lower limit of the gestational specific reference range in about 15% of pregnancies” (Moleti et al, 2019).

“Gestational transient thyrotoxicosis” (GTT) is usually mild and does not require any treatment. When GTT occurs naturally, it is driven by hGC hormone, secreted by the placenta, which stimulates the thyroid to secrete more hormone. It usually resolves by the end of the 1st trimester.

GTT is usually characterized by low TSH and high T4 levels. “By contrast, triiodothyronine (T3) is usually normal, or only slightly elevated in less than 20% of affected women” (Moleti et al, 2019).

Therefore, in nature, 20% of pregnant women experience mild elevation of T3 as well as T4.

A mild overdose of DTE would likely NOT be an overdose in the context of pregnancy because it fits this pattern that is natural and harmless in pregnancy.

A thyroid hormone overdose in the context of pregnancy, mainly causing risk to the mother, has to exceed the elevated T4 and/or occasionally mildly T3 hormone levels found in harmless cases of GTT.

Graves hyperthyroidism

The harms of genuine hyperthyroidism are not unique to pregnancy.

Whether or not a person is pregnant, having both T4 and T3 far above reference can cause harm to the heart and other organs.

Moleti et al write about the situation of severe excess of T4 and T3 found in untreated Graves’ hyperthyroidism, saying “uncontrolled thyrotoxicosis significantly increases the risk of maternal and fetal complications, such as pregnancy-induced hypertension, maternal congestive heart failure, pregnancy loss, prematurity, low birth weight, stillbirth, intrauterine growth restriction, along with neurobehavioral disorders in offspring in later life.”

This is a list summarizing what Moleti et al discuss in more detail. In fact, the former of these horrible conditions are the effects of extremely high T3 and T4 in the mother’s body, not in the fetus. The latter risks in the list are caused mainly by the Graves’ disease antibody.

“Fetal thyrotoxicosis” is not caused by excess T4 and T3 in the mother’s circulation. The placental expression of D3 can convert excess T4 thyroid hormone to RT3 and excess T3 hormone to T2.

Instead of risk being caused by the mother’s high thyroid hormone levels,

“fetal thyrotoxicosis” is theorized to be caused by TRAb antibody, since “TRAbs can cross the placenta and induce abnormal fetal thyroid gland stimulation” (Moleti et al, 2019).

In general, Graves’ hyperthyroidism has different pathway and presentation, and therefore it will have different maternal outcomes than a person with a damaged thyroid who is dosing DTE hormone under medical supervision.

In Graves’ disease, the thyroid hormones will be far higher than in a person whose T3 levels are mildly boosted by pharmaceutical error such as this.

The pharmaceutical error in question also has no control over patients’ expressing Graves’ disease antibodies during DTE treatment.

If Graves’ hyperthyroidism is diagnosed, a pregnant woman will not dose DTE, and if she was, it will be stopped. She will be given anti-thyroid medication as soon as her doctors know there’s a problem.

Risks of excess T4 in pregnancy

Because of the natural rise in T4 levels in pregnancy, women who are not on DTE therapy more often have problems with excess T4, rather than excess T3.

Excess T4 results in excess conversion to Reverse T3 within the mother. Excess Reverse T3 levels in the mother are associated with severe morning sickness, or “Hyperemesis gravidarum,” which is estimated to affect 0.3–2.0% of pregnant women. “Those affected have a low risk of miscarriage but a higher risk of premature birth.” (Asakura et al, 2000).

DTE dosing can prevent this health risk in pregnant women on thyroid therapy, while LT4 monotherapy cannot. DTE dosing normally results in a higher T3 than T4. Overdose of DTE would need to be severe before FT4 rises above reference range.

If a woman on DTE is experiencing GTT, they must either be extremely overdosed or one must suspect that Graves’ autoimmune hyperthyroidism (TSAb antibodies) are involved in overstimulating a remnant of active thyroid tissue.

Acella is not responsible for people overdosing NP Thyroid to a level that elevates T4 to the point of true thyrotoxicosis. The cautions are already in the patient information document.

Acella is also not responsible for the onset of Graves’ disease while on hypothyroid therapy, since it can happen at any stage of life and in any form of thyroid therapy.

The NP Thyroid recall has nothing to do with this risk to the mother because T4 potency was within specifications.

Subclinical hyperthyroidism: No risk

If only TSH is suppressed by the antibody and thyroid hormones are both within range, it is not a concern at all in pregnancy, according to guidelines.

“Subclinical hyperthyroidism is not associated with adverse obstetric effects” (Moleti et al, 2019).

If this is the case, guidelines should clearly permit a fully suppressed TSH during pregnancy when it is benignly over-suppressed despite normal FT3 and/or FT4.

And indeed, that is exactly what the guidelines say:

“In a small percentage of women [on no thyroid therapy], TSH can be very suppressed (<0.01 mIU/L) and yet still represent a normal pregnancy. “

(Stagnaro-Green et al, 2011)

The main perpetrator for the downward shift of “normal” TSH in pregnancy is the hCG hormone secreted by the placenta:

“In a study of 63 women with hCG concentrations >200,000 IU/L, TSH was suppressed (≤0.2 mIU/L) in 67% of women, and in 100% of women if hCG concentrations were >400,000 IU/L.” (Stagnaro-Green et al, 2011)

The 2011 guidelines go on to explain that

“Normal serum TSH values can be as low as 0.03 mIU/mL (or even undetectable) with upper limits of 2.5 mIU/mL in the first trimester and 3.0 mIU/mL in the second and third trimesters.

Any subnormal serum TSH value [below 0.03] should be evaluated in conjunction with serum FT4. The diagnosis of clinical hyperthyroidism is confirmed in the presence of a suppressed or undetectable serum TSH and an elevated FT4.”

The guidelines expressly state that pregnancy lowers the bar for “normal” TSH, and the guidelines recommend FT4 testing to discover whether it is “true” autoimmune Graves’ hyperthyroidism when TSH falls below 0.03.

Hypothyroidism and underdose: Significant risks

The core danger that is feared in pregnancy is “fetal brain T3 deficiency.” (Calvo et al, 1990). That is what causes brain damage leading to delayed mental development of children.

Lack of T3 in fetal brain is found in

  • untreated overt or subclinical hypothyroidism,
  • iodine deficiency, and
  • underdose with thyroid hormone.

Calvo’s research on hypothyroxinemia

Research by Calvo et al (1990) on fetal hormone levels in pregnant rats dosed with T3 hormone alone heightened what was already known about risks of low T4 in pregnancy.

“The infusion of T3 pool into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3.

The results show that

(a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency;

(b) maternal T4, but not T3, plays a crucial role in this protection, and

(c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus.”

Calvo et al, 1990 “Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3′-triiodothyronine in the protection of the fetal brain.”

The risks of FT4 Underdose on DTE

Question and answer:

Q. How could desiccated thyroid treatment (regardless of this NP Thyroid recall) lower maternal T4, which could then reduce T3 supply to the fetal brain?

A. If the mother has a healthy enough thyroid to be a “good converter,” she may achieve euthyroidism on NP Thyroid with a Free T4 below reference range and a Free T3 that is near the top of reference range. However, this ratio and amount of thyroid hormone may be enough for the mother, but may not be sufficient for the fetus.

Based on studies in rats, and based on studies excluding human mothers on DTE, it has been feared that not enough T3 and especially T4 will pass through the placenta to reach the fetus, and that not enough T3 and especially T4 will enter the fetal brain.

Research currently puts emphasis on local T4 conversion to T3 in the brain during fetal development.

It is clear to see which type of response to desiccated thyroid is at risk of a Low T4.

[NOTE: Grey zone = reference range. “Good converter” may have a T4 fall below reference]

In the model above, only the “Good Converter” is presently at risk of poor maternal outcomes because their T4 may fall too low.

Now consider that pregnancy itself can be a T4-booster in “good converters” who usually have some thyroid function. (It is highly likely that the “good converter” is able to convert well because of some residual thyroid tissue, according to Midgley et al, 2015, who see higher T3 ratios among them).

If a thyroid patient with residual thyroid function becomes pregnant, hCG hormone from the placenta will stimulate the thyroid tissue to hypersecrete T4, which will raise FT4 levels during DTE therapy even without an increase in dose.

The risk of raising the T3 dose alone is limited to the population of underdosed DTE patients,

  • Whose T4 remains low despite hCG stimulation of their thyroid fragment and
  • Who still have a measurable TSH.

A higher T3 would cause TSH to drop lower, which could lower T4 secretion if they have a viable thyroid gland remnant.

The Acella recall, therefore, is ethical to warn, but the risk due to this pharmaceutical error is facing pregnant patients whose thyroid health care system has institutionalized ignorance at many levels.

They will be at risk if their FT4 is unmonitored and their gland health status is unknown while their doctor, ignorant of the way that a suppressed TSH could remove risk in pregnant DTE patients, foolishly demands that their TSH not be permitted to fall low during pregnancy.

Medical ignorance is far more harmful than this small manufacturing error, and the removal of medical ignorance can effectively keep this type of error from causing any harm.

Dr. Evelyn Man’s studies on DTE in pregnancy

From 1968 to 1999, Dr. Evelyn Man coauthored 10 articles on “Thyroid function in human pregnancy” in which they used only Proloid, a brand of desiccated thyroid (DTE), to treat hypothyroid pregnant women.

A summary of these results was published in 1991, just after Calvo’s article.

Man and team studied maternal outcomes such as birth weight along with childhood development to age 7. They found the following:

  • Euthyroid: Excellent maternal and childhood development outcomes.
  • Euthyroid on Proloid (DTE) with sufficient T4: Excellent maternal and childhood development outcomes, with psychological scores even higher on average than healthy controls.
  • Underdosed on Proloid (DTE): Poor childhood development outcomes

All of Man’s attention was focused on ensuring T4 sufficiency while attaining true clinical euthyroidism for the mother. There was never any concern that the pregnant woman or fetus would suffer from an elevation of T3, and science still hasn’t found reason for such a concern. It clearly did not hurt the children to have unmonitored and likely high T3 levels.

We already have evidence that DTE can be completely effective in preventing pregnancy risk when properly dosed and monitored.

Why did policymakers suddenly decide that DTE was always dangerous in pregnancy?

ATA’s recommendations against DTE

The 2011 ATA guidelines for thyroid disease in pregnancy states in Recommendation 10:

“The recommended treatment of maternal hypothyroidism is with administration of oral LT4. It is strongly recommended not to use other thyroid preparations such as T3 or desiccated thyroid.”

Stagnaro-Green et al, 2011

This statement, without appropriate qualifiers and reasoning to inform clinicians and protect DTE and T3 patients, is misleading and harmful.

As you can now understand, this recommendation:

  • has nothing to do with risk of elevated T3 concentrations in pregnancy, but readers may easily misunderstand that an isolated higher T3 is the risk in pregnancy, when it is not.
  • gives no information about circumstances when LT3-LT4 combination and DTE dosing achieves the goals of preventing hypothyroxinemia, when it certainly can.
  • fails to acknowledge the strong health outcomes of well-dosed pregnant women’s children in Man’s study of desiccated thyroid, as well as the long history of successful pregnancies in the DTE-only era before synthetic thyroxine was available.

This is only a “strong recommendation.” It has scientific holes in it. Calvo et al’s pregnant rats are very different from humans in their thyroid hormone economy. One must seriously question the current theories proposed when a mother on T3-only therapy throughout pregnancy experienced no harm to herself or her child’s development (Boix Carreño et al, 2007). The evidence provided by even a single human mother and her child ought to trump a pregnant LT3-overdosed rat in a study led by people who may have wanted to prove the maternal risks of low T4. Contradictions like these point to errors in the current theory underpinning risk.

More research is needed on women who choose to stay on DTE or even T3 monotherapy throughout a pregnancy and have successful outcomes, and these women can be found if you look for them. But in the mean time it’s easier to ignore this healthy population exists and forbid the therapy that authorities currently do not favor. This is a form of paternalistic, intellectual laziness that leads to harm.

This guideline validates clinical discrimination against women who could be well dosed on DTE or synthetic T3-T4 combination and in no danger of hypothyroxinemia given T4 levels nowhere near the lower end of reference. Doctors are being given permission to engage in coersion. Forcing women to switch to levothyroxine during pregnancy may be harmful for some individuals. Poor converters of T4 may undergo a T3-ectomy without their informed voluntary consent. Some of them, after being switched to LT4, may then be at risk of Gestational Thyrotoxicosis due to elevated T4 and Reverse T3, as described above.

Thyroid pharmaceutical prejudice is unethical and unreasonable. It outlaws a competing safe, effective therapy pathway and promotes a narrow, monopolistic one-test-one-med paradigm that is truly not safe or effective for all.

Sadly, thyroid guideline writers have a general tendency to prohibit where their own ignorance, prejudice, and fear combine.

[Read more about the mechanisms and harms of thyroid hormone pharma prejudice.]

Continue to Page 2:

  • Risk of testing only TSH and not FT4 in pregnancy
  • Acella’s recall notice: Ethics, clarity, focus
  • Conclusion: What we can do
  • References

Leave a public reply here, on our website.

This site uses Akismet to reduce spam. Learn how your comment data is processed.