Pregnant Women Are Not Getting Enough Iodine

The authors reviewed 61 studies (including a total of 163,021 pregnant women) that estimated the prevalence of insufficient iodine intake during pregnancy in different regions of the world. The overall prevalence of insufficient iodine intake was 53%. The prevalence was 46% in the Americas (North and South America combined). Pregnant women living in countries with insufficient iodine status had a higher prevalence of inadequate iodine intake (86%) than women living in countries with sufficient iodine intake (51% prevalence).

Comment: Iodine deficiency in pregnant women can lead to impaired fetal growth and development. Low iodine status in utero and during infancy has been associated with lower IQ in later childhood. Although increased use of iodized salt has decreased the worldwide prevalence of iodine deficiency, an estimated 2 billion people around the world have insufficient iodine intake. The Endocrine Society, the American Thyroid Association, the Teratology Society, and the American Academy of Pediatrics recommend that women receive prenatal vitamins containing 150 µg per day of iodine during preconception, pregnancy, and lactation. Some prenatal vitamin products contain iodine, but others do not.

Patriota ES, et al. Prevalence of insufficient iodine intake in pregnancy worldwide: a systematic review and meta-analysis. Eur J Clin Nutr. 2022;76:703-715.

Melatonin Improves Sleep in Children with Autism Spectrum Disorder

This study enrolled 198 Japanese children (mean age, 11.2 years) with autism spectrum disorder who had average sleep onset latency of at least 30 minutes (i.e., it took them at least 30 minutes to fall asleep). The children were randomly assigned to receive, in double-blind fashion, melatonin (1 mg or 4 mg) or placebo before bedtime for 14 days. The primary outcome was sleep onset latency, as assessed with an electronic sleep diary. Sleep onset latency shortened significantly in the 1-mg and 4-mg melatonin groups compared with the placebo group (-22.0, -28.0, and -5.0 minutes, respectively; p < 0.0001 for each melatonin dose compared with placebo). No serious adverse events were reported.

Comment: This study found that melatonin can improve the ability of children with autism spectrum disorder to fall asleep. The lower dose (1 mg) was nearly as effective as the higher dose (4 mg). Although melatonin was generally well tolerated, it is important to remember that melatonin is a hormone, and that its long-term safety in children has not been well studied. Studies in elderly individuals with insomnia have found that, once melatonin resets the biological clock, it can be discontinued in many cases without causing a return of abnormal sleep patterns. An attempt should also be made to wean children from melatonin after it has achieved the desired benefit.

Hayashi M, et al. Melatonin treatment and adequate sleep hygiene interventions in children with autism spectrum disorder: a randomized controlled trial. J Autism Dev Disord. 2022;52:2784-2793.

Unexplained Iron Deficiency? Consider Helicobacter pylori Infection

The records were reviewed on 60 children (aged 2-18 years; mean, 14.8 years) in Israel with Helicobacter pylori infection and non-anemic iron deficiency (n = 39) or iron-deficiency anemia (n = 21). Hemoglobin and ferritin levels were measured before and 6 to 9 months after successful eradication of H. pylori. None of the children had recently been given iron supplements, and iron supplements were not given during the trial. The mean ferritin level increased from 6.3 µg/L at baseline to 15.1 µg/L at 6 to 9 months after eradication therapy, and became normal in 60% of the children. The mean hemoglobin concentration increased significantly in the group as a whole, and also among those with iron-deficiency anemia. In multiple logistic regression analysis, older age was the only factor associated with resolution of anemia following eradication therapy (odds ratio = 1.65; p = 0.005).

Comment: H. pylori is a well-known cause of peptic ulcers. It is not as well known that H. pylori can impair the capacity of the stomach to secrete hydrochloric acid. H. pylori-associated hypochlorhydria is frequently reversible once the infection has been eradicated. Hydrochloric acid plays a key role in the absorption of nonheme iron, and hypochlorhydria can increase the risk of developing iron deficiency. In the present study, eradication of H. pylori improved iron status in children with iron deficiency. H. pylori infection should be considered in the differential diagnosis of unexplained iron deficiency, particularly if iron supplementation fails to correct the deficiency or if ongoing iron therapy is needed to prevent a recurrence of iron deficiency.

Tanous O, et al. Resolution of iron deficiency following successful eradication of Helicobacter pylori in children. Acta Paediatr. 2022;111:1075-1082.

Evening Primrose Oil for Diabetic Neuropathy

One hundred patients (mean age, 60.7 years) at one of 11 clinics in South Korea who had painful diabetic peripheral neuropathy were randomly assigned to receive, in double-blind fashion, 320 mg per day of gamma-linolenic acid (GLA) from 3.6 g per day of evening primrose oil or 600 mg per day of alpha-lipoic acid for 12 weeks. The treatments were taken in two divided doses, 30 minutes before breakfast and dinner. Among the 73 patients who completed the trial, significant decreases (improvements) were seen in both groups in the mean visual analogue scale score for pain and in the total symptom score (a composite of stabbing pain, burning pain, paresthesias, and numbness). Evening primrose oil was nonsignificantly more effective than alpha-lipoic acid. For evening primrose oil, the mean visual analogue scale score (on a scale of 0 to 10) improved from 5.26 at baseline to 2.94 after 12 weeks (p < 0.0001), and the mean total symptom score (on a scale of 0 to 14.64) improved from 3.86 to 2.18.

Comment: Diabetic neuropathy is a disorder of peripheral nerves associated with diabetes. In animals with experimentally induced diabetes, supplementation with GLA or evening primrose oil (which contains GLA) prevented the development of nerve conduction velocity deficits without affecting the severity of the diabetes. In two double-blind trials conducted in the 1990s, treatment with 4.0 g to 5.3 g per day of evening primrose oil for 6 to 12 months resulted in significant improvements in subjective and objective signs of diabetic neuropathy, compared with placebo.^1,2 However, the principal investigator who conducted these clinical trials was subsequently found by the professional conduct committee of the General Medical Council (United Kingdom) to have falsified the results of the research.³ Now, some 30 years later, Korean researchers have demonstrated that evening primrose oil is indeed an effective treatment for painful diabetic neuropathy. In their study, evening primrose oil was at least as effective as alpha-lipoic acid, which has been demonstrated in multiple studies to be beneficial in the treatment of diabetic neuropathy.

Won JC, et al. gamma-Linolenic acid versus alpha-lipoic acid for treating painful diabetic neuropathy in adults: a 12-week, double-placebo, randomized, noninferiority trial. Diabetes Metab J. 2020;44:542-554.

Pickle Juice Relieves Muscle Cramps in People with Cirrhosis

Eighty-two patients (mean age, 57 years) with cirrhosis and more than four muscle cramps in the previous month were randomly assigned to consume one tablespoon of pickle juice or tap water at the onset of cramps. Participants were allowed to use pickle juice from the brine of dill or kosher pickles, but not from the brine of sweet pickles or bread and butter pickles. Patients on a sodium-restricted diet were instructed to consume no more than three tablespoons of pickle juice per day, in order to prevent volume overload. Cramp severity was assessed by a visual analogue scale with a range of 0 to 10, with higher numbers indicating worse cramps. At baseline, the medium number of cramps per month was 11 to 12, and average cramp severity was greater than 4. The primary outcome measure was the change in cramp severity after 28 days compared with baseline. The mean improvement on the visual analogue scale was greater with pickle juice than with tap water (-2.25 vs. -0.36; p = 0.03). More patients in the pickle juice group reported that cramps were aborted by the intervention (69% vs. 40%; p value not stated). Compared with tap water, pickle juice did not cause weight gain, either in patients with or without ascites.

Comment: Muscle cramps affect about two-thirds of patients with cirrhosis. The cramps cause pain and interfere with mobility and sleep, and are associated with poor health-related quality of life. Treatment options are limited. The results of the present study demonstrate that consumption of small amounts of pickle juice can improve the severity of cramps, without causing any significant adverse effects. The authors of this study suggested that the active ingredient in pickle juice is acetic acid, which increases vagal tone by acidic stimulation of oropharyngeal nerves. They further suggested that, if the mechanism of action is acid-related, then other acidic liquids such as apple cider vinegar might also be effective.

Tapper EB, et al. Pickle juice intervention for cirrhotic cramps reduction: the PICCLES randomized controlled trial. Am J Gastroenterol. 2022;117:895-901.

Intravenous Magnesium and Myasthenia Gravis

A woman in her 90s with a history of myasthenia gravis and atrial fibrillation presented to an emergency department after falling down. She was given intravenous magnesium to treat atrial fibrillation and the associated rapid ventricular rate. Shortly thereafter she developed acute respiratory failure, which required intubation and ventilation. Her respiratory function recovered quickly, and she was extubated the next day. On subsequent days, the patient received two further doses of intravenous magnesium, and on both of those occasions she again developed transient respiratory failure.

Comment: Myasthenia gravis is an autoimmune disorder characterized by skeletal muscle weakness that increases with exertion and improves with rest. Most people with myasthenia gravis have antibodies that damage or interfere with acetylcholine receptors at the neuromuscular junction, which results in a decrease in cholinergic stimulation of muscle contraction. Magnesium acts at the neuromuscular junction, where it competes with calcium and inhibits the release of acetylcholine. Magnesium therefore has the potential to exacerbate the deficiency of cholinergic stimulation that occurs in patients with myasthenia gravis. There have been several previous case reports in which intravenous administration of magnesium triggered a crisis (including respiratory failure) in patients with myasthenia gravis. Intravenous magnesium is therefore contraindicated in patients with this disease.

Jessop K. Intravenous magnesium sulfate inducing acute respiratory failure in a patient with myasthenia gravis. BMJ Case Rep. 2022;15:e250455.

Coenzyme Q10 and Alpha-Lipoic Acid for “Long Covid”

One hundred seventy-four Italian patients with chronic fatigue syndrome that had developed after a Covid-19 infection were treated at a clinic that provided multiple interventions, including analgesic and anti-inflammatory medications, antidepressants (mostly for treatment of pain), anticonvulsants that have an analgesic effect (pregabalin and gabapentin), psychological counselling, physio-kinesotherapy, physical reconditioning, and yoga/pilates. Two-thirds of the patients also received coenzyme Q10 and alpha-lipoic acid (100 mg per day of each) for two months, while 58 patients did not receive these supplements (control group). The treatment assignments were apparently not randomized. The proportion of patients who had a complete response (defined as at least a 50% improvement in the Fatigue Severity Scale score) was higher in the supplement group than in the control group (53.5% vs. 3.5%).

Comment: These findings suggest that the addition of coenzyme Q10 and alpha-lipoic acid to a comprehensive treatment program can improve outcomes in patients with “long covid.” The difference in complete-response rates between groups may at first glance seem implausibly large (53% vs. 3.5%). It should be noted, however, that 73% of the patients in the control group who failed to have a complete response did have an improvement of 20-50% on the Fatigue Severity Scale. Randomized controlled trials are needed to confirm the results of this study.

Barletta MA, et al. Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome. Clin Exp Med. 2022 Aug 22 [Online ahead of print].

Vitamin B12 for Diabetic Neuropathy: Revisiting an Old Iranian Paper

One hundred patients (mean age, 35 years) with symptomatic diabetic neuropathy without vitamin B12 deficiency were randomly assigned to receive, in single-blind fashion, vitamin B12 (2,000 µg intramuscularly twice a week for 3 months) or nortriptyline (10 mg once a day at night). The mean scores for pain (p < 0.001), paresthesias (p < 0.001), and tingling sensation (p < 0.001) improved to a significantly greater extent in the vitamin B12 group than in the nortriptyline group. Changes in vibration sensation, position sensation, pinprick sensation, and nerve conduction parameters did not differ significantly between groups. The authors concluded that vitamin B12 is more effective than nortriptyline for the treatment of painful diabetic neuropathy.

Comment: In my writings during the past 10 to 15 years, I cited a number of research papers from Iran. Over the past several years I developed concerns about the credibility of much of the nutrition research coming from that country. I have therefore begun taking another look at some of the research I cited in the past. The study described above, which was published in 2009, has a number of concerning issues. I have written to the journal that published this paper, and they stated that they will conduct an investigation.

Concerns about Talaei A, et al. Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int J Food Sci Nutr. 2009;60(Suppl 5):71-76.

1. The study was conducted over a three-month period, and the treatment lasted three months. That would mean that all 100 patients in the study would have had to start the study at the same time. That is very unusual for a clinical trial.

2. One of the inclusion criteria was having had type 2 diabetes for at least three years (type 1 diabetics were excluded). The paper reported that the mean age of the study participants was 35 years, which means the mean age at diagnosis of diabetes was 32 or younger. It would be very unusual to have such a young population of type 2 diabetics.

3. The control group received 10 mg per day of nortriptyline, which is usually a sub-therapeutic dose in the treatment of diabetic neuropathy. A typical treatment regimen is to start with 10 mg per day of nortriptyline and to increase progressively, according to response and tolerance, to a maximum of 75 mg per day. One wonders whether it is unethical to give the subjects in this study a treatment that is not likely to be effective.

4. All of the patients had been referred to a single clinic in Arak, Iran, for evaluation of diabetic neuropathy. However, only one of the four study authors was from Arak; the other three were from Isfahan, which is 3.5 hours away by car.

5. Implausibly large degree of improvement: Symptoms such as pain and tingling were measured on a 5-point visual analogue scale. In the group receiving vitamin B12, the mean improvement in pain was 3.66 points, with a range of 3.06 to 4.25. Most people would consider an improvement of 3.06 points on a 5-point scale to be a very large or even dramatic improvement. Thus, all 50 patients given vitamin B12 had a very large improvement. I cannot think of any treatment for any health condition that produces a very large benefit 100% of the time.

6. The paper stated, “All patients before, during and after the study were under their usual protocols and were managed appropriately.” However, since these patients had been referred from other clinics, one wonders how the researchers could have known that the patients had been managed appropriately before they were referred.

Talaei A, et al. Vitamin B₁₂ may be more effective than nortriptyline in improving painful diabetic neuropathy. Int J Food Sci Nutr. 2009;60(Suppl 5):71-76.