Retzler et al. report estimates of the economic cost of congenital cytomegalovirus (cCMV) in the United Kingdom.1 The projected costs of autism spectrum disorder (ASD) among persons with cCMV accounted for at least 50% of the total costs attributed to cCMV. However, an association between cCMV and ASD has not been conclusively established,2 and, in their analysis, Retzler et al. did not take into account the cost of ASD among children without cCMV.

Retzler et al. used published ASD prevalence estimates from a Dutch study of >30,000 children screened for cCMV at 6 years of age using stored dried blood specimens, of whom 133 were CMV-positive. Of 26 children classified with symptomatic cCMV, 2 (7.7%) had ASD, as did 2/107 (1.9%) with asymptomatic cCMV.3 Retzler et al. assumed 11% of children with cCMV are symptomatic, which implies a weighted average ASD prevalence of 2.5% among children with cCMV. Five of 274 (1.8%) matched children without cCMV in the Dutch study also had ASD. If ASD were causally associated with cCMV, which has not been shown, the cost of ASD attributable to cCMV would be the cost difference of ASD among children with and without cCMV. Therefore, the projected cost of cCMV has been overestimated. Moreover, if the reported association of cCMV with ASD turns out to be non-causal, the total cost of cCMV could be half that estimated by Retzler et al.

References
1. Retzler J, Hex N, Bartlett C, et al. Economic cost of congenital CMV in the UK. Arch Dis Child 2018 doi: 10.1136/archdischild-2018-316010 [published Online First: 2018/11/26]
2. Maeyama K, Tomioka K, Nagase H, et al. Congenital cytomegalovirus infection in children with autism spectrum disorder: systematic review and meta-analysis. J Autism Dev Disord 2018;48(5):1483-91. doi: 10.1007/s10803-017-3412-x [published Online First: 2017/12/01]
3. Korndewal MJ, Oudesluys-Murphy AM, Kroes ACM, et al. Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study. Dev Med Child Neurol 2017;59(12):1261-68. doi: 10.1111/dmcn.13556 [published Online First: 2017/10/11]

Authors (full names and academics degrees)
• Laura Moreno-Galarraga1 MD PhD
• Miguel Ángel Martínez-González2 MD PhD MPH
• Diego Mauricio Peñafiel Freire3 MD
• Elsie M Taveras4 MD MPH

Affiliations
1) Department of Pediatrics, Complejo Hospitalario de Navarra. IdisNa; Instituto de Investigación Sanitaria de Navarra, Health Research Institute of Navarra, Pamplona, Spain.
2) Department of Preventive Medicine and Public Health, University of Navarra Pamplona, Spain. Dpt. Nutrition, Harvard TH Chan School of Public Health, Boston, MA. CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
3) Department of Pediatrics, Complejo Hospitalario de Navarra, Pamplona, Spain
4) Division of General Academic Pediatrics, Massachusetts General Hospital for Children, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.

Dear Editor;

We have read the article about myths, milk and mucus, and we couldn’t agree more.1 We have observed the prevalence of the same myth and the same concern that many parents are limiting their child’s consumption of dairy products or replacing milk with vegetable drinks, despite the current recommendations.2

We conducted a study in 169 school-age children in Spain and we did not find any association between dairy products consumption (milk, cheese or yoghurt) and respiratory diseases (OR=0.85 95%CI (0.44-1.64))3. Additionally studies conducted in various populations have not found evidence that this association exists1 and some studies even indicate that cow-milk consumption in early life is a protector factor against asthma4. In infant nutrition several scientific societies, as the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN), maintain few indications for soy-based formula, and state that in healthy infants they have no nutritional advantages over cow's milk protein formulae, but their utilization rates keeps increasing.5

The question then remains: Why does the myth persist despite the evidence? Authors claim in their article: "Milk-mucus myth needs to be rebutted firmly by healthcare workers".1 But, how?

The perpetuation of this myth might be related to some commercial interests, that have been rigourously addressed by some investigators.6,7 We think that paediatricians should reinforce the current WHO recommendations on paediatric feeding, and specifically inform parents about this unsupported belief and the current scientific evidence. We think that the time has come to find a common ground on this issue; there probably is no need to conduct new clinical studies to discard this myth, but to defend the scientific truth. In the same way as policies to avoid formula milk advertisements that may compromise breast-feeding were implanted, we need now policies to defend the harmlessness of dairy products regarding respiratory problems.1,3,4 It is important to transmit to the general population that avoiding dairy products is not useful to prevent respiratory illnesses, and that vegetables drinks are not “kinds of milk”, that they do not have the same nutritional or health benefits, and that they are not better substitutes of milk during childhood.
Health myths are remarkably persistent. But, if the myth that milk is related to mucus or respiratory pathology has been unfounded by scientific evidence, we believe our next step should be to transmit evidence-based information to the population and to combat false advertising and fake information spreading on social media.

References:

1. Balfour-Lynn IM, Milk, mucus and myths. Arch Dis Child. 2019 Jan;104(1):91-93.
2. World Health Organization Global Strategy for Infant and Young Child Feeding. Geneva: World Health Organization; WHO nutrition publications. 2003. http://www.who.int/nutrition/publications/infantfeeding
3. Peñafiel Freire DM, Martín Calvo N, García Blanco L, et al. Association of dairy consumption with respiratory infections. Myth or reality?. Rev Pediatr Aten Primaria. 2018;20(1):45-52.
4. Lumia M, Takkinen HM, Luukkainen P, et al. Food consumption and risk of childhood asthma. Pediatr Allergy Immunol. 2015; 26(8): 789-96.
5. Agostoni C, Axelsson I, Goulet O, et al. Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition. JPediatr Gastroenterol Nutr. (2006) 42:352–61.
6. Nestle M.Corporate funding of food and nutrition research: science or marketing? JAMA Intern Med. 2016;176(1):13-14.
7. Lesser LI, Ebbeling CB, Goozner M, Wypij D, Ludwig DS. Relationship between funding source and conclusion among nutrition-related scientific articles. PLoS Med. 2007 Jan;4(1):e5.

Dear Sir,

We thank Dr Nadeem, for highlighting that the clinical features of drowsiness and infant focal seizures in our case report indicates that early treatment for viral/herpes encephalitis was an imperative.

We would like to reassure Dr Nadeem that our infant did indeed receive a combination of early intravenous antiviral treatment (acyclovir) and antibiotics (cefotaxime and amoxicillin) and this was continued until final viral/bacterial PCR and CSF culture results were obtained. The use of acyclovir and amoxicillin was omitted from the original report due to word count limitations.

Viral PCR tested was negative for a range of viruses including herpes simplex (HSV). Although PCR assay is an important diagnostic modality for viral encephalitis HSV, we would add that due to focal seizures, our infant case received investigations and treatment as per national (1) and local guidelines: immediate brain CT imaging was performed to exclude neurosurgical conditions, and a later cranial MRI scan did not show selective damage to the mesial temporal lobe structures or the hippocampus. In addition, an early electroencephalogram (EEG) was normal. The EEG severity and the presence of epileptic seizures at the initial presentation would be significant indicators for predicting the 6-month clinical outcome in patients with HSE.

The seriousness of HSV CNS infections suggests that clinicians maintain a high index of suspicion to initiate evaluation under suitable circumstances. We are grateful to the Editors for now publishing Dr Nadeem’s response to our letter to highlight this to our readers.

References
(1) Meningitis Research Foundation (MRF). Management of Bacterial Meningitis in infants <3 months (Neonatal Algorithm) [PDF]. London, United Kingdom: Meningitis Research Foundation (MRF); 2017 [updated Nov 2017]. Available from: https://www.meningitis.org/getmedia/75ce0638-a815-4154-b504-b18c462320c8....

I refer to the paper published by Palmer et al in Archives Diseases Childhood March 20181 that states the recommendation to avoid tramadol when breastfeeding and the contraindication to its use in children (including neonates) is inappropriate in their view. 1
I disagree with the authors that tramadol is a safe for babies of breastfeeding mothers. Their conclusion, in my opinion, is premature and not adequately evidence-based. While they acknowledge, the US Food and Drug Administration (FDA) reported cases, they ignore the serious warnings by both Manufacturer and FDA about administering tramadol to children and breast-feeding mothers. There is increasing concern that narcotics used for treating pain in breastfeeding mothers may increase the risk of adverse effects in newborns, including excessive sedation and respiratory depression. The American Academy of Pediatrics (AAP), the FDA and the American College of Obstetricians and Gynecologists (ACOG) advocate against the use of codeine and tramadol in women who are breastfeeding because their babies may suffer adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5 Patient safety should be foremost in our minds in making any recommendations that are contrary to Manufacturer, FDA, and AAP recommendations. It would be difficult to justify use of tramadol in a breastfeeding mother in the event of litigation arising from adverse effects of tramadol in the baby, when safer alternatives are available.
MANUFACTURER WARNING
In March 2008, Janssen Ortho, the manufacturer of tramadol (ULTRAM®) stated that the effects of tramadol on growth and functional maturation of child, and safety in infants and newborn has not been studied and it is not recommended for use in the pediatric population. It issued the following information concerning tramadol:
• LABOR AND DELIVERY
1. ULTRAM® should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn.
2. Tramadol crosses the placenta. The effect of ULTRAM®, if any, on the later growth, development, and functional maturation of the child is unknown.
• NURSING MOTHERS
ULTRAM® is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours, post-dose was 100μg of tramadol (0.1% of the maternal dose) and 27 μg of M1.
• PEDIATRIC USE
The safety and efficacy of ULTRAM® in patients under 16 years of age have not been established. The use of ULTRAM® in the pediatric population is not recommended. 6

FDA WARNINGS
1. In 2013, FDA placed restrictions on its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.7
2. FDA reviewed adverse event reports submitted to it from January 1969 to May 2015, and identified 64 cases of serious breathing problems, including 24 deaths, with codeine-containing medicines in children younger than 18 years. As this included only reports submitted to FDA, there may be additional cases about which FDA is unaware. FDA also identified nine cases of serious breathing problems, including three deaths, with the use of tramadol in children younger than 18 years from January 1969 to March 2016. Most of the serious side-effects with both codeine and tramadol occurred in children younger than 12 years, and some cases occurred after a single dose of the medicine.8
3. On July1, 2015, FDA issued warning about the potential risks of using codeine cough-and-cold medicines in children on July 1, 2015,4 and in September 21, 2015, FDA issued warning on the risks of using the pain medicine tramadol in children aged 17 and younger issued on September 21, 2015. 9
4. On 1-11-2018, the FDA restricted the use of codeine and tramadol medicines in children as these medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. FDA warned against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants. 10
5. Use of tramadol during pregnancy could make the baby dependent on the drug and cause Life-threatening withdrawal effects that may necessitate medical treatment for several weeks. 11
Additional concerns relating to the use of tramadol are suicidal thoughts and suicide attempts have emerged. In the article: Tramadol and Suicide attempt - from FDA reports, dated November 8, 2018, suicide attempt is found among people who take Tramadol, especially female, 40-49 old, who have been taking the drug for < 1 month. In the study based on reports of 102,114 people who have side effects when taking Tramadol from FDA, and is updated regularly. 102,114 people reported side effects when taking Tramadol. Among them, 765 people (0.75%) have attempted suicide. Suicide attempts are reported in children from the age of 10 years.12
In the light of the above data, there does not appear to be adequate evidence to support Palmer et al.’s contention that both Manufacturer and FDA recommendation to avoid use of tramadol when breastfeeding and contraindication to its use in children (including neonates) should be ignored.1 The AAP, the FDA, and the ACOG recommend against the use of codeine and tramadol in women who are breastfeeding because their newborns may have adverse reactions, including excessive sleepiness, difficulty breathing, and potentially fatal breathing problems. 2-5
Practice of medicine should be evidence-based. Patient safety comes foremost. Safer alternatives to tramadol are available. Acetaminophen and/or ibuprofen is recommended for pain management in women who are breastfeeding. If narcotic treatment is considered necessary, the lowest effective dose of morphine for the shortest time possible could be prescribed. 2
REFERENCE
1. Greta M Palmer, Brian J Anderson, David K Linscott, Michael J Paech, Karel Allegaert. Tramadol, breast feeding and safety in the newborn. (http://dx.doi.org/10.1136/archdischild-2017-313786).
2. Robert L. Barbieri. Editorial. Stop using codeine, oxycodone, hydrocodone, tramadol, and aspirin in women who are breast-feeding. OBG Manag. 2017 October;29(10):8-10,12. https://www.mdedge.com/obgyn/article/148018/obstetrics/stop-using-codein....
3. Sachs HC; Committee on Drugs. The transfer of drugs and therapeutics into human breast milk: an update on selected topics. Pediatrics. 2013;132(3):e796–e809.
4. US Food and Drug Administration. FDA Drug Safety Communication. FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD: US Food and Drug Administration. https://www.fda.gov/Drugs/DrugSafety/ucm118113.htm. Published April 2017.
5. Practice advisory on codeine and tramadol for breast feeding women. American College of Obstetricians and Gynecologists website. https://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-A.... Published April 27, 2017.
6. ULTRAM® (tramadol hydrochloride) Tablets. Full Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033...
7. FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. (2-20-2013). https://www.fda.gov/downloads/Drugs/DrugSafety/UCM339116.pdf - accessed February 16, 2019.
8. FDA Drug Safety Communication: FDA evaluating the potential risks of using codeine cough-and-cold medicines in children. https://www.fda.gov/Drugs/DrugSafety/ucm453125.htm
9. FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger. https://www.fda.gov/Drugs/DrugSafety/ucm462991.htm (9-21-2015).
10. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm (1-11-2018)
11. Kaci Durbin. (Updated 29-12-2018) Tramadol. https://www.drugs.com/tramadol.html
12. Tramadol and Suicide attempt - from FDA reports. http://www.ehealthme.com/ds/tramadol/suicide-attempt/

Conflict of Interest
None declared
Professor Dr. Davendralingam Sinniah