How Common Are Twins?

Patient Presentation
Dizygotic 5-day-old male and female twins came to clinic for their health maintenance visit after discharge from the newborn nursery. They were born to a 24 year old, G2P1 now 3, female at 36 5/7 week gestation by vaginal birth without complications. The mother was attempting to breastfeed each infant every other feed every 2-3 hours. They used formula supplementation after the feeding as needed and used formula for the other infant at each feeding. Her milk was starting to come in at this time. They seemed slightly jaundiced to the parents, but otherwise were doing well. The family history was positive for the mother being a twin herself and her twin sister also had 2 year old twins. There were also maternal cousins who were twins. The father’s family did not have twins in the family.

The pertinent physical exam showed twin infants with weights that were 4% and 6% down from birth weight. The male infant had jaundice to his abdomen and the female had jaundice to the nipple line, but were otherwise well. The laboratory evaluation showed a bilirubin of 12.3 mg/dl for the male and 8.4 mg/dl for the female, both of which were low-risk. The diagnosis of healthy twins was made and the family was to follow up in 5 days or sooner as needed.

Discussion
Twinning is the conception and development of more than one zygote during one pregnancy. Monozygotic (MZ) twins arise from one zygote that then splits to form two embryos so that the twins are necessarily of the same gender (male-male or female-female). Dizygotic (DZ) twinning arises from the development of two independent zygotes and therefore the genders may be the same or different (male-male, female-female or male-female).

Increased risks of spontaneous DZ twinning includes increased maternal age, parity and gravity, family history including familial clustering, maternal obesity and overweight and smoking. Nutrition itself may or may not play a role. Other factors also cited that are associated with increased rates of twinning are race (e.g. black), ethnicity (e.g. non-Hispanic) and socioeconomic status (e.g. higher). Recently two SNPs were identified which appear to contribute to familial reproductive capacity and DZ twinning (FSHB and SMAD3) in a multi-country, genome-wide association study.

While overall, twins that survive do well with normal outcomes, there can be problems. Maternal complications of twinning include increased stillbirth, neonatal death, premature birth, preeclampsia, post-partum hemorrhage and related problems. Neonatal complications of twinning include preterm birth, intrauterine growth restriction, and discordant growth. Societal costs are also increased for twins. Twins use more health care resources with increased costs than singletons. Some cite information that the cost of raising twins is more than two separate singletons.

Learning Point
While humans have a dominant ovarian follicle selection which usually causes singleton births, twinning is common in humans. Overall in the US, 1 in 30 people is a twin.

Until ~1970 the US rate of overall twin birth was ~1.9% and was constant. The rate has increased to 3.3% in 2009. This appears to be because more DZ twins (particularly opposite sex twins) are being born. Currently, for MZ twins the rate continues to be relatively constant at 3-4 births/1000 around the world. For DZ twins the rate is different with worldwide regional differences. Low rates are found in Asia and Latin America (~1%), but in Africa the rate is much higher at 40 twin births/1000 live births. The Yoruba in Nigeria have a rate of 5%.

The increased rates of DZ are felt to be multifactorial with pharmacological control of fertility, assisted reproductive technologies and increased maternal age being important factors. Note that assisted reproductive technologies also allows options for sperm and egg donations and therefore the DZ twins may be genetic half-siblings.

Questions for Further Discussion
1. Twin studies are common in research, so how would increased DZ twinning possibly affect participant selection for the research studies?
2. Are there differences in congenital anomalies for twins versus singleton deliveries?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Twins, Triples and Multiple Births

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Dawson AL, Tinker SC, Jamieson DJ, Hobbs CA, Rasmussen SA, Reefhuis J; National Birth Defects Prevention Study. Epidemiology of twinning in the National Birth Defects Prevention Study, 1997 to 2007. Birth Defects Res A Clin Mol Teratol. 2015 Feb;103(2):85-99.

Boothroyd C. Twinning: Double, double, toil and trouble? Aust N Z J Obstet Gynaecol. 2016 Oct;56(5):445-446.

Mbarek H, Steinberg S, Nyholt DR, et.al. Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Am J Hum Genet. 2016 May 5;98(5):898-908.

Rhea SA, Corley RP, Heath AC, Iacono WG, Neale MC, Hewitt JK.
Higher Rates of DZ Twinning in a Twenty-First Century Birth Cohort.
Behav Genet. 2017 Jul 15. (ePub ahead of publication).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

Publishing Our 600th Case Today

This week we are publishing our 600th Case for PediatricEducation.org!

We started in September 2004 to write a case of the week and it is amazing to see how all the information adds up.

We cannot have done it without you our patrons, so we thank you for all of your feedback and support. A very special, thank you to each of you.

Donna M. D’Alessandro, M.D. and Michael P. D’Alessandro, M.D.
Curators, PediatricEducation.org

What Proteins Cause Cow’s Milk Protein Allergy?

Patient Presentation
A 5-month-old female came to clinic because of blood in her stool x 2 the evening before. The blood was mixed in with soft, pudding-like, yellow, fecal material that was not malodorous. The mother said there was no mucous in the stool. She had another stool in the morning that did not have blood in it. The mother did not think there had been any change in the stool color, consistency or frequency over the past few days. The mother described no hard stools. The infant was acting normal with multiple wet diapers and a good appetite. She was exclusively breast fed except that the mother had started some rice cereal about 2 weeks previously without any problems. She had traveled to her grandparents farm 2 weeks previously but had been well as had everyone else who had been there. The past medical history was negative for eczema or rashes, breathing problems, or any gastrointestinal problems. She had an upper respiratory infection at age 3 months when she started child care. She was fully immunized. The review of systems was negative for nausea, emesis, rashes, urticaria, breathing problems, rhinorrhea or fever. There also was no other bleeding or bruising noted.

The pertinent physical exam showed a smiling infant with normal vital signs. Her weight was 25% and length was 50% and tracking along her growth curves. She had no rashes including no diaper rash. Her abdomen was soft, non-tender without organomegaly or masses. Her anus was patent without fissures. A rectal examination found normal tone with a small amount of yellow stool in the vault without obvious blood. The stool was guaiac positive.

The diagnosis of a well-appearing infant with a history of blood in her stool was made. The pediatrician considered that the cause of the blood could be an internal fissure, infection, or allergic cow’s milk protein colitis. She discussed with the mother about these possibilities and they agreed to monitor the infant. The mother was given some guaiac cards to test stools that had any signs of blood, or if she wasn’t seeing blood to test a couple of random stools. “She hasn’t had other signs of allergy before, and eliminating cow’s milk protein from your diet can be hard and I’m not sure at this time we need to do that. I think we can safely watch her and if it continues then we can think about if you would need to stop cow’s milk in your diet,” she counseled. The patient’s clinical course over the next 2 weeks, showed 1 stool that was guaiac positive one day after the visit, and 4 other stools that were negative after that time. No stools had frank blood in them and the infant continued to do well.

Discussion
Cow’s milk protein allergy (CMPA) is one of the most common food allergies. It is estimated to have an incidence of 2-7.5% in infants and a prevalence of 0.5% in breastfeed infants. The prevalence decreases with age at 1% in children > or = 6 years.
CMPA does not have a laboratory test and therefore is a clinical diagnosis. It is defined as a “hypersensitivity reaction brought on by specific immunologic mechanisms to cow’s milk.” Generally symptoms present within the first month of life and involve 2 of more systems with 2 or more symptoms. Systems are dermatologic (including atopic dermatitis, urticaria, oral pruritis), respiratory (including asthma, stridor, wheezing, rhinoconjunctivitis) and gastrointestinal (including emesis, diarrhea, constipation, malabsorption, gastroestophageal reflux disease) and other symptoms may include colic, irritability, failure to thrive or food aversion. IgE-mediated CMPA (Type 1 hypersensitivity reaction, ~50% of children) has symptoms that occur within minutes to 2 hours of ingestion of the CMP. Non-IgE mediated CMPA (Type 4 delayed hypersensitivity reaction) has symptoms that occur 4 or more hours (even up to 1 week) after exposure to CMP.

Allergic colitis can have blood mixed into stools that are usually non-foul smelling, mucousy or foamy. Blood can be hematochezia or melanotic or insidious. The mechanism for rectal bleeding is felt to be ulceration of thinned mucosa that is stretched over enlarged hyperplastic submucosal lymphatic tissue of the colon.

If the infant is suspected of having IgE mediated CMPA, then a specific blood IgE level or skin prick test in a clinical setting is often used to aid diagnoses. If positive, then CMP should be eliminated from the infant’s diet, or if the mother is breastfeeding, the mother’s diet. If the testing is negative, then a food challenge in a clinical setting can help. Usually CMP is eliminated from the diet for 12-18 months and then the patient is rechallenged in a clinical setting. If the patient still has reactivity, the elimination diet is continued for another 6-12 months and the patient again is rechallenged.

If non-IgE mediated CMPA is suspected, testing is not done, but elimination diets are implemented for 2-8 weeks and the patient should improve if CMPA is truly the cause of the symptoms. If with reintroduction of CMP, the symptoms reoccur then CMPA is assumed to be the cause, and the elimination diet is continued for 6 months (infant age 9-12 months). At that time, an oral food challenge can be tried at home. If the patient continues to react, then the diet is continued for another 6-12 months and again rechallenged. Patients with allergic colitis generally have cessation of frank blood by 3 weeks after the elimination diet is begun but occult blood can be detected until 6-12 weeks. Bleeding after 12 weeks is an indication for referral to a specialist as other causes of bleeding must be reconsidered and potentially other investigations such as sigmoidoscopy are indicated.

For formula fed infants, extensively hydrolyzed formula or an amino acid formula are usually used for elimination diets as there is a high rate of cross reactivity with soy. Plant protein juices (e.g. almond milk, rice milk, coconut) are not recommended as they are inadequate nutritionally for infants. Other mammalian milks (e.g. sheep, goat, etc.) are also not recommended as they are not nutritionally adequate and have an ~80% cross-reactivity rate. Other foods such as beef, veal, eggs, fish and wheat should not be avoided unless there is a documented specific allergy to the specific food. For breast-feeding mothers it can be difficult to follow a completely CMP-free diet, as CMP is used in many foods either as a major or minor component, and also as a binding or stabilizing agent in food manufacturing. Mothers following this diet need to have Vitamin D (400 IU) and calcium (1000 mg/day) supplementation.

Tolerance to CMP is developed over time in most patients. By age 5, 80-90% of children develop tolerance.

Learning Point
The causative proteins in CMPA differ by exposure. For infants and children drinking milk or cow’s milk based formulas the causative protein are thought to be casein or whey. For exclusively breast-fed infants, β-lactoglobulin in the breast milk 4-6 hours after maternal consumption of milk is thought to be the causative protein.

Questions for Further Discussion
1. How do you counsel breastfeeding mothers to do a CMP elimination diet?
2. What are indications for referral to an allergist or gastroenterologist for potential CMPA?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Food Allergy and Gastrointestinal Bleeding.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Vandenplas Y, Marchand J, Meyns L. Symptoms, Diagnosis, and Treatment of Cow’s Milk Allergy. Curr Pediatr Rev. 2015;11(4):293-7.

Nowak-Wegrzyn A, Katz Y, Mehr SS, Koletzko S. Non-IgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol. 2015 May;135(5):1114-24.

Martín-Munoz MF, Pineda F, Garcia Parrado G, Guillen D, Rivero D, Belver T, Quirce S. Food allergy in breastfeeding babies. Hidden allergens in human milk. Eur Ann Allergy Clin Immunol. 2016 Jul;48(4):123-8.

Mousan G, Kamat D. Cow’s Milk Protein Allergy.
Clin Pediatr (Phila). 2016 Oct;55(11):1054-63.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What is Internet Gaming Disorder?

Patient Presentation
A 15-year-old male came to clinic for his health maintenance examination. He was doing well, but his mother complained that he was spending more and more time playing computer games. She said that she had been able to curb some of the use because he was in school, but over the summer break he was unsupervised during the day when she was working. He said that he was spending time online with friends playing networked games. He didn’t see a problem with it as long as he had done whatever tasks his mother had asked him to do that day. He did say that he actually was spending more time playing games than he had previously told his mother – up to 8 hours or more/day. He still did his other activities including bike riding, swimming, soccer and doing some pleasure reading. He denied any problems with eating, sleeping or mood. He said that he could cut down or stop whenever he wanted but his mother wasn’t sure about this. The pertinent physical exam showed normal vital signs and growth parameters in the 75-90% and tracking. He was Tanner IV.

The diagnosis of a healthy male with increased online gaming and Internet use that was beginning to affect his life. The pediatrician voiced concern about the amount of screen time. He recommended that the teenager only have 2 hours/day which was met with great distress by the teenager. He complained, “but there will be nothing to do.” The physician talked about other activities the teen could pursue. His mother said that she thought it would get a little better once school started but she was still worried. The physician counseled that the problem of Internet and gaming use was increasing. He noted that the computer use was already causing some conflict at home and if the parent felt that it was affecting the teenager in other activities in daily life or he was having a problem stopping the gaming then counseling to help with the behavior was recommended. The mother thought that counseling would be good as she felt she was having other communication issues with her son. The teen did not want to go to counseling, but after he seemed to not be able to control the computer use when school started, he and his mother began in individual and family counseling.

Discussion
Computers are a part of most people’s daily lives. They are used for finance, transportation, communication, healthcare, business, manufacturing, utilities, construction and just about everywhere else. They offer incredible work saving, monitoring, data collection and storage applications that improve people’s lives.

In the past few years these incredible pieces of technology have taken a logarithmic advance in their capabilities and also use by the common person for more and more daily activities as a brief review of the history of computers shows:

  • Pre-19th Century – abacus, slide rule, Antikythera mechanism
  • 1833 – First mechanical computer developed by Charles Babbage
  • 1930s-70 – Massive computers in a large centralized locations for mainly government or business operations
    • 1930s – First electromagnetic computers – mainly vacuum tubes
    • 1936 – Turing machine developed by Alan Turing
    • 1955 – Computers with transistors
    • 1957 – Computers with integrated circuits
    • 1967 – ARPANET – first early packet switching network – the basic infrastructure of the Internet
  • 1970s-80s – Personal computers mainly for stationary use at home or work by individuals
    • 1973 – Xerox Alto which had a graphic user interface
    • 1975 – Internet protocol developed (TCP/IP) – method to do higher speed packet switching for networking
    • 1976 – First Apple® 1 developed by Steve Wozniak and Steve Jobs
    • 1977 – Commodore® PET = first successful mass marketed computer –
    • 1977 – Apple II introduced
    • 1980’s – Laptop computers
    • 1989 – Tim Berners Lee develops the World Wide Web (sometimes also referred to as the Internet)
  • 1990s-Present – Mobile Computers for non-stationary use by individuals
    • 1993 – Apple Newton – personal digital assistant
    • 1996 – Palm Pilot® – personal digital assistant with handwriting recognition
    • 1999 – SmartPhones released for mass market in Japan
    • 2008 – Apple App store and Google Play® (app store) opens fueling mobile revolution

  • Present to Near Future – Integrated computing – computers ubiquitously integrated into products for home, business, goverment that send/receive data and are networked with the potential for self-regulation or human interaction.

Notice that over time, the time periods are much shorter, and computers become smaller and are much less expensive. Today, smartphones are considered such a low cost product that they are given even to toddlers and infants to play with. With any technology there is an upside and a downside. Heat keeps us warm, and cooks our food giving us improved bodily comfort and nutrition, but if not controlled it can burn or cause fires. Computer technology is similar. There are great advantages but without controls it can cause hazards to our physical and mental health. Smartphones and other mobile or integrated computer devices are so prevalant today that there is an expectation that all persons have access to them and the computer networks they connect to at all times. Again this can be wonderful for everyone to have these tools, but that also means that people are expected to use them during a significant portion of their day (i.e. use the Internet all the time). This can lead to problems when people feel they cannot stop using them and have problem Internet use or behaviors similar to addiction.

Learning Point
Although gambling disorder is the only behavioral addiction (as opposed to a substance addiction) in the DSM-5, Internet gaming disorder (IGD) is included as an emerging disorder needing further study. IGD is defined as “Persistent and recurrent use of the Internet to engage in games, often with other players, leading to clinically significant impairment or distress.” (DSM-5 2013).
In a review of research publications from 1998-2016, the overall prevalence of IGD was 0.7-15.6% with an average of 4.7% across the years. There was one paper in 1998, none between 1999-2006 and then an overall steady trend. This study also found that “Internet gaming disorder, …, affects a small subset of the population exposed to online games, and does not appear to have increased in prevalence to the extent the [I]nternet usage has increased.”

Data shows “[s]ignificant overlap in the neurobiology underlying both [gaming and Internet] addictions and substance use disorders have been found in animal models and human brain imaging studies.” People with IGD can have similar symptoms to people with substance abuse disorders including building tolerance for the activity (i.e. needing more) and having withdrawal symptoms.

Another study of the addictive potential for the Internet in adolescent (12-19 years) generalized Internet users (GIU) and Internet gamers (IG) found that gaming had the strongest addictive potential in boys followed by social networking and chatting (β= 0.29, 0.19, and 0.17 respectively). For girls, chatting and social networking had the strongest addictive potential followed by gaming (β= 0.24, 0.23, and 0.14 respectively). Other activities evaluated included gambling, sexual content, shopping, emailing and researching information. Overall problematic IG had more psychosocial problems including high psychosocial burden and dysfunctional coping strategies, than non-problematic IG.

IGD and high levels of Internet use are being recognized as public health problems and the World Health Organization and various countries are evaluating or making policies to try to assist their citizens. First there is a necessary increased recognition of the actual problem by individuals, governments and agencies. Types of intervention include educational programs including school-based, online education, workshops, and public health messaging, and technical interventions (mandatory blocking/shutdown of device or software, censoring of software) including legislation of such interventions. Some of the education focuses on what is healthy use, creating appropriate environments physically (e.g. device-free bedrooms) and online (e.g. age appropriate applications). Selective prevention could include restricted hours of Internet availabliity (e.g. not during school or later in evening/night), limit setting software, and alternative to Internet use (e.g. use a wrist watch to check time instead of phone). Some people may need more intervention including group or individual counseling or rehabilitation. An overview of prevention strategies for hazardous Internet use can be found here ).

Questions for Further Discussion
1. What other recommendations do you offer for healthy computer/device use and how do those change in different ages?
2. What musculoskeletal problems can be caused by computer use and how can they be prevented?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Internet Safety and Compulsive Gambling.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Computer History Articles. Wikipedia.


Feng W, Ramo DE, Chan SR, Bourgeois JA. Internet gaming disorder: Trends in prevalence 1998-2016. Addict Behav. 2017 Jun 16;75:17-24.

Rosenkranz T, Muller KW, Dreier M, Beutel ME, Wolfling K.
Addictive Potential of Internet Applications and Differential Correlates of Problematic Use in Internet Gamers versus Generalized Internet Users in a Representative Sample of Adolescents. Eur Addict Res. 2017;23(3):148-156.

King DL, Delfabbro PH, Doh YY, Wu AMS, Kuss DJ, Pallesen S, Mentzoni R, Carragher N, Sakuma H. Policy and Prevention Approaches for Disordered and Hazardous Gaming and Internet Use: an International Perspective.
Prev Sci. 2017 Jul 4. doi: 10.1007/s11121-017-0813-1.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa