Two metabolic disorders that affect embryonic develop-ment or fertility are covered here: phenyl ketonuria (PKU) and celiac disease.
Phenylketonuria (PKU)
Phenylketonuria (also called hyperphenylalaninemia) is the most frequently inherited disorder of amino-acid meta bolism and one of the few preventable causes of mental retardation. It oc-curs in roughly 1 in 10,000 individuals.76
insulin stimulate the ovaries to produce androgens (such as testosterone), and excess androgens disrupt develop-ment of follicles.71 High blood levels of androgens also lead to excess hair growth on the face and other parts of the body, while high insulin levels raise triglyceride and lower HDL-cholesterol levels.72
PCOS appears to have a genetic component, and its development is influenced by environment-gene inter-actions. It tends to run in families where females have a history of infertility, menstrual problems, type 2 diabetes, central obesity, and hirusutism. Inutero exposures that affect fetal gene programming may be a factor in its de-velopment. Although obesity does not cause PCOS, it ex-acerbates reproductive and metabolic problems associated with it. Rates of PCOS in teens and women increase with increasing rates of overweight and obesity in females.62 Women with PCOS are at increased risk of spontaneous abortions, gestational and type 2 diabetes, hypertension, and cardiovascular disease.73
Nutritional Management of Women with PCOS
“Many women with PCOS have their symptoms ignored for years and have never received the proper diagnosis and treatment. She may have been told ‘just lose weight!’ and admonished when she found that very hard to do.”
Martha McKittrick, RD, CDN, CDE75
The primary goal in the treatment of PCOS is to increase in-sulin sensitivity. A number of inin-sulin-sensitizing drugs, such as metformin and rosiglitazone, can be used to lower blood insulin levels and reduce the excess production of andro-gens by the ovaries.83 Other drugs may be used to stimu-late ovulation. The preferred first-line treatment for women with PCOS, however, is dietory modification, weight loss and exercise.83 Weight los s and exercise improve insulin sensitivity, benefit blood lipids and insulin levels, and lower
Table 3.4 Variation in clinical signs associated with PCOS69,72,74
Clinical Sign
Percent of Women with PCOS Affected
Menstrual irregularities 90%
Polycystic ovaries 67–86%
Excess abdominal fat 80%
Insulin resistance 80%
Overweight, obesity 80%
Abnormal facial and body hair 70%
High testosterone levels 70%
Infertility 70%
Low HDL-cholesterol levels 64%
High triglycerides 47%
Phenylketonuria (PKU) An inherited error in phenylalanine metabolism most commonly caused by a deficiency of phenyl-alanine hydroxylase, which converts the essential amino acid phenylalanine to the nonessential amino acid tyrosine. Also called hyperphenylalaninemia.
Celiac Disease An autoimmune disease that causes malabsorption due to an inherited sensitivity to the gliadin portion of gluten in wheat, rye, and barley. It is often responsible for iron, folate, zinc, and other deficiencies.
Also called celiac sprue and nontropical sprue.
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protein make them light-headed and easily confused. They may find it difficult to comprehend all the information they receive after the inborn error is diagnosed.81
Maternal PKU Twenty-five years ago, it was thought that children with PKU could safely go off the PKU diet after the brain developed. Later it was made abundantly clear that PKU diets are for life. Elevated phenylalanine levels continue to impair mental functions and health long after the growing years.79 Women who go off the PKU diet after childhood and become pregnant are at risk for a condition called “maternal PKU.”
Uncontrolled PKU in women represents risks for the fetus during pregnancy, even in fetuses that did not inherit the disorder. The extent of the harm caused to the fetus increases with increased maternal phenylalanine levels.
Adverse effect on the fetus can be minimized if maternal phenylalanine levels are well controlled from the beginning of pregnancy and energy and nutrient needs of the mother are met.76,79
In the 1960s, the United States adopted newborn screening programs that test infants for a variety of genetic disorders including PKU.79 States track individu-als testing positive for PKU to ensure they are provided with medical and nutrition services and prescription low-phenylalanine formulas and are made aware of the potential adverse effects of uncontrolled PKU through-out pregnancy. Not all women are able to follow the diet, however, because it is expensive and unpalatable to them, while others may get confused and have trouble staying on the diet.79
Alternatives to diet therapy for PKU management are being developed and tested. In the future, it is likely that PKU will be managed largely by techniques such as cell transplantation or gene therapy.80
Phenylketonuria derives its name from the characteris-tic presence of phenylalanine in the urine of people with this condition. PKU is an inherited problem that causes elevation in blood phenylalanine levels due to very low levels or lack of the enzyme phenyl alanine hydroxylase.
Lack of this enzyme diminishes the conversion of the es-sential amino acid phenyl alanine to tyrosine, a nonessen-tial amino acid, and causes phenylalanine to accumulate in blood.
If pres ent during early pregnancy, high levels of phenylalanine accumulate in the embryo and fetus and impair normal central nervous system development. El-evated phenylalanine levels in the first 8 weeks of preg-nancy increase the risk of heart defects. The risk increases if high blood levels of phenylalanine are combined with low-protein diets early in pregnancy.85 Untreated women with PKU have a 92% chance of delivering a newborn with mental retardation, and a 73% chance that the infant will be born with an abnormally small head (microcephaly).86,87
Infants born to women with high blood levels of phenylalanine during pregnancy are at elevated risk of seizures, hyperactivity, and abnormal behavioral patterns later in life.76
Not all infants born to a parent with PKU inherit the disorder, and some infants inherit it from parents who do not have PKU. It is important that infants born with PKU be identified and started on low-phenylalanine for-mula as soon after birth as possible. Table 3.5 presents a brief case study of the journey of a woman born with PKU that was identified late and inadequately controlled.
Individuals born with PKU who adhere to an adequate, low-phenylalanine diet during childhood and later in life tend to develop normally or at levels that are somewhat below normal (Illustration 3.1).78
People with undiagnosed PKU may self-select low-protein foods because meat and other rich sources of
Illustration 3.1 You can’t pick a person with well-controlled PKU out of a crowd.
Table 3.5 One Person’s PKU Experience
Margaret was a healthy newborn but during her first year of life she started to experience seizures and difficulty in standing and walking. When she was 13 months old she was diagnosed with PKU and started on a low-phenylalanine diet. Her development improved until the age of 8 years when she was taken off the diet. It was reasoned that she no longer needed the low-phenylalanine diet because “her brain had grown.” Around the age of 19 Margaret became violent, destructive, hysterical, and self-abusive. Her family put her back on the PKU diet and although she continued to have seizures and remain profoundly retarded, her behaviors and quality of life improved.77
Andi Berger, 2009/Used under license from Shutterstock.com
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Nutritional Management of Celiac Disease
Treatment of celiac disease centers on the goals of elimi-nation of gluten from the diet, correction of vitamin and mineral deficiences, and the long-term maintenance of health. The cornerstone of treatment—elimination of gluten—can be challenging. Gluten is found in a variety of nongrain foods, including hot dogs, deli meats, some vitamin and mineral supplements, flavored potato chips, bouillon, and salad dressing. Table 3.7 lists foods that contain gluten and others that do not. An example of a gluten-free one-day diet for an adult with celiac disease is shown in Table 3.8.
People with celiac disease are generally avid food-label readers and eventually become skilled at selecting gluten-free foods. In 2008, the Food and Drug Admin-istration started allowing gluten-free foods to be labeled
“gluten-free” if they qualify according to a standard definition.93
Many different food-product labels announce “gluten-free,” “without gluten,” and “no gluten,” but there are no federal inspections in place to guarantee that food so labeled actually qualifies as gluten-free. The Gluten-Free Certifica-tion OrganizaCertifica-tion tests food products for gluten content and certifies them with a
GF mark (Illustration 3.2) if found to contain less than 10 ppm, or 3 mg, gluten per serving. Reliable Internet re-sources for people with celiac disease are listed at the end of this chapter.
Nutritional Management of PKU
PKU can be successfully managed by a low-phenylalanine diet, instituted and monitored with the help of an expe-rienced registered dietitian. PKU diets are individual-ized based on blood phenylalanine response to protein foods. Successful PKU diets maintain blood concentra-tions of phenylalanine in the range of 120–360 μmol/L (2–6 mg/dL).79 High phenylalanine protein foods such as meat, fish, eggs, and wheat are excluded from the diet. Protein needs are met primarily though con-sumption of high-protein, low-phenylalanine formu-las and other formulated products. The formulated products are generally fortified with tyrosine, vitamins, and minerals. Vegetables, fruits, fats, sugars and high-carbohydrate foods, and phenylalanine-free breads, flour, and pasta are included in the diet. Milk is allowed if needed to maintain a minimal blood phenylalanine level.76
The PKU diet should be followed throughout life, but it is critical that it be adhered to prior to conception and maintained throughout pregnancy. It usually takes about 4 to 6 months to learn and implement the PKU diet and to lower blood phenylalanine levels.81
Celiac Disease
Celiac disease, highlighted in the “In Focus” box on page 84 is related to somewhat higher rates of infertility and to substantially higher rates of subfertility.88 In males, untreated celiac disease is related to alterations in the actions of androgens, delayed sexual maturation, and hypogonadism. Hypogonadism is marked by a defi-ciency of sex hormones and poor development and func-tioning of the reproductive system. In females, untreated celiac disease is associated with amenorrhea, increased rates of miscarriage, fetal growth restriction, low birth-weight deliveries, and a short duration of lactation. It is hypothesized that the effects of celiac disease on re-productive functions in males and females is related to malabsorption-induced deficiencies of nutrients such as vitamins A, E, and D; folate; and iron,89 and direct ef-fects of inflammation on intestinal and other tissues.90 Table 3.6 lists vitamin and mineral deficiencies and other health consequences of untreated celiac disease.
Normal reproductive functions return after celiac dis-ease has been stabilized with a nutritionally adequate gluten-free diet.89,90
Not all individuals with celiac disease have overt symptoms, so it may be missed as a underlying cause of infertility. It should be considered in unexplained cases of infertility, early pregnacy loss, and poor pregnancy out-comes.91 Case Study 3.2 describes the experience of a woman ultimately diagnosed with celiac disease.
Table 3.6 Vitamin and mineral deficiencies and other health consequences that may occur in people with untreated celiac disease83,92
Vitamin Deficiencies
Other Potential Health Problems Folate Lactose maldigestion,
intolerance Vitamin B12 Weight loss
Vitamin A Anemia
Vitamin D Osteoporosis
Vitamin E Subfertility
Vitamin K Growth failure (in children and adolescents) Irritable bowel disease Mineral Deficiencies
Calcium Iron
Gluten-free A food labeling term that indicates a product does not contain any species of wheat, rye, barley, or their hybrids, or ingredients that contain these grains, or 20 or more parts per million (ppm) gluten (about 6 mg per serving). (FDA proposed definition.83)
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Evidence-Based Nutrition Practice Guidelines for Celiac Disease Evidence-based nutrition practice guide-lines and the Nutrition Care Process for celiac disease have been recently developed by the American Dietetic Associa-tion.99 Major components of nutrition care services and the Nutrition Care Process are highlighted in Table 3.9. Moni-toring individuals for abnormalities in nutritional status that may impact reproductive outcomes is an important part of the Nutrition Care Process for celiac disease.