Hypothyroidism in pregnant women

Hypothyroidism during pregnancy is a clinical syndrome caused by a long-term, persistent deficiency of thyroid hormones in the body or a decrease in their biological effect at the tissue level.

Pregnancy is a period that places great physiological stress on both the mother and the fetus. When pregnancy is complicated by endocrine disorders such as hypothyroidism, the potential for adverse effects on the mother and fetus can be enormous.

Women with hypothyroidism have decreased fertility; even if they become pregnant, the risk of abortion is increased, and the risk of gestational hypertension, anemia, placental abruption, and postpartum hemorrhage is increased.[ 1 ] The risk of these complications is higher in women with overt rather than subclinical hypothyroidism.

Epidemiology

In regions with mild iodine deficiency, pregnancy is a fairly strong factor in stimulating the thyroid gland. Thyroid function is stimulated during gestation by increasing the degree of binding of thyroid hormones to blood proteins, increasing the level of human chorionic gonadotropin (hCG), which has a weak "thyrotropic" effect, insufficient supply of iodine to the mother's thyroid gland due to increased excretion of iodine in the urine during pregnancy and iodine consumption by the fetoplacental complex, as well as increased placental deiodination of thyroxine (T4). All of the above mechanisms are of an adaptive physiological nature and, in the presence of a sufficient amount of iodine, lead to the fact that the production of thyroid hormones in the first half of pregnancy increases by 30-50%. Reduced iodine intake during pregnancy leads to chronic stimulation of the thyroid gland, relative gestational hypothyroxinemia (an increase in T4 production of only 15–20%) and the formation of goiter, both in the mother and the fetus.

The incidence of newly diagnosed hypothyroidism during pregnancy (according to various sources) ranges from 2 to 5%. The prevalence of thyroid peroxidase antibodies in the population of pregnant women is 5–14%. The prevalence of thyroid antibodies (even with normal initial function and structure of the thyroid gland) during pregnancy is accompanied by an increased risk of spontaneous abortion in the early stages, manifestation of hypothyroidism, and development of postpartum thyroiditis.

In this regard, according to modern recommendations, all women living in iodine deficiency zones, at 8–12 weeks of pregnancy (and optimally at the pregnancy planning stage), need to determine the level of thyroid stimulating hormone (TSH), free T4 and antibodies to thyroid peroxidase in the blood serum.

The prevalence of hypothyroidism during pregnancy is estimated to be 0.3–0.5% for overt hypothyroidism and 2–3% for subclinical hypothyroidism.[ 2 ]

Causes hypothyroidism in pregnant women

Autoimmune thyroiditis is the most common cause of hypothyroidism during pregnancy. Other causes include radioiodine ablation of the thyroid gland for the treatment of hyperthyroidism or thyroid cancer, surgery for thyroid tumors, and, less commonly, central hypothyroidism, including ectopic thyroid glands, and drugs such as rifampin and phenytoin, which accelerate thyroid metabolism. However, iodine deficiency remains one of the leading causes of hypothyroidism, both overt and subclinical, worldwide.

Symptoms hypothyroidism in pregnant women

Hypothyroidism during pregnancy is usually asymptomatic, especially in the subclinical form. Signs and symptoms suggestive of hypothyroidism include inadequate weight gain, cold intolerance, dry skin, and delayed relaxation of deep tendon reflexes. Other symptoms such as constipation, fatigue, and lethargy are commonly associated with pregnancy.

Subclinical hypothyroidism

Subclinical hypothyroidism is defined as elevated TSH with normal FT4 and FT3 concentrations. The prevalence of subclinical hypothyroidism during pregnancy is estimated to be 2–5%.[ 3 ] It is almost always asymptomatic. Women with subclinical hypothyroidism are more likely than euthyroid women to be positive for TPO antibodies (31% vs. 5%).[ 4 ] The etiology is similar to that of overt hypothyroidism. Because numerous studies have shown that subclinical hypothyroidism is associated with adverse maternal and fetal outcomes, most guidelines recommend thyroxine replacement therapy in women with subclinical hypothyroidism. However, although thyroxine treatment has been shown to improve obstetric outcomes, it has not been shown to alter long-term neurologic development of the offspring.

Forms

A distinction is made between primary hypothyroidism, caused by a decrease in the amount of functioning thyroid tissue, and central hypothyroidism (pituitary and hypothalamic).

The danger of hypothyroidism for the mother and fetus

Inadequate treatment of maternal hypothyroidism can lead to pregnancy complications such as spontaneous miscarriages (19.8%), early toxicosis (33%), threatened termination of pregnancy at various stages of gestation (62%), iron deficiency anemia (66%), gestosis (11.2%), fetoplacental insufficiency (70%), placental abruption (5%), intrauterine fetal death (2–7%), and postpartum hemorrhage (4.2%).

In the fetus, transplacental passage of maternal thyroxine in early pregnancy may play a critical role in normal brain development. Thus, we observed manifestations of perinatal encephalopathy in 19.8% of children. The frequency of ante- and intranatal hypoxia and asphyxia among this contingent of newborns was 19.6%, hypotrophy - 13.7%. Even when born healthy, 50% of children from mothers with insufficiently well-compensated hypothyroidism may have impaired puberty, decreased intellectual function, and high morbidity. In children born to mothers with increased levels of antibodies to thyroid peroxidase, even with normal thyroid function, the risk of mental retardation increases.

Complications and consequences

Untreated maternal hypothyroidism can lead to preterm birth, low birth weight, and respiratory failure in the newborn.

A number of studies by Man et al., [ 5 ] Haddow et al., [ 6 ] and more recent studies by Rowett et al. and Pop et al., [ 7 ] have provided convincing evidence that children born to mothers with hypothyroidism had a significantly increased risk of impairment in IQ, neurodevelopmental performance, and learning abilities. Children born to untreated women with hypothyroidism had an IQ that was 7 points lower than the average IQ of children born to healthy women and to women receiving thyroxine supplements. This risk applies not only to children born to untreated women but also to women receiving suboptimal supplements. The study by Rowett et al. showed that these children had mild deficits in general intelligence, but visual-spatial abilities, language, fine motor skills, and preschool abilities were unaffected. This study highlights the need for adequate follow-up of women after initiation of treatment.

Children born to iodine-deficient mothers fared even worse: the average global IQ deficit was over 10 points, and many also had attention deficit hyperactivity disorder.[ 8 ]

Diagnostics hypothyroidism in pregnant women

In subclinical primary hypothyroidism, an isolated increase in the concentration of thyroid-stimulating hormone is detected with a normal content of free T4; in manifest primary hypothyroidism, a combination of an increased level of TSH and a decreased concentration of free T4 is detected. In secondary hypothyroidism, the content of both TSH and T4 is reduced.

In almost 90% of cases, the cause of spontaneous hypothyroidism is autoimmune thyroiditis. The basis for the diagnosis of autoimmune thyroiditis, according to the recommendations of the Russian Association of Endocrinologists (2002), is considered to be the following "major" clinical and laboratory signs.

• Primary hypothyroidism (manifest or persistent subclinical).
• The presence of antibodies to thyroid tissue and ultrasound signs of autoimmune pathology (increased volume in the hypertrophic form, diffuse decrease or increase in echogenicity and heterogeneity of thyroid tissue). Antithyroid antibodies ( antibodies to thyroglobulin, antibodies to thyroid peroxidase) are determined in autoimmune thyroiditis in 80-90% of cases, and, as a rule, in very high titers. Among antibodies to thyroid tissue, antibodies to thyroid peroxidase are of fundamental importance in the diagnosis of autoimmune disease, since isolated carriage of antibodies to thyroglobulin is extremely rare and has less clinical and diagnostic significance.

In the absence of at least one of these diagnostic signs, the diagnosis of autoimmune thyroiditis is probabilistic.

If thyroid antibodies and/or ultrasound signs of autoimmune thyroiditis are detected in women planning pregnancy in the absence of hypothyroidism, it is necessary to examine thyroid function (concentrations of TSH and free T4 in the blood) before conception and to monitor it in each trimester of pregnancy. If hypothyroidism (manifest or subclinical) is detected, sodium levothyroxine therapy is immediately prescribed.

Dynamic monitoring of a pregnant woman with hypothyroidism

• In the compensated state of hypothyroidism, the frequency of observation by an endocrinologist is once every 8–12 weeks, and by an obstetrician-gynecologist – according to the standards.
• Prenatal diagnostics of the fetus's condition is performed during genetic screening: ultrasound at 10-14 weeks to assess the fetal anatomy and the condition of the chorion with measurement of the nuchal translucency thickness to form a risk group for congenital malformations and chromosomal pathology; at 22-24 weeks to assess the fetal anatomy, the condition of the placenta and the amount of amniotic fluid in order to identify congenital malformations and markers (absolute and relative) of chromosomal pathology in the fetus; at 34 weeks to assess the anatomy and degree of fetal development, to identify congenital malformations in the fetus with their late detection. At 16-20 weeks, blood samples from the mother are taken to test at least two serum markers: α-fetoprotein (AFP) and hCG. Invasive diagnostics of the fetus's condition (aminocentesis, cordocentesis, chorionic biopsy) is performed according to indications after consultation with a geneticist).
• Starting from the 20th week, Doppler ultrasound examination of blood flow in the umbilical artery, aorta and middle cerebral artery of the fetus is performed. The frequency of ultrasound examination is once every 4 weeks.
• From the 12th week of pregnancy, once a month - a study of fetoplacental complex hormones (placental lactogen, progesterone, estriol, cortisol) and AFP. The assessment of the results obtained should be dynamic, comprehensive, using a percentile assessment of all five parameters.
• Starting from the 26th week of pregnancy, a cardiotocographic study is indicated with an objective assessment of uterine motility indicators and fetal heart rate (HR).

Treatment hypothyroidism in pregnant women

Treatment of hypothyroidism during pregnancy is reduced to the prescription of replacement therapy with thyroid hormones (levothyroxine sodium), and immediately after the onset of pregnancy, the dose of levothyroxine sodium is increased by approximately 50 mcg/day.

In case of hypothyroidism first detected during pregnancy (both manifest and subclinical) or in case of decompensation of previously existing hypothyroidism, the full replacement dose of sodium levothyroxine is prescribed immediately, i.e. without a gradual increase.

Levothyroxine sodium should be taken on an empty stomach 30-40 minutes before meals. Considering that some medications can significantly reduce the bioavailability of levothyroxine sodium (e.g. calcium carbonate, iron preparations), taking any other medications should be postponed, if possible, for 4 hours after taking levothyroxine sodium.

Studies of TSH and free T4 concentrations during the intake of sodium levothyroxine are performed every 8–12 weeks. The TSH content changes very slowly when thyroid hormones are prescribed, therefore, during pregnancy, the final selection of the dose of sodium levothyroxine is performed based on the concentration of free T4 in the blood serum, which should be closer to the upper limit of the laboratory norm.

When determining the free T4 content in pregnant women on replacement therapy with sodium levothyroxine, the drug should not be taken before blood is taken for hormonal analysis, since in this case the test results may be somewhat overestimated. When only TSH is being tested, taking sodium levothyroxine will not affect the test results in any way.

The dose of levothyroxine sodium is gradually increased throughout the gestation process, and by the end of pregnancy it is increased by 30–50%.

There is no reason to refuse the mandatory intake of prophylactic physiological (200 mcg/day potassium iodide) doses of iodine for all pregnant women living in iodine-deficient regions (patients with autoimmune thyroiditis and isolated carriage of antibodies to the thyroid gland are no exception).

Treatment of threatened miscarriage

Treatment is carried out according to generally accepted schemes. Preparations from the group of β-adrenomimetics (fenoterol, hexoprinaline) are not contraindicated in the treatment of threatened miscarriage in patients with hypothyroidism.

Prevention and treatment of fetoplacental insufficiency

Taking into account the high risk of developing fetoplacental insufficiency in patients with hypothyroidism, it is advisable to use a metabolic therapy complex for 21 days in the second and third trimesters of pregnancy for prophylactic purposes.

When clinical and laboratory signs of fetoplacental insufficiency appear, treatment is carried out in an obstetric hospital. Complex treatment of fetoplacental insufficiency includes infusions of vasoactive, metabolic and metabolic-improving drugs.

Heparin inhalations

In the treatment of fetoplacental insufficiency in pregnant women with thyroid diseases, it is advisable to use sodium heparin inhalations. The advantages of the method include the absence of coagulation (bleeding, thrombocytopenia, "rebound" symptom) and injection (hematomas, necrosis, abscesses) complications, the possibility of its long-term use and the absence of the need for strict coagulation control during therapy.

Indications:

• primary fetoplacental insufficiency;
• decompensated form of fetoplacental insufficiency;
• prevention of gestosis;
• the presence of mild to moderate gestosis.

Considering the impermeability of the placental barrier for sodium heparin, its use is possible at any stage of gestation. Contraindications:

• established hemostasis defect (hemophilia);
• decrease in prothrombin content to less than 50%;
• thrombocytopenia below 100 g/l;
• hypofibrinogenemia less than 1 g/l. Dosage

For the prevention of gestosis: daily dose - 250-300 U/kg, course duration - 5-7 days, number of courses - 2-3, intervals between courses - 2 days.

For the treatment of fetoplacental insufficiency and gestosis: daily dose - 500–700 U/kg, course duration - 21–28 days, number of courses - 1–2, intervals between courses - 2–3 weeks.

Inhalations are carried out 2 times a day with an interval of 12 hours.

To treat anemia in pregnant women with hypothyroidism, a combination of iron, folic acid and B vitamins is necessary, since hypothyroidism reduces the acidity of gastric juice and, under conditions of achlorhydria, the absorption of the above vitamins and microelements decreases. The recommended drug is iron sulfate + folic acid + cyanocobalamin (Ferro-Folgamma), 1 capsule 3 times a day, after meals. The course duration is 4 weeks.

Indications for hospitalization

• In case of a severe threat of termination of pregnancy, hospitalization in an obstetric hospital is indicated for therapy aimed at prolonging the pregnancy.
• If signs of fetoplacental insufficiency are detected, hospitalization at any stage of gestation for examination and treatment.
• At 37–38 weeks – hospitalization for careful monitoring of the fetus, treatment of obstetric complications and selection of the optimal time and method of delivery.

Selection of the dose of levothyroxine sodium in the absence of gestational complications does not require inpatient treatment and is possible on an outpatient basis.

Management of labor in patients with hypothyroidism

The course of labor in hypothyroidism is often complicated by untimely rupture of amniotic fluid, a pathological preliminary period, fetal hypoxia, and postpartum hemorrhage.

To prevent possible abnormalities of labor in this category of patients, it is advisable to carry out programmed labor when the body is absolutely biologically ready for labor:

• if necessary, provide therapeutic obstetric anesthesia during childbirth and provide adequate pain relief;
• In case of untimely discharge of amniotic fluid, use drugs from the prostaglandin group or oxytocin to induce labor; if weakness of labor is detected, use oxytocin in a timely manner to induce labor in adequate dosages.

According to our data, the frequency of postpartum hemorrhage in patients with hypothyroidism is 4.2% (with an average population rate of 0.5%). Almost every 10th patient with hypothyroidism has a complicated course of the placental and early postpartum period. In this regard, the prevention of hemorrhage in this category of pregnant women is of particular importance (labor management with the connection of an infusion system, adequate pain relief, timely administration of uterotonic drugs).

Lactation

Lactation is not contraindicated for patients with hypothyroidism. After delivery, the dose of levothyroxine sodium should be reduced to the initial dose. In the presence of full lactation, the need for levothyroxine sodium may increase by an average of 20%.

In the postpartum period, women carrying antibodies to the thyroid gland may develop postpartum thyroiditis. After an optional phase of destructive hyperthyroidism, which occurs as painless asymptomatic thyroiditis (1-4th month of the postpartum period), in approximately 23% of cases a phase of persistent hypothyroidism occurs (5-7th month of the postpartum period). In this case, replacement therapy with sodium levothyroxine is prescribed according to the usual scheme.

Prevention

Considering the fact that the early stages of embryogenesis (up to 12 weeks) are controlled only by maternal thyroid hormones, hypothyroidism compensation should be carried out at the pregravid preparation stage. Compensated hypothyroidism is not a contraindication to pregnancy planning.

At the pregravid stage, the free T4 content in the blood serum is determined, and the dose of sodium levothyroxine is adjusted. It is believed that adequate compensation for hypothyroidism at the pregnancy planning stage corresponds to a TSH concentration of 0.4–2.0 mIU/l and a free thyroxine (T4) concentration closer to the upper limit of the norm.

Women with decompensated hypothyroidism often experience menstrual cycle disorders of varying severity (most often, hypoluteinism), which can lead to a risk of early termination of pregnancy and the development of primary fetoplacental insufficiency (FPI) when pregnancy occurs. In addition, hyperprolactinemia is detected in approximately 40% of patients with primary hypothyroidism. Adequate replacement therapy with sodium levothyroxine normalizes prolactin secretion in most cases.

Considering the high frequency of congenital malformations of the fetus (CMF) in newborns from mothers with hypothyroidism (according to our data - 10.3%), in the periconceptional period (optimally 2-3 months before conception) and up to 12 weeks of pregnancy, the use of multivitamin preparations with a high content of folic acid (0.8-1.0 mg) or tableted folic acid 1 mg/day is indicated.

Forecast

The prognosis for hypothyroidism is favorable. If hypothyroidism is first detected during pregnancy (especially subclinical), thyroxine may be discontinued in the postpartum period with subsequent revision of the diagnosis.

1. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41–6.
2. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid. 2002;12:63–6.
3. Man EB, Jones WS, Holden RH, Mellits ED. Thyroid function in human pregnancy, 8, Retardation of progeny aged 7 years: Relationships to maternal age and maternal thyroid function. Am J Obstet Gynecol. 1971;111:905–16.
4. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341:549–55.
5. Rovet JF. Neurodevelopmental consequences of maternal hypothyroidism during pregnancy (abstract 88; annual Meeting of the American Thyroid Association) Thyroid. 2004;14:710.
6. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149–55.
7. Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: A possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab. 2004;89:6054–60.
8. Woeber K.A. Subclinical thyroid dysfunction. Arch Intern Med. 1997;157:1065–8.
9. Jayme JJ, Ladenson PW. Subclinical thyroid dysfunction in the elderly. Trends Endocrinol Metab. 1994;5:79–86.