Definitions for the quality of the evidence based on the United States Preventative Services Task Force [USPSTF] levels (good, fair, and poor) and Grading of Recommendations Assessment, Development and Evaluation [GRADE] levels (+OOO, ++OO, +++O, and ++++) and the strength of the recommendation (USPSTF: A, B, C, D, I and GRADE: 1 or 2) are provided at the end of the "Major Recommendations" field.
Hypothyroidism and Pregnancy: Maternal and Fetal Aspects
Both maternal and fetal hypothyroidism are known to have serious adverse effects on the fetus. Therefore maternal hypothyroidism should be avoided. For overt hypothyroidism (OH), The United States Preventive Service Task Force (USPSTF) recommendation level is A; evidence is fair. Targeted case finding is recommended at the first prenatal visit. The USPSTF recommendation level is B; evidence is fair (GRADE 2 | ++OO) (Abalovich et al., 2002; Klein et al., 1991; Haddow et al., 1999; Glinoer et al., 1994).
If hypothyroidism has been diagnosed before pregnancy, the guideline panel recommends adjustment of the preconception thyroxine dose to reach before pregnancy a thyroid-stimulating hormone (TSH) level not higher than 2.5 mIU/liter. The USPSTF recommendation level is I; evidence is poor (GRADE 2 | +OOO) (Demers & Spencer, 2002; Baloch et al., 2003; Panesar, Li, & Rogers, 2001).
The thyroxine dose often needs to be incremented by 4 to 6 weeks gestation and may require a 30 to 50% increment in dosage. The USPSTF recommendation level is A; evidence is good (GRADE 1 | +++O) (Mandel et al., 1990; Kaplan, 1992).
If OH is diagnosed during pregnancy, thyroid function tests should be normalized as rapidly as possible. Thyroxine dosage should be titrated to rapidly reach and thereafter maintain serum TSH concentrations of less than 2.5 mI/liter in the first trimester (or 3 mIU/liter in second and third trimesters) or to trimester-specific normal TSH ranges. Thyroid function tests should be remeasured within 30 to 40 days. The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++) (Soldin et al., 2004; Sapin, D'Herbomez, & Schlienger, 2004; Panesar, Li, & Rogers, 2001).
Women with thyroid autoimmunity (TAI) who are euthyroid in the early stages of pregnancy are at risk of developing hypothyroidism and should be monitored for elevation of TSH above the normal range. The USPSTF recommendation level is A; evidence is fair (GRADE 1 | +++O) (Alexander et al., 2004; Glinoer et al., 1994).
Subclinical hypothyroidism (SCH) (serum TSH concentration above the upper limit of the reference range with a normal free T4) has been shown to be associated with an adverse outcome for both the mother and offspring. Thyroxine treatment has been shown to improve obstetrical outcome, but has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks, the panel recommends thyroxine replacement in women with subclinical hypothyroidism. For obstetrical outcome, the USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO); for neurological outcome, the USPSTF recommendation level is I; evidence is poor (OOOO) (Abalovich et al., 2002; Leung et al., 1993; Casey et al., 2005; Glinoer, 1997).
After delivery, most hypothyroid women need to decrease the thyroxine dosage they received during pregnancy. The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++) (Caixas et al., 1999).
Management of Maternal Hyperthyroidism: Maternal Aspects
If a subnormal serum TSH concentration is detected during gestation, hyperthyroidism must be distinguished from both normal physiology of pregnancy and hyperemesis gravidarum because of the adverse effects of OH on the mother and fetus. Differentiation of Graves' disease from gestational thyrotoxicosis is supported by presence of clinical evidence of autoimmunity, a typical goiter, and presence of TSH-receptor antibodies (TRAb). The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++) (Mestman, 2004; Goodwin, Montoro, & Mestman, 1992; Tan et al., 2002; Davis et al., 1989; Millar et al., 1994).
For OH due to Graves' disease or thyroid nodules, antithyroid drug (ATD) therapy should be either initiated (for those with new diagnoses) or adjusted (for those with a prior history) to maintain the maternal thyroid hormone levels for free T4 in the upper nonpregnant reference range. The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++) (Momotani et al., 1986; Mortimer et al., 1990).
Because available evidence suggests that methimazole (MMI) may be associated with congenital anomalies, propylthiouracil (PTU) should be used as a first-line drug, if available, especially during first-trimester organogenesis. MMI may be prescribed if propylthiouracil is not available, or if a patient cannot tolerate or has an adverse response to propylthiouracil. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO) (Mandel, Brent, & Larsen, 1994; Martinez-Frias et al., 1992; Clementi et al., 1999; Johnsson, Larsson, & Ljunggren, 1997; Di Gianantonio et al., 2001; Greenberg, 1987; Wilson et al., 1998).
Subtotal thyroidectomy may be indicated during pregnancy as therapy for maternal Graves' disease if 1) a patient has a severe adverse reaction to ATD therapy, 2) persistently high doses of ATD are required, or 3) a patient is nonadherent to ATD therapy and has uncontrolled hyperthyroidism. The optimal timing of surgery is in the second trimester. The USPSTF recommendation level is I; evidence is poor (+OOO) (Stice et al., 1984; Burrow, 1985; Brodsky et al., 1980).
There is no evidence that treatment of subclinical hyperthyroidism improves pregnancy outcome, and treatment could potentially adversely affect fetal outcome. The USPSTF recommendation level is I; evidence is poor (+OOO) (Goodwin, Montoro, & Mestman, 1992; Tan et al., 2002; Casey et al., 2006; Momotani et al., 1986).
Management of Maternal Hyperthyroidism: Fetal Aspects
Because thyroid receptor antibodies (thyroid receptor stimulating, binding, or inhibiting antibodies) freely cross the placenta and can stimulate the fetal thyroid, these antibodies should be measured by the end of the second trimester in mothers with current Graves' disease or with a history of Graves' disease and treatment with 131-I or thyroidectomy before pregnancy, or with a previous neonate with Graves' disease. Women who have a negative TSH-receptor antibodies (TRAb) and do not require ATD have a very low risk of fetal or neonatal thyroid dysfunction. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | +++O) (Nachum et al., 2003; Peleg et al., 2002; McKenzie & Zakarija, 1992; Laurberg et al., 1998; Luton et al., 2005).
131-I should not be given to a woman who is or may be pregnant. If inadvertently treated, the patient should be promptly informed of the radiation danger to the fetus, including thyroid destruction if treated after the 12th week of gestation. The USPSTF recommendation level is A; evidence is good (GRADE 1 | +OOO). There are no data for or against recommending termination of pregnancy after 131-I exposure. The USPSTF recommendation level is I; evidence is poor (+OOO) (Zanzonico, 1997; Berg et al., 1998; Lowe, 2004; Bydder et al., 2005; Gorman, 1999).
In women with elevated TRAb or in women treated with ATD, fetal ultrasound should be performed to look for evidence of fetal thyroid dysfunction, which could include growth restriction, hydrops, presence of goiter, advanced bone age, or cardiac failure. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | +++O) (Nachum et al., 2003; McKenzie & Zakarija, 1992; Laurberg et al., 1998; Mitsuda et al., 1992; Luton et al., 2005).
Umbilical blood sampling should be considered only if the diagnosis of fetal thyroid disease is not reasonably certain from the clinical data and the information gained would change the treatment. The USPSTF recommendation level is B; evidence is fair (GRADE 2 | +OOO) (Davidson et al., 1991; Nachum et al., 2003; Porreco & Bloch, 1990; Wenstrom et al., 1990; Cohen et al., 2003; Fisher, 1997; Polak et al., 1997; Wallace, Couch, & Ginsberg, 1995; Luton et al., 2005; Van Kamp et al., 2005; Polak et al., 2004).
All newborns of mothers with Graves' disease should be evaluated by a medical care provider for thyroid dysfunction and treated if necessary. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | +++O) (McKenzie & Zakarija, 1992, Mitsuda et al., 1992; Luton et al., 2005).
Gestational Hyperemesis and Hyperthyroidism
Thyroid function tests should be measured in all patients with hyperemesis gravidarum (5% weight loss, dehydration, and ketonuria). The USPSTF recommendation level is B; evidence is poor (GRADE 2 | +OOO) (Goodwin, Montoro, & Mestman, 1992; Tan et al., 2002; Goodwin et al., 1992; Lazarus, 2005).
Few women with hyperemesis gravidarum will require ATD treatment. The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++). Overt hyperthyroidism believed to be due to coincident Graves' disease should be treated with ATDs. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO). Gestational hyperthyroidism with clearly elevated thyroid hormone levels (free T4 above the reference range or total T4 >150% of top normal pregnancy value and TSH <0.1 microU/ml) and evidence of hyperthyroidism may require treatment as long as clinically necessary. The USPSTF recommendation level is I; evidence is poor (+OOO) (Goodwin, Montoro, & Mestman, 1992; Tan et al., 2002; Goodwin et al., 1992; Lazarus, 2005).
Autoimmune Thyroid Disease and Miscarriage
Although a positive association exists between the presence of thyroid antibodies and pregnancy loss, universal screening for antithyroid antibodies, and possible treatment, cannot be recommended at this time. As of this date, only one adequately designed intervention trial has demonstrated a decrease in the miscarriage rate in thyroid antibody-positive euthyroid women. The USPSTF recommendation level is C; evidence is fair (GRADE | +OOO) (Stagnaro-Green et al., 1990; De Carolis et al., 2004; Sher et al., 1998).
Thyroid Nodules and Cancer
Fine needle aspiration (FNA) cytology should be performed for single or dominant thyroid nodules larger than 1 cm discovered in pregnancy. Ultrasound guided FNA may have an advantage for minimizing inadequate sampling. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | +++O) (Kung et al., 2002; Mazzaferri & Jhiang, 1994; Moosa & Mazzaferri, 1997; Vini et al., 1999).
When nodules are discovered in the first or early second trimester to be malignant on cytopathological analysis or exhibit rapid growth, pregnancy should not be interrupted but surgery should be offered in the second trimester, before fetal viability. Women found to have cytology indicative of papillary cancer or follicular neoplasm without evidence of advanced disease, who prefer to wait until the postpartum period for definitive surgery, may be reassured that most well-differentiated thyroid cancers are slow growing and that surgical treatment soon after delivery is unlikely to change prognosis. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO) (Mazzaferri & Jhiang, 1994; Moosa & Mazzaferri, 1997; Vini et al., 1999; Herzon et al., 1994).
It is appropriate to administer thyroid hormone to achieve a suppressed but detectable TSH in pregnant women with a previously treated thyroid cancer, or a FNA positive for or suspicious for cancer, and those who elect to delay surgical treatment until postpartum. High-risk patients may benefit more from a greater degree of TSH suppression compared with low-risk patients. The free T4 or total T4 levels should ideally not be increased above the normal range for pregnancy. The USPSTF recommendation level is I; evidence is poor (+OOO) (Rosen, Korman, & Walfish, 1997).
Radioactive iodine (RAI) with 131-I should not be given to women who are breast-feeding. The USPSTF recommendation level is B; evidence is fair. Furthermore, pregnancy should be avoided for 6 months to 1 year in women with thyroid cancer who receive therapeutic RAI doses to ensure stability of thyroid function, and confirm remission of thyroid cancer. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO) (Choe & McDougall, 1994; Schlumberger et al., 1995; Chow et al., 2004).
Iodine Nutrition during Pregnancy
Women in the childbearing age should have an average iodine intake of 150 micrograms/day. During pregnancy and breast-feeding, women should increase their daily iodine intake to 250 micrograms on average. The USPSTF recommendation level A; evidence is good (GRADE 1| +++O) (Glinoer, 2001; Glinoer, 2003; World Health Organization, 2005; Hollowell et al., 1998).
Iodine intake during pregnancy and breastfeeding should not exceed twice the daily recommended nutrient intake (RNI) for iodine (i.e. 500 micrograms iodine/day). The USPSTF recommendation level is I; evidence is poor (+OOO) (Glinoer, 2001; Glinoer, 2003; World Health Organization, 2005; Hollowell et al., 1998).
To assess the adequacy of the iodine intake during pregnancy in a population, urinary iodine concentration (UIC) should be measured in a representative cohort of the population. UIC should ideally range between 150 and 250 micrograms/liter. The USPSTF recommendation level A; evidence is good (GRADE 1 | ++++) (Delange, 2004).
To reach the daily RNI for iodine, multiple means must be considered, tailored to the iodine intake level in a given population. Different situations must therefore be distinguished: 1) countries with iodine sufficiency and/or with a well-established universal salt iodinization (USI) program, 2) countries without a USI program or with an established USI program where the coverage is known to be only partial, and 3) remote areas with no accessible USI program and difficult socioeconomic conditions. The USPSTF recommendation level is A; evidence is good (GRADE 1 | ++++) (Glinoer et al., 1995; Chaouki & Benmiloud, 1994; Liesenkotter et al., 1996; Nohr & Laurberg, 2000; Romano et al., 1991).
Postpartum Thyroiditis
There are insufficient data to recommend screening of all women for postpartum thyroiditis (PPT). The USPSTF recommendation level is I; evidence is poor (+OOO) (Stagnaro-Green, 2002; Muller, Drexhage, & Berghout, 2001).
Women known to be thyroid peroxidase antibody (TPO-Ab)-positive should have a TSH performed at 3 and 6 months postpartum. The USPSTF recommendation level is A; evidence is good (GRADE 1 | +++O) (Stagnaro-Green, 2002; Premawardhana et al., 2004).
The prevalence of PPT in women with type 1 diabetes mellitus (DM) is 3-fold greater than in the general population. Postpartum screening (TSH determination) is recommended for women with type 1 DM at 3 and 6 months postpartum. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO) (McCanlies et al., 1998; Alvarez-Marfany et al., 1994; Gerstein, 1993).
Women with a history of PPT have a markedly increased risk of developing permanent primary hypothyroidism in the 5-to 10-year period following the episode of PPT. An annual TSH level should be performed in these women. The USPSTF recommendation level is A; evidence is good (GRADE 1 | +++O) (Azizi, 2005; Othman et al., 1990; Premawardhana et al., 2000; Tachi et al., 1988).
Asymptomatic women with PPT who have a TSH above the reference range but less than 10 U/ml and who are not planning a subsequent pregnancy do not necessarily require intervention, but should, if untreated, be remonitored in 4 to 8 weeks. Symptomatic women and women with a TSH above normal and who are attempting pregnancy should be treated with levothyroxine. The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO) (Stagnaro-Green, 2002).
There is insufficient evidence to conclude whether an association exists between postpartum depression (PPD) and either PPT or thyroid antibody positivity (in women who did not develop PPT). The USPSTF recommendation level is I; evidence is poor (Kuijpens et al., 1998; Lucas et al., 2000; Cox, Murray, & Chapman, 1993; Stamp & Crowther, 1994; Harris et al., 1992; Pop et al., 1993). However, as hypothyroidism is a potentially reversible cause of depression, women with postpartum depression should be screened for hypothyroidism and appropriately treated. The USPSTF recommendation level is B; evidence is fair (GRADE 2 | ++OO) (Cleare et al., 1996).
Screening for Thyroid Dysfunction during Pregnancy
Although the benefits of universal screening for hypothyroidism may not be justified by current evidence, as presented in Sections 1 to 7 in the original guideline document, we recommend case finding among the following groups of women at high risk for thyroid dysfunction:
- Women with a history of hyperthyroid or hypothyroid disease, PPT, or thyroid lobectomy
- Women with a family history of thyroid disease
- Women with a goiter
- Women with thyroid antibodies (when known)
- Women with symptoms or clinical signs suggestive of thyroid underfunction or overfunction, including anemia, elevated cholesterol, and hyponatremia
- Women with type I diabetes
- Women with other autoimmune disorders
- Women with infertility should have screening with TSH as part of their infertility work-up
- Women with prior therapeutic head or neck irradiation
- Women with a prior history of miscarriage or preterm delivery
The USPSTF recommendation level is B; evidence is fair (GRADE 1 | ++OO).
Definitions:
Strength of Evidence
The United States Preventive Services Task Force (USPSTF) grades the overall evidence for a service on a three-point scale (good, fair, or poor):
Good: Evidence includes consistent results from well designed, well conducted studies in representative populations that directly assess effects on health outcomes.
Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes.
Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.
Strength of Recommendation
A: The USPSTF strongly recommends that clinicians provide (the service) to eligible patients. The USPSTF found good evidence that (the service) improves important health outcomes and concludes that benefits substantially outweigh harms.
B: The USPSTF recommends that clinicians provide (the service) to eligible patients. The USPSTF found at least fair evidence that (the service) improves important health outcomes and concludes that benefits outweigh harms.
C: The USPSTF makes no recommendation for or against routine provision of (the service). The USPSTF found at least fair evidence that (the service) can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation.
D: The USPSTF recommends against routinely providing (the service) to asymptomatic patients. The USPSTF found good evidence that (the service) is ineffective or that harms outweigh benefits.
I: The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing (the service). Evidence that (the service) is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined.
Evidence Level by GRADE System
High: ++++ or +++O
Moderate: ++OO
Low: +OOO
Very Low: OOOO
Recommendation Level by GRADE System
1: Strong
2: Moderate
