Dietary Iodine Sufficiency and Moderate Insufficiency in the Lactating Mother and Nursing Infant: A Computational Perspective

Abstract

The Institute of Medicine recommends that lactating women ingest 290 μg iodide/d and a nursing infant, less than two years of age, 110 μg/d. The World Health Organization, United Nations Children's Fund, and International Council for the Control of Iodine Deficiency Disorders recommend population maternal and infant urinary iodide concentrations ≥ 100 μg/L to ensure iodide sufficiency. For breast milk, researchers have proposed an iodide concentration range of 150-180 μg/L indicates iodide sufficiency for the mother and infant, however no national or international guidelines exist for breast milk iodine concentration. For the first time, a lactating woman and nursing infant biologically based model, from delivery to 90 days postpartum, was constructed to predict maternal and infant urinary iodide concentration, breast milk iodide concentration, the amount of iodide transferred in breast milk to the nursing infant each day and maternal and infant serum thyroid hormone kinetics. The maternal and infant models each consisted of three sub-models, iodide, thyroxine (T4), and triiodothyronine (T3). Using our model to simulate a maternal intake of 290 μg iodide/d, the average daily amount of iodide ingested by the nursing infant, after 4 days of life, gradually increased from 50 to 101 μg/day over 90 days postpartum. The predicted average lactating mother and infant urinary iodide concentrations were both in excess of 100 μg/L and the predicted average breast milk iodide concentration, 157 μg/L. The predicted serum thyroid hormones (T4, free T4 (fT4), and T3) in both the nursing infant and lactating mother were indicative of euthyroidism. The model was calibrated using serum thyroid hormone concentrations for lactating women from the United States and was successful in predicting serum T4 and fT4 levels (within a factor of two) for lactating women in other countries. T3 levels were adequately predicted. Infant serum thyroid hormone levels were adequately predicted for most data. For moderate iodide deficient conditions, where dietary iodide intake may range from 50 to 150 μg/d for the lactating mother, the model satisfactorily described the iodide measurements, although with some variation, in urine and breast milk. Predictions of serum thyroid hormones in moderately iodide deficient lactating women (50 μg/d) and nursing infants did not closely agree with mean reported serum thyroid hormone levels, however, predictions were usually within a factor of two. Excellent agreement between prediction and observation was obtained for a recent moderate iodide deficiency study in lactating women. Measurements included iodide levels in urine of infant and mother, iodide in breast milk, and serum thyroid hormone levels in infant and mother. A maternal iodide intake of 50 μg/d resulted in a predicted 29-32% reduction in serum T4 and fT4 in nursing infants, however the reduced serum levels of T4 and fT4 were within most of the published reference intervals for infant. This biologically based model is an important first step at integrating the rapid changes that occur in the thyroid system of the nursing newborn in order to predict adverse outcomes from exposure to thyroid acting chemicals, drugs, radioactive materials or iodine deficiency.

Fig 1. Schematic of the biologically based lactating mother and nursing infant model for thyroid hormone homeostasis from infant birth to 90 days postpartum.

The lactating mother iodide sub-model consists of five compartments, two of which are subdivided (thyroid and mammary glands) and in the nursing infant three compartments comprise the iodide sub-model, of which one compartment is subdivided (thyroid gland). The thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) in the lactating mother and the nursing infant are represented using apparent volumes of distribution. Elemental iodine is ingested from food for the lactating mother and from breast milk for the nursing infant. The sodium iodide symporter protein (NIS) actively transports iodide into the thyroid gland of the lactating mother and infant and mother’s breast milk (bold arrows) and is excreted into urine. Thyroid hormones are produced in the thyroid gland and secreted into its volume of distribution (dashed lines). Maternal and infant T4 is metabolized (deiodination, major pathway) to T3 and rT3, and excreted into urine (minor pathway) and breast milk (minor maternal pathway) or conjugated and excreted in feces. Maternal and infant T3 is metabolized (deiodination, major pathway), and excreted in feces and breast milk (minor maternal pathway). Urinary excretion of T3 in the infant and mother, a minor pathway, is not described because of a lack of kinetic data. Iodide released from metabolism of thyroid hormones is recycled into the iodide sub-model and represents an important functional aspect of the HPT axis for maintaining iodide balance. For the infant, important age-dependent functional aspects of the HPT axis are described in the model (see Methods).

Fig 2. Model calibration predictions are for maternal intake of 250 μg/d iodide, divided equally among three meals per day and an infant nursing eight times during the day.

(A) Measured concentrations (μg/L) of iodide in breast milk (●) from individual lactating women [16] in Boston, MA USA and reported mean and median values from lactating women (Day 60, ■) representing a wide range of postpartum days [35]. A larger maternal dose of 400 μg/d of iodide is shown representing possible ingestion of supplemental iodine (e.g., vitamins). The daily peak and trough shape of the breast milk concentrations represent the mother’s schedule for daily dietary intake of iodide over a 12 hr period. (B) Measured concentrations (μg/L) of maternal urinary iodide (■) from individual lactating women [16] in the Boston, MA USA. Model calibrated prediction of urinary iodide concentration for maternal dietary iodide intake of 250 μg/d with accompanying prediction for 400 μg/d maternal dietary iodide. (C) Measured concentrations (μg/L) of iodide in infant urine (■) from individual nursing infants [16] in Boston, MA, USA. Model calibrated prediction of nursing infant urinary iodide concentration for maternal intake of 250 μg/d of iodide and accompanying prediction for 400 μg/d maternal dietary iodide.

Fig 3. Model evaluation for iodide assuming maternal dietary iodide intake of 250 and 400 μg/d.

(A) Measured concentrations (μg/L) of iodide in maternal urine (■) from individual lactating women [24] in the United States (250 μg/d, lower line and 400 μg/d, upper line). (B) Measured concentrations (μg/L) of urinary iodide from individual nursing infants (■) [58] over 90 days postpartum and another 43 nursing infants [18] shown as an average age of 63 days (■).

Fig 4. Measured maternal serum T4, fT4, and T3 concentrations (nmol/L) in 16 lactating women (■) residing in the United States [24].

Solid lines represent model calibrated predictions for serum thyroid hormones assuming a maternal iodide intake of 250 μg/d. Simulations performed for maternal dietary intake of 400 μg/d resulted in very slight increases of serum thyroid hormones.

Fig 5. Model calibration (Fig 5A) and model evaluation (Fig 5B) of infant serum thyroid hormones.

(A) Model calibrated predictions of nursing infant serum thyroid hormones, assuming a maternal dietary iodide intake of 250 μg/d and using reference intervals (2.5, 50, and 97.5%) for infant serum T4, fT4, and T3 concentrations [23]. Infant serum thyroid hormone concentration predictions for a maternal intake of 400 μg/d were identical to a maternal intake of 250 μg/d of iodide. (B) Measured and simulated infant serum T4, fT4, and T3 concentrations assuming a maternal intake of 250 or 400 μg/d of iodide. Verberg et al. [60] reported reference intervals (2.5, 50, and 97.5%) for fT4 only in infants from Germany on 7, 14, 21, 28 and 90 days of age (▲). Elmlinger et al. [59] reported reference intervals (2.5, 50, and 97.5%) for 8–15 days of age for infants from Germany and are shown as 15 days of age (■). Franklin et al. [61] from New Zealand reported mean ±SD infant serum T4, fT4, and T3 concentrations on days 5 (n = 40), 10 (n = 35), and 15 (n = 33) (■). Williams et al. [62] from the United Kingdom reported mean ±SD infant serum T4, fT4, and T3 concentrations on days 7 (n = 163), 14 (n = 6), and 28 (n = 9).

Fig 6. Model predictions of moderate iodide deficiency assuming a maternal dietary iodide intake of 150 μg/d.

Costeira et al. [63] measured iodide in breast milk and maternal and infant urine (median and 25 and 75% interquartiles) and later reported maternal serum thyroid hormones [64]. (A) Maternal urinary iodide concentrations. (B) Breast milk iodide concentrations. (C) Nursing infant urinary iodide concentrations. (D) Maternal serum thyroid hormone concentrations.

Fig 7. Model predictions of moderate iodide deficiency assuming a dietary iodide intake of 50 μg/d.

Mulrine et al. [69] measured iodide in breast milk and maternal and infant urine of an iodide deficient population from New Zealand (mean ±SD). (A) Maternal urine. (B) Breast milk. (C) Infant urine.