Adequate Levothyroxine Doses for the Treatment of Hypothyroidism Newly Discovered During Pregnancy

Abstract

Background:

Recent guidelines recommend thyrotropin (TSH) target levels of ≤2.5 mIU/L for the first trimester and ≤3 mIU/L for the subsequent trimesters. Euthyroidism should be attained as soon as possible, but there are no precise indications about the initial levothyrorine (LT4) dose. The aim of our study was to determine the appropriate LT4 doses in order to normalize TSH levels in patients with newly discovered subclinical hypothyroidism (SCH) during pregnancy, and to correlate them with basal TSH levels. The adequate LT4 doses for women with SCH were also compared to those required in pregnant women with overt hypothyroidism (OH).

Methods:

Seventy-seven patients with newly diagnosed hypothyroidism during pregnancy were retrospectively analyzed. Patients were assigned to group 1 (n=64) with SCH or group 2 (n=13) with OH. SCH patients were subdivided into two groups: group 1a serum TSH >2.5 (1st trimester) or >3 (2nd or 3rd trimester) to 4.2 mIU/L; and group 1b TSH level >4.21–10 mIU/L. All patients were treated with LT4 as soon as hypothyroidism was diagnosed. The dose that allowed a TSH of ≤2.5 mIU/L to be reached in the first trimester or one that allowed a TSH of ≤3 mIU/L to be reached during the second and third trimesters was considered the appropriate one.

Results:

A significant difference (p<0.0001) in the appropriate LT4 dose (mean±SD, μg/kg/day) was observed between group 1 and group 2: 1.31±0.36 versus 2.33±0.59. Patients in group 1a required a significantly lower LT4 dose (p<0.014) than group1b: 1.20±0.39 versus 1.42±0.31 μg/kg/day. In 57 of the 64 (89.06%) women with SCH and in 10/13 (76.92%) women with OH, the appropriate LT4 dose coincided with the initial dose. Only 11% and 23% respectively required additional adjustments. Once the appropriate dose of LT4 was prescribed, the time at which euthyroidism (mean±SD, weeks) was confirmed was similar in patients with SCH (6.06±3.3) and OH (5.3±1.8). There were no miscarriages or premature deliveries.

Conclusions:

When hypothyroidism is newly discovered during pregnancy, we suggest initiating the treatment with the following LT4 doses: 1.20 μg/kg/day for SCH with TSH ≤4.2 mIU/L, 1.42 μg/kg/day with TSH >4.2–10, and 2.33 μg/kg/day for OH. By taking this approach, patients will promptly attain the euthyroid state avoiding additional increments and, probably, obstetric risks.

Introduction

T hough less frequent than overt hypothyroidism (OH), subclinical hypothyroidism (SCH) during pregnancy has been associated with adverse events such as miscarriage (1 –4), prematurity (5,6), gestational hypertension (5,7), placental abruption (6), as well as intellectual impairment in the offspring (8 –10). On the other hand, some authors have not found that SCH causes alterations or adverse effects either in pregnancy (11) or offspring (12,13).

The recommended treatment for maternal hypothyroidism consists in the oral administration of levothyroxine (LT4). Although still debated, LT4 therapy in women with SCH has been shown to improve the outcome of pregnancies (1,14). Therefore, when SCH has been diagnosed during pregnancy, LT4 treatment has been recommended for thyrotropin (TSH) levels >2.5 mIU/L because of potential benefits (15), especially in patients with positive thyroid peroxidase autoantibodies (TPOAbs) (16).

Euthyroidism should be reached as soon as possible to prevent pregnancy complications. Hence, it is very important to identify the adequate LT4 dose rapidly. Suggested doses vary and are usually based on expert opinion. There is scarce information about the recommended initial LT4 dose for the treatment of newly diagnosed SCH during pregnancy (17).

The aim of our study was to determine the appropriate dose in μg/day and μg/kg/day LT4 doses to normalize TSH levels in patients with newly discovered SCH during pregnancy, and to correlate these doses to basal TSH levels. Adequate LT4 doses for women with SCH were also compared with those required in pregnant women with OH.

Patients and Methods

We reviewed 361 medical records of pregnant women with hypothyroidism evaluated in our institution from November 2008 to December 2011.

Among them, 77 patients between 18 and 45 years old with newly discovered hypothyroidism during pregnancy were included. Women with LT4 treatment before pregnancy were excluded. Patients were assigned to two groups: 64 with SCH (group 1) and 13 with OH (group 2). SCH was defined as a serum TSH level >2.5 mIU/L (1st trimester) or >3 mIU/L (2nd and 3rd trimesters) but <10 mIU/L with normal serum free T4 (FT4). OH was defined as a TSH level >2.5 mIU/L (1st trimester) or 3 mIU/L (2nd and 3rd trimesters) with decreased FT4 concentration or TSH >10 mIU/L irrespective of the FT4 levels (16).

SCH patients were subdivided into two groups: group 1a with serum TSH >2.5 mIU/L (or 3) to 4.2 mIU/L (the normal upper limit provided by the manufacturer), and group 1b with serum TSH >4.2–10 mIU/L.

All patients were treated with LT4 as soon as hypothyroidism was diagnosed during pregnancy, and they were monitored every 4–6 weeks. LT4 dose was considered adequate when a serum TSH of ≤2.5 mIU/L was reached in the first trimester, or levels ≤3 mIU/L during the remaining time of pregnancy were reached (16). The patient's body weight at the moment of prescribing the optimal dose was taken into account in order to establish the appropriate dose per kg/day.

Serum TSH and FT4 were measured by Immulite 2000 chemiluminometric assay (Siemens Healthcare Diagnostics, Deerfield, IL). Venous blood samples were drawn between 7 a.m. and 8 a.m. The reference range for nonpregnant women was TSH 0.5–4.2 mIU/L and FT4 0.8–1.8 ng/dL.

Results are reported as mean±standard deviation (SD). Significant differences in distribution were calculated using Student's t-test (two-tailed) for unpaired variables and nonparametric Mann–Whitney U-test. Statistical significance was considered to be p<0.05.

This study was approved by the Ethics Committee of the C.G. Durand Hospital, Buenos Aires.

Results

In 33 out of 64 patients with SCH and in 12 out of 13 with OH, Hashimoto's thyroiditis was diagnosed by positive TPOAbs in 41 cases and by ultrasound abnormalities in the remaining four cases. In 43.3% of the patients included in group 1a, and in 48.4% of those in group 1b, positive TPOAbs were found (p=n.s.). In 34 out of 75 women (45%), thyroid autoantibodies were negative (33 SCH and 1 OH), and in two patients, thyroid autoantibodies were not determined. Of the 33 patients with negative TPOAbs, 17 were diagnosed in the second trimester and five in the third trimester. There were no patients with hypothyroidism secondary to ¹³¹I or surgical treatment. One patient with SCH was treated with amiodarone until pregnancy. Two patients with Graves' disease, one with OH and one with SCH, had discontinued the antithyroid drugs 14 and 108 months before pregnancy, respectively.

At the moment when the LT4 dose was prescribed, there was no significant difference in body weight between the groups (mean±SD, kg: group 1=66.9±13.4; group 1a=65.7±12.9; group 1b=68.1±14; group 2=64.1±12.7).

The adequate LT4 doses in μg/day and μg/kg/day in pregnant women with SCH and OH are shown in Table 1. A significant difference was observed in the appropriate LT4 dose (mean±SD, μg/day and μg/kg/day) for women with SCH (86.94±25.21 and 1.31±0.36, respectively) compared to the adequate dose for patients with OH (147.08±29.83 and 2.33±0.59, respectively). Moreover, group 1a women required a LT4 dose (mean±SD μg/kg/day) that was significantly lower (p<0.014) than the one required by group 1b patients (1.20±0.39 vs. 1.42±0.31 μg/kg/day, respectively).

Table 1.

Adequate Levothyroxine Doses (μg/Day and μg/kg/Day) in Pregnant Women with Newly Diagnosed Subclinical Hypothyroidism and Overt Hypothyroidism

			LT4 dose
	Basal TSH (mIU/L)	TSH on LT4 (mIU/L)	μg/day	μg/kg/day
Group 1a (n=31)	3.56±0.39	1.42±0.55	77.98±27.56^a	1.20±0.39^b
Group 1b (n=33)	5.43±1.32	1.51±0.87	95.35±19.71^a	1.42±0.31^b
Group 1 (1a+1b) (n=64)	4.52±1.36	1.47±0.72	86.94±25.21^c	1.31±0.36^d
Group 2 (n=13)	40.33±28.66	1.14±0.79	147.08±29.83^c	2.33±0.59^d

Groups: 1a, TSH >2.5 (or 3) to 4.2 mIU/L; 1b, TSH >4.2–10 mIU/L; 1, subclinical hypothyroidism; 2, overt hypothyroidism.

p<0.005; ^b p<0.014; ^c p<0.0001; ^d p<0.0001.

TSH, thyrotropin; LT4, levothyroxine.

There were no significant differences between the adequate μg/kg/day doses in different trimesters of pregnancy: SCH, first trimester 1.40±0.30, second trimester 1.30±0.41, and third trimester 1.27±0.33 (p=not significant [n.s.]); OH, first trimester 2.25±0.28, second trimester 2.32±0.24, and third trimester 2.36±0.46 (p=n.s.).

Out of 64 women with SCH, 57 (89.06%) reached the appropriate LT4 dose with the initial dose, and the remaining seven required additional dose titration. Similarly, 10 out of 13 (76.92%) women with OH reached the appropriate dose with the starting LT4 replacement, and three patients required additional LT4 increments.

Among the patients with SCH, 54 (84.37%) attained the appropriate LT4 dose in the same trimester of pregnancy during which they were evaluated: 16/19 (84.2%), 26/33 (78.7%), and 12/12 (100%) patients who were referred to our institution in the first, second, and third trimesters, respectively. The 3/57 patients with SCH who reached the appropriate LT4 dose with the initial dose but not in the same trimester consulted close to the end of the trimester. All patients were euthyroid before delivery.

No significant difference was found between the initial and the adequate final dose in each group: group 1 initial dose=84.85±24.74 μg/day, 1.28±0.36 μg/kg/day, and final dose=86.94±25.21 μg/day, 1.31±0.36 μg/kg/day; group 2 initial dose=133.44±16.46 μg/day, 2.06±0.46 μg/kg/day, and final dose 147.08±29.83 μg/day, 2.33±0.59 μg/kg/day.

Once the appropriate dose of LT4 was prescribed, the time at which euthyroidism was confirmed did not differ between SCH and OH patients (mean±SD, weeks: 6.06±3.3 and 5.3±1.8 respectively; p=n.s.).

The obstetric and perinatal adverse events found in nine patients with SCH (14%) and in two patients with OH (15.6%) are shown in Table 2. In 7 out of 10 women (70%), positive TPOAbs were found, and in the remaining one, they were not determined. Gestational hypertension was found in five patients with SCH (7.8%) and was the most frequent complication. Two newborns had congenital malformations; their mothers reached euthyroidism late in the third trimester. There were no miscarriages or premature deliveries in any of the patients.

Table 2.

Obstetric and Perinatal Adverse Events in Women with Subclinical and Overt Hypothyroidism According to the Trimester in Which Euthyroidism Was Attained

	Trimester^a (n=11)			TPOAbs (n=11)
Obstetric and perinatal adverse events	1^st (n=4)	2^nd (n=4)	3^rd (n=3)	Positive (n=7)	Negative (n=3)	nd (n=1)
SCH
Gestational hypertension/pre-eclampsia	1^b	4		3	1	1
Low birth weight (<2500 g)	1		1	2
Congenital malformations
Cleft palate/harelip			1		1
Transposition of the great vessels			1		1
OH
Premature rupture of membranes	1			1
Fetal distress in labor	1			1

Gestational hypertension: blood pressure >130–90 mmHg discovered after the 20th week of pregnancy. Premature rupture of membranes: leakage of amniotic fluid before the onset of labor.

Trimester of pregnancy in which euthyroidism was achieved.

Gestational diabetes–associated.

SCH, subclinical hypothyroidism; OH, overt hypothyroidism; nd, data not available.

Discussion

The mother is the only source of T4 for the fetus during the first trimester, and it is the predominant source during the first half of gestation, at the time when key structures develop in the fetal brain (18).

Because an adverse outcome can affect mother, fetus, and offspring, OH should be treated immediately after diagnosis. The aim is to provide mothers with an LT4 dose leading to euthyroidism as soon as possible.

In the case of SCH, the impact of treatment is debated (11,19). There is evidence that treatment can improve the course of pregnancy and prevent obstetrical complications (15,20), but it has not been proven that treatment improves the neuro-intellectual status of the offspring (13).

The recommended LT4 doses for OH treatment are variable and are based on expert opinion: doses up to 150 μg/day (21), 2–2.4 μg/kg/day, or initiation of LT4 therapy by doubling the estimated dose for nonpregnant women have been proposed (21 –24).

In relation to the treatment of newly diagnosed SCH during pregnancy, reports making dose recommendations for levothyroxine are scarce. It is assumed that 50–75 μg/day of LT4 may be sufficient (21). Verga et al. used 75 μg/day (1.13 μg/kg/day) as initial doses but had to increase them to 95 μg/day (1.28 μg/kg/day) at the end of pregnancy (17).

In a recent paper, the average LT4 dose at the start of treatment (median 13 weeks and 3 days) was approximately 150 μg/day, and 85% of women continued with their initial dose after their checkup 6 weeks after screening (13). However, not all the women from the group screened had SCH; some of them had OH and others only hypothyroxinemia (13). Recently, the updated Endocrine Society guidelines recommended a starting LT4 dose of 50 μg/day or more (25).

In our study, we observed that the LT4 dose to attain euthyroidism in patients with SCH diagnosed during pregnancy was ∼88 μg/day (1.3 μg/kg/day). The estimated dose was dependent on the basal TSH level; patients with a TSH up to 4.2 mIU/L required significantly lower doses (∼80 μg/day; 1.2 μg/kg/day) than patients with TSH levels between 4.2 and 10 mIU/L (∼95μg/day; 1.42 μg/kg/day). As expected, patients with OH required higher doses of LT4 (∼148 μg/day; 2.33±0.59 μg/kg/day) than those patients with SCH in order to reach the euthyroid state.

Thus, a high percentage of women with SCH (nearly 85%) reached euthyroidism in the same trimester they were evaluated. Furthermore, about 90% of patients did not require any additional increments. The effectiveness of this treatment of newly diagnosed hypothyroidism during pregnancy is supported by the absence of significant differences between the initial and the final LT4 dose. Euthyroidism was promptly confirmed in both SCH and OH women within about 6 weeks. Even this period could have been shortened if some patients had been evaluated earlier in pregnancy.

Unlike our report, Verga et al. had to increase the LT4 dose in 80% of the women with newly discovered SCH during pregnancy one or more times; 66.7% of the patients reached the definitive dose late within the third trimester (17). Likewise, Idris et al. had to increase the LT4 dose significantly (50%) during pregnancy (26).

We found gestational hypertension in five patients (7.8%), one of them with associated gestational diabetes. This percentage is lower than the 15–17% found by other authors (5,6), although it is not clear what percentage of patients were under adequate treatment in these series. Even though there were two newborns with congenital malformations (3.1%) whose mothers achieved euthyroidism late in the third trimester, in a previous report, we described 6% of malformations in infants whose mothers received adequate treatment in the first trimester (1). Therefore, these malformations do not seem to be due to inadequate treatment. There were no miscarriages or premature deliveries, although these are usually the most frequently described complications (1 –6). Attaining the appropriate LT4 dose as soon as possible could have contributed to avoiding miscarriages in 16 of 19 patients who consulted in the first trimester. This represents the 25% of patients with SCH. The remaining women, who were diagnosed during the second and third trimester, also quickly achieved euthyroidism, and this may have avoided premature deliveries. While 55.8% of all patients had positive TPOAbs, the present study did not show an association between thyroid autoantibody positivity and miscarriages or preterm deliveries.

In conclusion, when subclinical hypothyroidism is newly discovered during pregnancy, we suggest using 1.2 μg/kg/day of LT4 when serum TSH is >2.5–4.2 mIU/L and 1.42 μg/kg/day if TSH is 4.2–10 mIU/L. In women with OH, we suggest using 2.33 μg/kg/day. Thereby, patients will quickly reach an euthyroid state, which may have an impact on decreasing obstetric risks due to inadequate treatment.

Footnotes

Acknowledgments

The authors are grateful to Dr. Oscar Levalle, Mrs. Mónica López, and Mrs. Hadasa Helfgot for their contributions.

Author Disclosure Statement

All authors have nothing to declare.

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