The role of levothyroxine in obstetric practice

Figures & data

Table 1. Current definitions for thyroid dysfunction entities.

	Definition
Overt hypothyroidism (OH)	TSH > upper limit of the pregnancy-specific reference range^a plus FT4 < 2.5–5th percentile of the reference range^b.
Subclinical hypothyroidism (SCH)	TSH > upper limit of the pregnancy-specific reference range with normal FT4 concentration.
Isolated hypothyroxinemia (IH)	Normal maternal TSH concentration with FT4 < 2.5–5th percentile of the reference range.
Thyroid autoimmunity (TAI)	Presence of antithyroid antibodies that can be:  – Antiperoxidase (TPOAb)  – Anti-thyroglobulin (TgAb)

^a The ATA recommends population-based trimester-specific references ranges for serum TSH (obtained from pregnant women with no known thyroid disease, optimal iodine intake and negative TPOAb status. In abscence of own reference range, the ATA suggest a TSH upper reference limit of 4.0 mUI/L within weeks 7–12 of gestation.

^b The ATA also recommends assay method-specific and trimester-specific pregnancy references ranges for serum Free T4.

Table 2. Meta-analysis and observational studies relating thyroid dysfunction and pregnancy complications.

	Subclinical hypothyroidism (SCH)	Thyroid autoimmunity (TAI)
Pregnancy loss Miscarriage	Meta-analysis Maraka [6] (2016) OR: 2.01 Zhang [33] (2017) RR: 1.90	Meta-analysis Van den Boogaard [5] (2011) OR: 3.73 Thangaratinam [34] (2011) OR: 3.90
Preterm delivery	Meta-analysis Maraka [6] (2016) OR: 1.20 Observational studies Arbib [35] (2016) OR: 1.81	Meta-analysis Van den Boogaard [5] (2011) OR: 1.9 Thangaratinam [34] (2011) OR: 2.07 He [36] (2012) RR: 1.41 Observational studies Korevaar [37] (2013) OR: 2.05 Karakosta [38] (2012) OR: 1.70
Growth restriction	Meta-analysis Maraka [6] (2016) OR: 2.14 Tong [39] (2016) OR: 0.98 Observational studies Karakosta [38] (2012) OR: 3.10 Chen [40] (2014) OR: 3.34	Meta-analysis Tong [39] (2016) OR: 1.57
Hypertensive disorders, pre-eclampsia	Meta-analysis Van den Boogaard [5] (2011) OR: 1.70 Maraka [6] (2016) OR:1.22 Observational studies Chen [40] (2014) OR: 2.24	Meta-analysis Van den Boogaard [5] (2011) OR: 1.2
Gestational diabetes	Meta-analysis Van den Boogaard [5] (2011) OR: 1.40 Toulis [41] (2014) OR: 1.39 Maraka [6] (2016) OR: 1.28 Gong [42] (2016) OR: 1.56 Observational studies Karakosta [38] (2012) OR: 4.30 Ying [43] (2016) OR: 1.37	Observational studies Ying [43] (2016) OR: 1.70

Note: Observational studies included in meta-analysis have not been reported in this table.

Table 3. Interventional studies with levothyroxine in subclinical hypothyroidism or thyroid autoimmunity during pregnancy.

	Study design	Intervention	Results	Comments
Vissenberg et al. (2012) [67]	Meta-analysis	Included Abalovich et al. (2002) [54] and Negro et al. (2010) [56] for SCH. Five studies reported on the effect of LT4 therapy for TAI.	SCH: ↓ Miscarriage ↓ Preterm delivery TAI: Miscarriage (not significant) ↓ Preterm delivery.	Conclusion: For SCH and TAI, evidence is insufficient to recommend treatment with thyroxine.
Yan et al. (2012) [68]	Prospective non-randomized	53 pregnancies from 34 patients TPO Ab (+) with recurrent miscarriage: — 17 pregnancies with LT4 treatment. — 36 pregnancies without treatment.	NO significant difference in the outcome between groups in live birth rate.	Empirical thyroxine therapy in TPOAb(+) pregnant women did not seem to improve outcome.
Lepoutre et al. (2012) [69]	Retrospective	96 TPO Ab (+) pregnant women — 49 treated with LT4. — 47 no treated.	↓ Miscarriage rate	Potential benefit of universal screening and LT4 treatment in pregnant women with TAI.
Reid et al. (2013) [70]	Meta-analysis	For SCH included Rotondi et al. (2004) [71], Negro et al. (2006) [72], Negro et al. (2007) [73] and Yassa (2010) [16].	↓ Preterm delivery. No effect on pre-eclampsia.	There was a trend towards reduced risk of miscarriage with LT4, but did not reach statistical significance.
Velkeniers et al. (2013) [74]	Meta-analysis	Women with SCH undergoing ART. Included Negro et al. (2005) [75], Abdel Rahman et al. (2010) [76] and Kim et al. (2011) [77].	↑ Delivery rate. ↓ Miscarriage rate.	In an ART setting, no data are available on the effects of LT4 treatment on preterm delivery or pre-eclampsia.
Bernardi et al. (2013) [78]	Prospective non-randomized	Women with SCH and history of recurrent early pregnancy loss — 24 treated with LT4. — 15 no treated.	NO significant difference in the outcome between groups in live birth rate.	The prevalence of SCH in this recurrent early pregnancy loss (REPL) cohort was 19%.
Bartáková et al. (2013) [79]	Prospective non-randomized	Cost-effectiveness analysis of screening and treatment after spontaneous abortion (SpA) — 73 SCH and/or TAI treated with LT4. 38 SCH and/or TAI untreated.	↑ Successfully completed subsequent pregnancies.	Screening for thyroid disorders in women after SpA and treatment with LT4 is cost-saving and it improves the subsequent pregnancy rate.
Lata et al. (2013) [80]	Prospective non-randomized	Women with two or more consecutive miscarriages. — 31 with TAI and 27 with SCH were treated with LT4. Compared to 100 healthy women without a history of miscarriage.	Following LT4 treatment, NO difference in miscarriage rate between hypothyroid and euthyroid individuals in TPO Ab (+) women.	The prevalence of TAI was higher in pregnant women with a history of recurrent miscarriage compared with healthy pregnant control population.
Ma et al. (2015) [81]	Prospective non-randomized	Screening group (675 pregnancies) was compared to control group (996 pregnancies). 105 SCH from screening group were treated with LT4. 252 SCH from control group did not receive treatment.	↓ Miscarriage rate. ↓ Foetal macrosomia risk. ↑ Caesarean risk.	Screening and intervention of SCH can reduce the risk of miscarriage. No significant differences were observed in other pregnancy outcomes between the two groups.
Maraka et al. (2016) [82]	Retrospective	82 women with SCH were treated. 284 women with SCH did not received treatment with LT4.	↓ Risk of low birth weight. ↓ Risk of low Apgar score.	Other pregnancy-related adverse outcomes were similar between the two groups.
Negro et al. (2016) [83]	Prospective Randomized	198 euthyroid, TAI (+) treated with LT4. 195 euthyroid, TAI (+) untreated. 197 euthyroid, TAI (−) untreated.	NO significant difference in miscarriage or preterm delivery rate between the three groups.	Levothyroxine intervention had no impact on the rate of miscarriage or preterm delivery in euthyroid TAI (+) women.
Nazarpour et al. (2016) [84]	Prospective Randomized	65 TPO Ab (+) women treated with LT4. 66 TPO Ab (+) women untreated. 131 TPO Ab (−) women untreated.	↓ Preterm delivery rate.	The number needed to treat (NNT) for preterm birth was 1.7
Ju et al. (2017) [85]	Prospective non-randomized	184 women with SCH were treated. 273 women with SCH did not received treatment with LT4.	↓ Gestational diabetes. ↓Foetal macrosomia.	The earlier the gestational week when the target TSH is achieved through treatment, the lower incidence of complications.
Blumenthal et al. (2017) [86]	Prospective non-randomized	28 women with SCH were treated. 111 euthyroid women (control group).	NO adverse outcomes in women diagnosed and treated for SCH.	No significant differences were observed between the two groups.

Note: Observational studies included in meta-analysis have not been reported in this table.

Table 4. Summary of current evidence for the use of levothyroxine in thyroid dysfunction.

	Indications	Warnings
Overt hypothyroidism (OH)	— All the cases must be treated	— Treatment should be carefully monitored.  — Avoid sub/over treatments.
Subclinical hypothyroidism (SCH)	— Treatment reduces the risk of:    – Miscarriage.    – Preterm delivery.    – Assisted reproductive techniques (ART).  — No evidence of effectiveness for:    – Gestational diabetes.    – Hypertensive disorders    – Infant cognitive function.	— The diagnosis must be based on reliable and own trimester-specific reference range.  — If reference levels are not available, the indications for treatment should be considered with caution (TSH >4 mUI/L or TPOAb positive with TSH >2.5 mUI/L).
Thyroid autoimmunity (TAI)	— Treatment can be considered in cases of:    – Assisted reproductive techniques (ART).    – Recurrent miscarriage.    – Preterm delivery^a.  — No evidence of benefits in:    – Any other obstetric complications.	— The use of thyroxine must be offered individually in cases of high-risk factors or history of adverse reproductive events.  — The use of thyroxine in absence of obstetric risk factors is not currently justified.
Isolated hypothyroxinemia (IH)	— There is no available evidence of benefits from thyroxine therapy.	— Use of iodine supplementation can be useful in iodine-deficient areas.  — Interventional studies in cases of IH are lacking.
Normal thyroid function	— There is no indication for use of thyroxine in normal conditions.	— Potential risks of iatrogenic use of thyroxine in pregnancy:  – Growth restriction  – Abnormal brain morphology in children.

^a This recommendation is based on observational studies.

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