Effects of levothyroxine treatment on fertility and pregnancy outcomes in subclinical hypothyroidism: a systematic review and meta-analysis of randomized controlled trials.

Feb 19, 2024

Experts: Akiko Sankoda, Hitomi Suzuki, Misa Imaizumi, Ai Yoshihara, Sakiko Kobayashi, Miyuki Katai, Katsuhiko Hamada, Yoh Hidaka, Aya Yoshihara, Hannah Nakamura, Sumihisa Kubota, Maiko Kakita-Kobayashi, Akira Iwase, Takashi Sugiyama, Erika Ota, Naoko Arata

Subclinical hypothyroidism, elevated thyroid-stimulating hormone (TSH) and normal free thyroxine (FT4) levels, is associated with multiple adverse pregnancy outcomes. Despite the uncertainty regarding the effectiveness of levothyroxine treatment on pregnancy outcomes in subclinical hypothyroidism, levothyroxine is widely administered with a threshold TSH level of 2.5 mU/L. The aim of this study is to investigate the efficacy of periconceptional levothyroxine treatment for subclinical hypothyroidism, including TSH levels >2.5 mU/L, and identify the characteristics of subclinical hypothyroidism that can benefit from levothyroxine treatment.
We conducted a systematic review and meta-analysis of randomized controlled trials from inception to February 2023. We analyzed the pooled effects of levothyroxine on subclinical hypothyroidism before and during pregnancy. The main outcomes before pregnancy were live birth, pregnancy, and miscarriage. The main outcomes during pregnancy were live birth, miscarriage, and preterm birth. We conducted subgroup analyses to compare the effects of levothyroxine on subclinical hypothyroidism with TSH levels of 2.5-4.0 mU/L and >4.0 mU/L.
Of the 795 studies identified, 25 full-text articles were screened for eligibility. Finally, five studies on pre-conception treatment with 763 participants and seven studies on treatment during early pregnancy with 2,504 participants were analyzed. Pre-conception levothyroxine treatment showed no effect in improving live births and pregnancies, or decreasing miscarriages (risk ratio (RR):1.41; 95% confidence interval (CI):0.84-2.36, RR:1.73; 95%CI:0.88-3.39, and RR:0.46; 95%CI:0.11-2.00, respectively). Levothyroxine treatment during pregnancy showed no effect in improving live births (RR:1.03; 95%CI:0.98-1.09) or decreasing miscarriage rates (RR:0.99; 95%CI:0.65-1.51). The effect of levothyroxine treatment on preterm birth during pregnancy was significantly different depending on the TSH values (p=0.04); a positive effect was shown in the subclinical hypothyroidism subgroup with TSH >4.0 mU/L (RR:0.47; 95%CI:0.20-1.10), while no effect was shown in the subgroup with TSH 2.5-4.0 mU/L (RR:1.35; 95%CI:0.79-2.31).
Pre-conceptional levothyroxine treatment does not improve fertility or decrease the incidence of miscarriages. However, further well-designed studies are needed for pre-conceptional treatment, especially in TSH >4.0 mU/L. Levothyroxine treatment during pregnancy had a positive effect on preterm birth; nevertheless, this was only applicable to subclinical hypothyroidism with TSH >4.0 mU/L.

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ABOUT THE EXPERTS

Akiko Sankoda, Hitomi Suzuki, Misa Imaizumi, Ai Yoshihara, Sakiko Kobayashi, Miyuki Katai, Katsuhiko Hamada, Yoh Hidaka, Aya Yoshihara, Hannah Nakamura, Sumihisa Kubota, Maiko Kakita-Kobayashi, Akira Iwase, Takashi Sugiyama, Erika Ota, Naoko Arata

Akiko Sankoda

National Center for Child Health and Development, 13611, Division of Maternal Medicine, Center for Maternal-Fetal-Neonatal and Reproductive Medicine, Tokyo, Japan; sankoda-a@ncchd.go.jp.

Hitomi Suzuki

National Center for Child Health and Development, 13611, Division of Maternal Medicine, Center for Maternal-Fetal-Neonatal and Reproductive Medicine, Tokyo, Japan.

St Luke’s International University, 83911, Global Health Nursing, Graduate School of Nursing Science, Chuo-ku, Tokyo, Japan; suzuki-hi@ncchd.go.jp.

Misa Imaizumi

Radiation Effects Research Foundation, 1-8-6, Nakagawa, Nagasaki, Japan, 850-0013; misaima@rerf.or.jp.

Ai Yoshihara

Ito Hospital, internal medicine, 4-3-6 Jingumae, Shibuya-ku, Tokyo, Japan, 1508308; a-yoshihara@ito-hospital.jp.

Sakiko Kobayashi

NHO Tokyo Medical Center, Department of Endocrinology, Metabolism and Nephrology, Meguro-ku, Tokyo, Japan; s-k815@qk2.so-net.ne.jp.

Miyuki Katai

National Graduate Institute for Policy Studies, 12787, Health Services Center, Minato-ku, Tokyo, Japan; mkataimd@grips.ac.jp.

Katsuhiko Hamada

Tajiri Thyroid Clinic, Kumamoto, Japan; khamada1978@gmail.com.

Yoh Hidaka

Osaka University Graduate School of Medicine, Laboratory Medicine, 2-2-D2 Yamadaoka, Suita, Osaka, Japan, 565-0871.

Japan; hidaka@hp-lab.med.osaka-u.ac.jp.

Aya Yoshihara

Showa University Northern Yokohama Hospital, 220878, Department of Internal Medicine, Yokohama, Kanagawa, Japan; aya.yoshihara@med.showa-u.ac.jp.

Hannah Nakamura

Tohoku Medical and Pharmaceutical University, 34836, Division of Nephrology and Endocrinology, Faculty of Medicine, , Sendai, Miyagi, Japan; hannah_nakamura@tohoku-mpu.ac.jp.

Sumihisa Kubota

Kubota Thyroid Clinic, Nishinomiya, Japan; dfdcm447@kcc.zaq.ne.jp.

Maiko Kakita-Kobayashi

Kansai Medical University, 12880, Department of Obstetrics and Gynecology, Moriguchi, Osaka, Japan; maikokk1207@gmail.com.

Akira Iwase

Gunma University Graduate School of Medicine, Department of Obstetrics and Gynecology, Maebashi, Japan; akiwase@gunma-u.ac.jp.

Takashi Sugiyama

Ehime University Graduate School of Medicine, Department of Obstetrics and Gynecology, Toon, Japan; sugiyama@m.ehime-u.ac.jp.

Erika Ota

St. Luke’s International University, Global Health Nursing, Graduate School of Nursing Science, Tokyo, Japan.

The Tokyo Foundation for Policy Research, 438832, Minato-ku, Tokyo, Japan; ota@slcn.ac.jp.

Naoko Arata

National Center for Child Health and Development, 13611, 2-10-1, Okura, Setagayaku, Tokyo, Setagaya-ku, US and Canada only, Japan, 1578535; arata-n@ncchd.go.jp.