Background
Methods
Literature search
Study selection
Quality assessment and data extraction
Statistical analysis
Sensitivity analyses
Results
Study and research institution | Study design and Size (N) | Geographic Region and Period | Serum TSH and fT4 for SCH diagnosis | Gestational age levothyroxine started with initial dose and adjustment | Outcomes | Findings |
---|---|---|---|---|---|---|
Bernardi et al.; 2013 [32] University of Chicago | Cohort study N = 39 | United States July 2004–December 2011 | TSH > 2.5mIU/L with normal fT4 level (0.9–1.7 ng/dL) measured before conception | Initiated if SCH was identified pre-conception Initial dose and adjustment unknown. | Live-birth rates | Among women with a history of > 2 pregnancy losses and SCH, women who received treatment for SCH did not have an increased live birth rate compared to women who did not receive levothyroxine treatment (per-pregnancy live birth rate: SCH treated: 48% (22/46) vs. SCH untreated: 52% (12/23). |
Maraka et al. 2016 [33] Mayo Clinic | Retrospective Cohort N = 366 | Rochester, Minnesota January 2011–December 2013 | TSH 2.5–10 mIU/L in first trimester & 3–10 mIU/L in other trimesters normal fT4 (> 0.8 ng/dL) | Started at median GA 9.1 weeks | Pregnancy loss defined as miscarriage and stillbirth, preterm delivery (< 37 weeks), premature rupture of membranes, placental abruption, gestational diabetes, gestational hypertension, pre-eclampsia, eclampsia, intrauterine growth restriction, birth weight, Apgar score at 5 min, admission to the neonatal intensive care unit, neonatal death (during immediate postpartum period until discharge of the mother) and duration of hospital stay. | Treated pregnancies had a lower birth weights and no Apgar score less than 7. Other pregnancy outcomes were statistically similar between groups. Pregnancy loss OR: 2.44; 95% CI: 0.80–8.87 Preterm delivery OR: 3.06; 95% CI: 0.96–12.28 Gestational diabetes OR: 3.31; 95% CI: 0.91–16.57 Gestational hypertension OR: 0.64; 95% CI: 0.23–1.93 Pre-eclampsia OR: 3.37; 95% CI: 0.66–26.84 Premature rupture of membranes OR: 0.71; 95% CI: 0.29–1.79 Intrauterine growth restriction OR: 1.45; 95% CI: 0.23–28.1 Placenta previa and placental abruption: not enough events to do multivariate analyses NICU admission OR: 1.94; 95% CI: 0.38–15.36 Birth weight < 2500 g OR: 16.4; 95% CI: 2.7–326.9 Neonatal death and congenital malformations: not enough events to do multivariate analyses |
Al-Anbari, 2017 | Prospective study N=149 | High Institute of Infertility diagnosis and assisted reproductive technologies/Al-Nahrain University, Iraq | TSH > 2.5mIU/L prior to conception | Initiated if SCH was identified pre-conception | Pregnancy rate, miscarriage rate, multiple pregnancy rate and live birth rate | Significantly increased pregnancy rate (19/75 among levothyroxine treated versus 8/74 among women not given treatment). No multiple pregnancies in both groups. No difference in miscarriage rate (2/75 among levothyroxine treated versus vs 2/74 among women not given treatment). |
Maraka et al. 2017 [34] OptumLabs Data Warehouse | Retrospective Cohort N = 5405 | United States January 2010–December 2014 | TSH 2.5–10 mIU/L from 1 month prior to 3 months after first prenatal visit fT4 0.8 ng/dL or total thyroxine 7.5 mcg/dL | Started at median GA 28.7 weeks before birth Unknown initial dose. Median dose: 50 mcg daily (range 25–300mcg daily) | Pregnancy loss defined as miscarriage and still-birth, preterm delivery, preterm labor, premature rupture of membranes, placental abruption, gestational diabetes, gestational hypertension, pre-eclampsia, poor fetal growth, tachycardia | Treatment of SCH was associated with decreased risk of pregnancy loss but was associated with increased risk of other adverse pregnancy related outcomes. Pregnancy loss OR: 0.62; 95% CI: 0.48–0.82 Preterm delivery OR: 1.6; 95% CI: 1.14–2.24 Preterm labor OR: 1.14; 95% CI: 0.89–1.46 Premature rupture of membranes OR: 0.97; 95% CI: 0.66–1.42 Placental abruption OR: 1.60; 95% CI: 0.65–3.93 Gestational diabetes OR: 1.37; 95% CI: 1.05–1.79 Gestational hypertension OR: 1.27; 95% CI: 0.88–1.82 Pre-eclampsia OR: 1.61; 95% CI: 1.10–2.37 Poor fetal growth OR: 1.12; 95% CI: 0.84–1.5 Tachycardia OR: 1.77; 95% CI: 1–3.11 |
Nazarpour et al. 2017 [35] Shahid Beheshti Medical University | RCT N = 1294 | Tehran, Iran September 2013–February 2016 | TSH 2.5–10 mIU/L fT4 1–4.5 TPOAb positive | Started 4 to 8 d after prenatal visit, the mean GA at initial visit was 10.8 weeks. 1 mcg/kg daily Dose adjustment not described. | Preterm delivery, neonatal admission, placental abruption, still birth, GA mean birth weight, neonate height, birth head circumference, neonatal TSH | There were no significant differences in preterm delivery or neonatal admission between treated and untreated women with SCH (TSH < 4mIU/L) treated versus untreated but there were significant differences in preterm delivery and neonatal admission between treated and untreated women with TSH > 4mIU/L. There was also a significant decrease in neonatal admission among women treated for SCH versus women who did not receive treatment [number (%): 2 (3.6) vs.12 (20.7)] There were no significant differences in placental abruption, still birth, and gestational age between treated versus untreated women with SCH. There were no significant differences in mean birth weight, head circumference and neonate TSH levels between study groups. |
Nazarpour et al. 2018 [36] Shahid Beheshti Medical University | RCT N = 354 | Tehran, Iran September 2013–February 2016 | TSH 2.5–10 mIU/L fT4 1–4.5 TPOAb negative | Started 4–8 days after first prenatal visit, which was at 11.2–12.2 weeks of gestation Dosed at 1 mcg/kg daily. Dose adjustment not described | Preterm delivery, placental abruption, stillbirth, neonatal admission, birth weight, mean gestational age neonate height, birth head circumference neonatal TSH | Significant difference in pre-term delivery when TSH > 4 mIU/L and treated with levothyroxine versus no treatment, RR: 0.38; 95% CI: 0.15–0.98. There was no significant difference in the risk of other adverse pregnancy outcomes among women with SCH treated versus untreated. Number (%) of outcomes treated versus untreated: Preterm delivery: 18 (9.8) vs. 21 (11.5) Neonatal admission: 8 (4.5) vs. 9 (4.9) Placental abruption: 3 (1.6) vs. 0 Stillbirth: 0 vs. 0 Gestational age: 38.03 (1.4) vs. 37.9 (1.5) Mean (standard deviation) Birth weight: 3190.82 g (455.13) vs. 3203.1 g (497.1) Neonate height: 50.1 cm (2.3) vs. 50.2 cm (2.7) Birth head circumference: 34.6 cm (1.4) vs. 34.7 cm (1.6) Neonatal TSH (mIU/L): 1.1 (0.5–1.9) vs. 1.1 (0.5–2.1) |
Casey et al. 2017 [37] | RCT N = 677 women with SCH, 526 with hypothyroxinemia | United States October 2006–October 2009 | TSH > 3mIU/L or fT4 < 0.86 ng/dl with TSH between 0.08 and 3.99mIU/L | Started at GA 10–24 weeks; average GA 16.6 +/− 3 week standard deviation Initial dose 100 mcg daily. Monthly adjustment to maintain TSH 0.1–2.5 mIU/L Max dose: 200 mcg daily Treatment group normalized TSH by median of GA 21 weeks | Multiple pregnancy and neonatal outcomes. For maternal outcomes: preterm birth (< 34 and < 37 weeks), placental abruption, gestational hypertension, preeclampsia, gestational diabetes. For fetal and neonatal outcomes: stillbirth/miscarriage, neonatal death, Apgar score at 1 and 5 min, birth weight (< 10 percentile), head circumference, respiratory distress syndrome, necrotizing enteritis, bronchopulmonary dysplasia, respiratory therapy > 1 day, number of days in nursery. Annual cognitive testing over first 5 years, IQ at 5 yo. or general conceptual ability at 3 yo | No differences in adverse pregnancy and neonatal outcomes between levothyroxine treated versus placebo group. No differences in IQ score at the age of 5 years or death at the age of < 3 years between treated and untreated SCH (median IQ score for children in levothyroxine treated group: 97 (95% CI: 94–99) versus 94 (95% CI: 91–95) in placebo. |
Lazarus et al. 2012 [38] | RCT N = 794 | Wales & Cardiff, UK Ospendale Sant’Anna, Turin, Italy Period of time not mentioned but followed children at age 3 years | TSH > 97.5th percentile and f T4 < 2.5th percentile | Started at GA 12–13 weeks Initial dose of 150 mcg daily. Adjustment 6 weeks after beginning treatment and at 30 weeks GA to target TSH 0.1–1 mIU/L | IQ at 3 years of age | No significant differences in IQ scores at age 3 years between children born of mothers with SCH treated versus placebo during pregnancy: IQ score treated: 99.2 +/− 13.3 vs. untreated: 100 +/− 13.3. |
Kim et al. 2011 [39] | RCT N = 64 | Seoul, South Korea March 2006–September 2009 | TSH > 4.5mIU/L with normal fT4 | Started prior to IVF/ICSI treatment (before pregnancy). Initial dose 50 mcg daily. Adjustment: First trimester titration to maintain TSH < 2.5 mIU/L to max dose 100mcg daily (12/17) and 125mcg daily (1/17) | Embryo implantation rate, total amount and days of rhFSH administered, number of retrieved, mature, fertilized oocytes, and good quality embryos, clinical pregnancy rate per cycle, and miscarriage rate, preterm birth (< 34 weeks) and live birth (delivery of fetus> 20 weeks with signs of life) | Significant increase in embyro quality and implantation when women with SCH were treated versus untreated. Significant decrease in miscarriage and increase in live birth rate per cycle when women with SCH were treated versus untreated. Miscarriage rate in treated versus untreated: 0/17 vs. 4/12 Live birth rate per cycle in treated versus untreated: 17/32 vs. 8/32 |
Ju et al. 2016 [40] Beijing Friendship Hospital of Capital Medical University | Prospective cohort N = 457 | Beijing, China October 2010–September 2013 | TSH > 97.5th percentile and fT4 2.5th–97.5th percentile | Started at approx. GA 10 weeks Initial dose 100 mcg daily. Adjusted by 100 mcg to maintain TSH 2.5–97.5 percentile. | Premature rupture of membranes, fetal macrosomia, gestational diabetes, hypertensive disorders in pregnancy, postpartum hemorrhage, preterm labor, oligohydramnios, fetal distress, and low birth weight | Overall risk of pregnancy complications in control group significantly higher than in treated group (OR: 1.219; 95% CI 1.139–1.304). For single outcomes, there was a statistically increased risk of gestational diabetes among untreated versus treated women with SCH (OR: 1.938; 95% CI: 1.267–2.964) and fetal macrosomia (OR:3.081; 95% CI: 1.783–5.326). |
Wang et al. 2012 [41] Liaoning Provincial Key Laboratory of Endocrine Diseases | Prospective cohort N = 196 | Shenyang, China 2007–2009 | TSH > 2.5 mIU/L with a fT4 between 12 pmol/L and 23.34 pmol/L in the first 12 weeks of pregnancy | Started at approximately 6 weeks. Initial dose at 50 μg, 75 μg, or 100 μg daily Adjustment every 4 weeks by serum TSH (mIU/L): 2.5–5: 50 μg daily 5–8: 70 μg daily > 8: 100 μg daily | Spontaneous abortion, anemia, hypertension, premature delivery, low birth weight, post-partum hemorrhage, Apgar score ≤ 7 at 5 min | Levothyroxine treatment in women with SCH decreased the incidence of spontaneous abortions compared to no treatment but this was not statistically significant. Outcomes in treated versus untreated women with SCH: Spontaneous abortions: 2 (7.14%) vs. 26 (15.47%) Anemia: 3 (10.71%) vs. 35 (20.83%) Hypertension: 1 (3.57%) vs. 2 (1.19%) Premature delivery: 0 vs. 9 (5.36%) Low birth weight: 0 vs. 4 (2.38%) Hemorrhage: 0 vs. 2 (1.19%) Apgar score < 7 at 5 min: 0 vs. 4 (2.38%) |
Zhao et al. 2018 [42] Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine | RCT N = 93 | Shanghai, China January 2014–October 2016 | T1:TSH > 2.5mIU/L T2: TSH > 3mIU/L | Started either in T1 at 8-10 weeks or T2 at 13–16 weeks. Initial dose 25mcg daily. Max dose: 100 mcg daily | Gestational hypertension, anemia, gestational diabetes, pre-eclampsia, premature labor, pregnancy loss, post-partum hemorrhage, low birth weight (< 2500 g) | Pregnancy complications: no significant different between treated versus untreated groups for individual outcomes. However, for combined outcomes: treatment given during T1 had significantly less complications than women who were not treated (Number of total adverse pregnancy outcomes among women treated at T1: 1/31 vs. 10/31 (treated at T2) vs. 12/31 (no treatment). |
Zhang et al. 2017 [12] | Retrospective cohort N = 9 | ZhongDa, China January 2014–May 2014 | TSH 0.27–4.2 mIU/L and fT4 0.93–1.70 ng/dL (in T2) | Started in second trimester. Dose at 50 mcg daily | Premature delivery (< 37 weeks), Apgar score, birth weight | No significant differences in the rate of premature delivery (0/1 in treated vs. 3/8 untreated), Apgar (10 +/− 0 in treated vs. 9.8+/− 0.61 untreated), and birth weight (3.67+/− 0.6 kg in treated vs. 3.48+/− 0.54 kg in untreated) in women with treated and untreated SCH. |
Quality assessment
RCTs
Observational studies
Fetal outcomes
Outcomes | No. of studies | Pooled sample | Risk ratio (95% CI)* |
---|---|---|---|
Fetal | |||
Congenital malformation | 1 | 336 | 0.37 (0.02 to 6.8) |
Fetal distress | 1 | 457 | 0.78 (0.59 to 1.0) |
Fetal macrosomia | 1 | 457 | 0.32 (0.19 to 0.56) |
Intrauterine growth restriction | 2 | 5771 | 1.06 (0.59 to 1.90) |
Oligohydramnios | 1 | 457 | 1.48 (0.60 to 3.7) |
Placenta abruption | 5 | 6928 | 0.98 (0.37 to 2.61) |
Placenta previa | 1 | 366 | 0.49 (0.03 to 9.5) |
Spontaneous abortion | 4 | 366 | 0.45 (0.13 to 1.56) |
Pregnancy loss (still births and spontaneous abortions) | 10 | 7342 | 0.79 (0.67 to 0.93) |
Perinatal | |||
Postpartum hemorrhage | 3 | 746 | 0.88 (0.18 to 4.22) |
Premature rupture of membranes | 3 | 6228 | 0.94 (0.52 to 1.70) |
Preterm delivery | 7 | 7217 | 0.77 (0.47 to 1.25) |
Preterm labour | 2 | 5862 | 1.05 (0.56 to 1.97) |
Still birth | 4 | 536 | NA |
Neonatal | |||
APGAR under 7 at five minutes | 3 | 1209 | 0.42 (0.03 to 5.31) |
Low birth weight | 5 | 1759 | 0.80 (0.26 to 2.43) |
Neonatal death | 2 | 1013 | 0.35 (0.17 to 0.72) |
Observational studies | Randomized controlled trials | |||
---|---|---|---|---|
Outcomes | No. of studies | Risk ratio (95% CI)* | No. of studies | Risk ratio (95% CI) |
Fetal | ||||
Intrauterine growth restriction | 2 | 1.06 (0.59 to 1.90) | 0 | NA |
Placenta abruption | 2 | 1.06 (0.81 to 1.38) | 3 | 0.93 (0.01 to 101.99) |
Spontaneous abortion | 1 | 0.46 (0.12 to 1.84) | 3 | 0.44 (0.03 to 6.83) |
Pregnancy loss (still births and spontaneous abortions) | 4 | 0.81 (0.62 to 1.05) | 6 | 0.51 (0.25 to 1.05) |
Perinatal | ||||
Postpartum hemorrhage | 2 | 1.16 (1.06 to 1.27) | 1 | 0.33 (0.06 to 1.89) |
Premature rupture of membranes | 3 | 0.94 (0.52 to 1.70) | 0 | NA |
Preterm delivery | 3 | 0.82 (0.13 to 4.98) | 4 | 0.72 (0.39 to 1.35) |
Preterm labour | 2 | 1.05 (0.56 to 1.97) | 0 | NA |
Still birth | 4 | 0.75 (0.39 to 1.42) | 0 | NA |
Neonatal | ||||
APGAR under 7 at five minutes | 2 | 0.24 (0.00 to 68,937.70)* | 1 | 0.66 (0.11 to 3.95) |
Low birth weight | 3 | 0.55 (0.03 to 11.63) | 2 | 0.86 (0.00 to 3722.22) |
Neonatal death | 1 | 0.37 (0.02 to 6.83) | 1 | 0.33 (0.01 to 8.13) |
Perinatal outcomes
Neonatal outcomes
Outcomes | Unit of measure | No. of Studies | Pooled Sample | Mean Difference (95% CI) |
---|---|---|---|---|
Neonatal | ||||
Neonatal head circumference (at birth) | cm | 2 | 1031 | −0.042 (−0.67 to 0.58) |
Pediatric | ||||
Child Behaviour Checklist T-score at 3 years old | percentile | 2 | 1409 | −0.50 (−4.5 to 3.5) |
IQ at 3 to 5 years old | percentile | 2 | 1443 | 0.94 (−23 to 25) |