Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health(review)

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1 Cochrane Database of Systematic Reviews Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health(review) SpencerL,BubnerT,BainE,MiddletonP SpencerL,BubnerT,BainE,MiddletonP. health. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD DOI: / CD pub2. health(review) Copyright 2015 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure ADDITIONAL SUMMARY OF FINDINGS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 1 Thyroid dysfunction diagnosed in pregnancy: hypothyroid Analysis 1.2. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 2 Thyroid dysfunction diagnosed in pregnancy: hyperthyroid Analysis 1.3. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 3 Thyroid dysfunction diagnosed in pregnancy: hypothyroid (subgroups based on baseline risk) Analysis 1.4. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 4 Thyroid dysfunction diagnosed in pregnancy: hyperthyroid (subgroups based on baseline risk) Analysis 1.5. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 5 Pre-eclampsia Analysis 1.6. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 6 Pre-eclampsia (subgroups based on baseline risk and thyroid status) Analysis 1.7. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 7 Preterm birth Analysis 1.8. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 8 Preterm birth (subgroups based on baseline risk and thyroid status) Analysis 1.9. Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 9 Pharmacological treatment for thyroid dysfunction: thyroxine for hypothyroidism Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 10 Miscarriage Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 11 Pregnancy-induced hypertension Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 12 Gestational diabetes Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 13 Congestive heart failure Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 14 Thyroid storm Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 15 Mode of birth: caesarean Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 16 Preterm labour i

3 Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 17 Placental abruption Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 18 Fetal and neonatal death Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 19 Respiratory distress syndrome Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 20 Low birthweight Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 21 Neonatal intensive care unit admission Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 22 Other congenital malformations Analysis Comparison 1 Universal screening versus case finding in pregnancy for any thyroid dysfunction, Outcome 23 At least one adverse outcome Analysis 2.1. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 1 Thyroid dysfunction diagnosed in pregnancy: Hypothyroid Analysis 2.2. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 2 Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/intellectual impairment, at latest time reported): IQ < 85 at 3 years of age Analysis 2.3. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 3 Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/intellectual impairment, at latest time reported): IQ Z-score < 1 at 3 years of age Analysis 2.4. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 4 Pharmacological treatment for thyroid dysfunction: thyroxine for hypothyroidism Analysis 2.5. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 5 Developmental delay/intellectual impairment: Mean standardised IQ at 3 years of age Analysis 2.6. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 6 Developmental delay/intellectual impairment: Mean IQ Z-score at 3 years of age Analysis 2.7. Comparison 2 Universal screening versus no screening in pregnancy for hypothyroidism, Outcome 7 Developmental delay/intellectual impairment: Mean CBCL T-score at 3 years of age CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS ii

4 [Intervention Review] Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health Laura Spencer 1, Tanya Bubner 1, Emily Bain 1, Philippa Middleton 2 1 ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia. 2 Women s and Children s Research Institute, The University of Adelaide, Adelaide, Australia Contact address: Laura Spencer, ARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, 72 King William Road, Adelaide, SA, 5006, Australia. laura.spencer@adelaide.edu.au. Editorial group: Cochrane Pregnancy and Childbirth Group. Publication status and date: New, published in Issue 9, Citation: Spencer L, Bubner T, Bain E, Middleton P. Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Thyroid dysfunction pre-pregnancy and during pregnancy (both hyper- and hypothyroidism) is associated with increased risk of adverse outcomes for mothers and infants in the short- and long-term. Managing the thyroid dysfunction (e.g. thyroxine for hypothyroidism, or antithyroid medication for hyperthyroidism) may improve outcomes. The best method of screening to identify and subsequently manage thyroid dysfunction pre-pregnancy and during pregnancy is unknown. Objectives To assess the effects of different screening methods (and subsequent management) for thyroid dysfunction pre-pregnancy and during pregnancy on maternal and infant outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group s Trials Register (14 July 2015) and reference lists of retrieved studies. Selection criteria Randomised or quasi-randomised controlled trials, comparing any screening method (e.g. tool, program, guideline/protocol) for detecting thyroid dysfunction (including hypothyroidism, hyperthyroidism, and/or thyroid autoimmunity) pre-pregnancy or during pregnancy with no screening, or alternative screening methods. Data collection and analysis Two review authors independently assessed eligibility of studies, extracted and checked data accuracy, and assessed the risk of bias of included studies. 1

5 Main results We included two randomised controlled trials (involving 26,408 women) - these trials were considered to be at low risk of bias. Universal screening (screening all women) versus case finding (screening only those at perceived increased risk) in pregnancy for thyroid dysfunction One trial (4562 women) compared universal screening with case finding for thyroid dysfunction. Before 11 weeks gestation, women in the universal screening group, and high-risk women in the case finding group had their sera tested for TSH (thyroid stimulating hormone), ft4 (free thyroxine) and TPO-Ab (thyroid peroxidase antibody); women with hypothyroidism (TSH > 2.5 miu/litre) received levothyroxine; women with hyperthyroidism (undetectable TSH and elevated ft4) received antithyroid medication. In regards to this review s primary outcomes, compared with the case finding group, more women in the universal screening group were diagnosed with hypothyroidism (risk ratio (RR) 3.15, 95% confidence interval (CI) 1.91 to 5.20; 4562 women; GRADE: high quality evidence), with a trend towards more women being diagnosed with hyperthyroidism (RR 4.50, 95% CI 0.97 to 20.82; 4562 women; P = 0.05; GRADE: moderate quality evidence). No clear differences were seen in the risks of pre-eclampsia (RR 0.87, 95% CI 0.64 to 1.18; 4516 women; GRADE: moderate quality evidence), or preterm birth (RR 0.99, 95% CI 0.80 to 1.24; 4516 women; GRADE: high quality evidence) between groups. This trial did not report on neurosensory disability for the infant as a child. Considering this review s secondary outcomes, more women in the universal screening group received pharmacological treatment for thyroid dysfunction (RR 3.15, 95% CI 1.91 to 5.20; 4562 women). No clear differences between groups were observed for miscarriage (RR 0.90, 95% CI 0.68 to 1.19; 4516 women; GRADE: moderate quality evidence), fetal and neonatal death (RR 0.92, 95% CI 0.42 to 2.02; 4516 infants; GRADE: moderate quality evidence), or other secondary outcomes: pregnancy-induced hypertension, gestational diabetes, congestive heart failure, thyroid storm, mode of birth (caesarean section), preterm labour, placental abruption, respiratory distress syndrome, low birthweight, neonatal intensive care unit admission, or other congenital malformations. The trial did not report on a number of outcomes including adverse effects associated with the intervention. Universal screening versus no screening in pregnancy for hypothyroidism One trial (21,846 women) compared universal screening with no screening for hypothyroidism. Before weeks gestation, women in the universal screening group had their sera tested; women who screened positive (TSH > 97.5th percentile, ft4 < 2.5th percentile, or both) received levothyroxine. Considering primary review outcomes, compared with the no screening group, more women in the universal screening screened positive for hypothyroidism (RR , 95% CI to 15,978.48; 21,839 women; GRADE: high quality evidence). No data were provided for the outcome pre-eclampsia, and for preterm birth, the trial reported rates of 5.6% and 7.9% for the screening and no screening groups respectively (it was unclear if these percentages related to the entire cohort or women who screened positive). No clear difference was seen for neurosensory disability for the infant as a child (three-year follow-up IQ score < 85) (RR 0.85, 95% CI 0.60 to 1.22; 794 infants; GRADE: moderate quality evidence). More women in the universal screening group received pharmacological treatment for thyroid dysfunction (RR , 95% CI to 17,610.46; 1050 women); 10% had their dose lowered because of low TSH, high ft4 or minor side effects. No clear differences were observed for other secondary outcomes, including developmental delay/intellectual impairment at three years. Most of our secondary outcomes, including miscarriage, fetal or neonatal death were not reported. Authors conclusions Based on the existing evidence, though universal screening for thyroid dysfunction in pregnancy increases the number of women diagnosed with hypothyroidism who can be subsequently treated, it does not clearly impact (benefit or harm) maternal and infant outcomes. While universal screening versus case finding for thyroid dysfunction increased diagnosis and subsequent treatment, we found no clear differences for the primary outcomes: pre-eclampsia or preterm birth. No clear differences were seen for secondary outcomes, including miscarriage and fetal or neonatal death; data were lacking for the primary outcome: neurosensory disability for the infant as a child, and for many secondary outcomes. Though universal screening versus no screening for hypothyroidism similarly increased diagnosis and subsequent treatment, no clear difference was seen for the primary outcome: neurosensory disability for the infant as a child (IQ < 85 at three years); data were lacking for the other primary outcomes: pre-eclampsia and preterm birth, and for the majority of secondary outcomes. 2

6 For outcomes assessed using the GRADE approach the evidence was considered to be moderate or high quality, with any downgrading of the evidence based on the presence of wide confidence intervals crossing the line of no effect. More evidence is needed to assess the benefits or harms of different screening methods for thyroid dysfunction in pregnancy, on maternal, infant and child health outcomes. Future trials should assess impacts on use of health services and costs, and be adequately powered to evaluate the effects on short- and long-term outcomes. P L A I N L A N G U A G E S U M M A R Y Screening and subsequent treatment for thyroid dysfunction before or during pregnancy to improve outcomes for mothers and their babies What is the issue? What are the effects of different screening methods (for example screening all women versus screening only some women, or not screening women) for thyroid dysfunction before or during pregnancy on outcomes for the mother and her baby? Why is this important? The thyroid is a large gland in the neck that produces hormones that help to regulate the chemical processes in the body that maintain life, including growth and energy use. If a woman has an overactive thyroid (hyperthyroidism), or an underactive thyroid (hypothyroidism) in pregnancy which is not managed, there is a possibility of poor outcomes for the mother and her baby. The mother may be more likely to develop high blood pressure and protein in the urine (pre-eclampsia), give birth before 37 weeks of gestation (preterm birth), and her baby may develop disabilities (such as cerebral palsy, blindness, deafness and other developmental delays including intellectual impairment). Managing thyroid dysfunction in pregnancy (e.g. thyroxine for hypothyroidism, or antithyroid medication for hyperthyroidism) may improve outcomes for mothers and their babies. There are different methods of screening for thyroid dysfunction, including case finding, which means screening only pregnant women who are thought to be at high risk of thyroid dysfunction, or universal screening, which involves screening all pregnant women. Although universal screening may help to diagnose more women with hyperthyroidism or hypothyroidism than case finding, it could also lead to more women having medications and may be costly. It is not currently clear what the effects are of these different methods of screening for thyroid dysfunction for the mother and her baby, and health services. What evidence did we find? In our search of the medical literature we found two randomised controlled trials, involving 26,408 women. The quality of the included trials was high, and the quality of the evidence they provided was moderate to high. (1) Universal screening for thyroid dysfunction in pregnancy, and hypothyroidism specifically, increased the number of women diagnosed with hypothyroidism, who were subsequently treated (one trial involving 4562 women; and one trial involving 21,839 women). The study of 4562 women also showed that there may have been an increase in the number of women diagnosed with hyperthyroidism with universal screening. (2) Universal screening and subsequent treatment did not show clear benefits or harms for the women or their babies as it did not change the number of women with pre-eclampsia (in the one trial involving 4516 of 4562 women for this outcome), the number of women who gave birth preterm (one trial involving 4516 women), or the number of children with a disability (an intelligence quotient (IQ) less than 85 at three years of age) (one trial involving 794 children whose mothers had hypothyroidism from the total of 21,839 women). (3) One of the included trials did not report on later disabilities for the baby, and the other trial did not report on pre-eclampsia or preterm birth. Neither of the trials reported on use of health services or costs. What does this mean? Although the overall quality of the evidence was moderate to high, apart from finding that universal screening can help to diagnose more women with hypothyroidism (who may then be treated), there were no clear differences in outcomes for the mothers and their babies between universal screening and case finding (or not screening at all). Even though the two included studies involved a large number of women, further evidence is needed to assess the potential short- and long-term benefits or harms of different screening methods, along with the impact on health services including costs. 3

7 4 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Universal screening versus case finding in pregnancy for any thyroid dysfunction Patient or population: women during pregnancy Setting: Italy Intervention: universal screening Comparison: case finding in pregnancy for any thyroid dysfunction Outcomes Anticipatedabsoluteeffects (95%CI) Relativeeffect (95% CI) Thyroid dysfunction diagnosed in pregnancy: hypothyroid Thyroid dysfunction diagnosed in pregnancy: hyperthyroid Risk with case finding in pregnancy for any thyroid dysfunction Risk with Universal screening Study population RR 3.15 (1.91 to 5.20) 9 per per 1000 (17 to 46) Study population RR 4.50 (0.97 to 20.82) 1 per per 1000 (1 to 18) Pre-eclampsia Study population RR 0.87 (0.64 to 1.18) 37 per per 1000 (24 to 44) Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/ intellectual impairment, at latest time reported) : IQ < 85 at 3 years of No data were available on this outcome. of participants (studies) 4562 (1 RCT) 4562 (1 RCT) 4516 (1 RCT) Quality of the evidence (GRADE) HIGH MODERATE 1 MODERATE 1 Comments

8 age Preterm birth Study population RR 0.99 (0.80 to 1.24) 66 per per 1000 (52 to 81) Miscarriage Study population RR 0.90 (0.68 to 1.19) 45 per per 1000 (31 to 54) Adverse effects associated with the intervention Fetal and neonatal death No data were available on this outcome. Study population RR 0.92 (0.42 to 2.02) 6 per per 1000 (2 to 12) 4516 (1 RCT) 4516 (1 RCT) 4516 (1 RCT) HIGH MODERATE 1 MODERATE 1 *Theriskintheinterventiongroup(and its 95%confidence interval) is based on the assumed risk in the comparison group and therelativeeffect of the intervention (and its 95%CI). CI: confidence interval; RR: risk ratio GRADE Working Group grades of evidence Highquality:We are very confident that the true effect lies close to that of the estimate of the effect Moderatequality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect 1 Wide CI crossing the line of no effect (-1) 5

9 B A C K G R O U N D Description of the condition Thyroid dysfunction in pregnancy Thyroid dysfunction in pregnancy has been associated with a range of adverse maternal and fetal/infant outcomes, including miscarriage, pre-eclampsia (high blood pressure and protein in the urine), preterm birth (birth before 37 weeks of gestation) and maternal thyroid dysfunction in the postpartum period (Stagnaro-Green 2011). Questions have also been raised about increased risks of cognitive dysfunction and other adverse neurodevelopmental outcomes for children born to mothers with thyroid dysfunction during pregnancy (Stagnaro-Green 2012). Thyroid dysfunction in pregnancy may be categorised as: hypothyroidism (subclinical and overt), isolated hypothyroxinaemia, thyroid autoimmunity, and hyperthyroidism (including Graves disease and gestational thyrotoxicosis) (Negro 2011a). Debate continues surrounding the most appropriate strategies to identify and subsequently manage women with thyroid dysfunction before, during and after pregnancy, to prevent the potential adverse consequences. Normal pregnancy is associated with important and complex changes in maternal thyroid physiology and hormone production, and maternal and fetal thyroid hormone profiles change as gestation progresses. During the first trimester, normal thyroid function results in an increase in thyroxine (T4) and triiodothyronine (T3) production, and a subsequent inhibition of thyroid-stimulating hormone (TSH), in part due to the production of high concentrations of human chorionic gonadotrophin (hcg) (a hormone produced in pregnancy), which stimulates the TSH receptor (Krajewski 2011). The relationship between maternal and fetal thyroid hormone production is particularly important during the first half of pregnancy. Thyroid hormone is critical for the early development and maturation of the fetal brain, and thus the maternal transfer of thyroid hormone is essential, especially during the first trimester (Cooper 2012). The fetal thyroid gland does not begin to synthesise thyroid hormone until approximately 12 to 13 weeks gestation and prior to this time any requirement for thyroid hormone is reliant on the mother (Casey 2006). Thyroid dysfunction during pregnancy, its associated adverse outcomes, as well as management strategies, have been widely researched over the last few decades; and clinical practice guidelines have been produced to assist health practitioners in the provision of appropriate care (De Groot 2012; Stagnaro-Green 2011). Ongoing debate however, continues regarding the most effective way to identify women with thyroid dysfunction prior to and during pregnancy, and also women who may be at risk of developing thyroid dysfunction during pregnancy. Hypothyroidism Overt hypothyroidism (OH) is characterised by an underactive thyroid gland, or symptomatic thyroid hormone deficiency, defined by low T4 and high TSH concentrations. The prevalence of overt hypothyroidism has been estimated between 0.2% and 1.0% (Negro 2011a). Confirmation of hypothyroidism is achieved through measuring serum TSH. Globally, the most common causal factor for maternal hypothyroidism is iodine deficiency, with maternal iodine deficiency impairing the synthesis of maternal and fetal thyroid hormones. Iodine is an important substance for the thyroid gland to produce and secrete thyroid hormones (Krajewski 2011). Due to increased thyroid hormone production, increased renal excretion of iodine in addition to the iodine requirements of the fetus, iodine requirements for women during pregnancy are higher than for non-pregnant women. The World Health Organization recommends an iodine intake of 250 micrograms per day to meet the increased demand during pregnancy. In high-income countries where iodine deficiency is less common, autoimmune thyroiditis (or Hashimoto s disease) is a more common cause of maternal hypothyroidism (Stagnaro-Green 2011). Untreated maternal OH may be associated with significant complications for a mother and her baby, including hypertension, pre-eclampsia, miscarriage, placental abruption (a complication of pregnancy, where the placental lining separates from the uterus) and postpartum haemorrhage (loss of blood following birth). Fetal or infant complications associated with untreated maternal OH include preterm birth and low birthweight (Stagnaro-Green 2012). Deficiency of thyroid hormone during critical periods of development has the potential to damage the nervous system, and while specific effects are not certain, evidence has accumulated to suggest thyroid hormone deficiency might be one of the causes of cerebral palsy (Hong 2008). A number of observational studies have linked maternal thyroid hormone concentrations in pregnancy with childhood neurodevelopmental outcomes; for example, in two studies, children born to mothers with untreated hypothyroidism during pregnancy, were shown to have significantly lower intelligence quotient (IQ) scores, when compared with control children (Haddow 1999; Mitchell 2004). OH may be treated with levothyroxine, a thyroxine replacement, with the goal of maintaining a euthyroid state (thyroid hormones within a normal range) throughout the duration of pregnancy. Treatment is considered critical to reduce the complications associated with untreated disease, and while treatment has been consistently supported in clinical practice guidelines (De Groot 2012; Stagnaro-Green 2011), the relevant Cochrane review (Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy) recently highlighted the lack of randomised controlled trial evidence in this area (Reid 2013). Subclinical hypothyroidism (SH) refers to biological evidence of thyroid hormone deficiency in women who experience none, or very few clinical symptoms. SH is defined as a normal free T4 6

10 concentration with high TSH concentration. SH is considered to be the most common thyroid disorder to occur in pregnancy and the prevalence has been estimated between 1.5% and 4% (Negro 2011a). SH during pregnancy has been associated with an increased incidence of adverse outcomes similar to those associated with OH, however, in contrast to OH, SH represents a less severe degree of thyroid dysfunction (Cooper 2012). Studies have associated untreated maternal SH to early loss of pregnancy, increased rates of placental abruption and preterm birth (Le Beau 2006). Pregnancy loss, or miscarriage, is often noted as one of the most common complications linked to SH. Data from a prospective cohort study by Benhadi and colleagues reported an increased risk of miscarriage, fetal death and neonatal death with increasing concentrations of TSH during pregnancy, even in healthy women with no overt thyroid disorder (Benhadi 2009). Treatment of SH with levothyroxine is not universally accepted, with recommendations differing between professional organisations (Stagnaro-Green 2012), and no clear evidence to support treatment from the relevant Cochrane review (Reid 2013). Isolated hypothyroxinaemia (IH) during pregnancy is defined by the detection of low serum-free thyroxine (FT4) with TSH concentration within the normal range. Data suggest wide variation in the incidence of IH due to global differences in maternal iodine intake and the reliability of diagnostic tools (Negro 2011a). Several studies have demonstrated that IH, largely caused by iodine deficiency (Morreale 2000), like hypothyroidism, can be associated with negative effects on fetal brain development and thus neurodevelopmental outcomes; increased risks of cognitive, language and motor dysfunction, including cerebral palsy have been reported (Hong 2008). For example, low maternal FT4 has been associated with an increased risk of impaired psychomotor development for children at 10-month follow-up (Pop 1999) and delayed mental and motor function at 12 and 24 months (Pop 2003); increased risks of impaired motor and intellectual development at 25 to 30 months (Li 2010); and expressive language delay and nonverbal cognitive delay at 18- to 30-month follow-up have also been reported (Ghassabian 2014). Thyroid autoimmunity Maternal thyroid autoimmunity refers to the detection of thyroid antibodies against thyroperoxidase (TPO-Ab) and/or thyroglobulin (Tg-Ab) in combination with normal thyroid function. The estimated incidence of thyroid autoimmunity in women of reproductive age has been reported to be between 8% and 14% (Vissenberg 2012). The precise mechanisms that underpin thyroid autoimmunity are not known, however it has been hypothesised that the presence of antibodies are part of an undefined autoimmune response, or that they may reflect a subtle reduction in optimum thyroid function (Negro 2011b). Thyroid autoimmunity has been associated with an increased risk of the development of maternal hypothyroidism during pregnancy (van den Boogaard 2011), and postpartum thyroid dysfunction (Stagnaro-Green 2011). The detection of thyroid antibodies in the early stages of pregnancy confers a 33% to 50% chance of the woman developing postpartum thyroiditis (Stagnaro-Green 2004). Women with thyroid antibodies during pregnancy who recover from postpartum thyroiditis experience a 70% recurrence rate in future pregnancies, and additionally, are at a significantly higher risk of developing permanent hypothyroidism (Samuels 2012). Thyroid autoimmunity during pregnancy has been associated with poor fertility outcomes, recurrent miscarriage and preterm birth (Thangaratinam 2011; van den Boogaard 2011). Thyroid autoimmunity in combination with high TSH concentrations early in gestation has also been associated with a four-fold increased risk of gestational diabetes for the mother (Karakosta 2012). For women with insulin dependent diabetes mellitus, the presence of TPO- Ab prior to pregnancy has been suggested to confer an increased risk of poorer glucose control and an increased risk of developing hypothyroidism (Fernandez-Soto 1997). While the exact relationships between the conditions are unclear, both thyroid autoimmunity and postpartum thyroiditis have been associated with depression (Stagnaro-Green 2004). In a recent study, pregnant TPO-Ab positive women were shown to have higher depressive symptoms during pregnancy, and higher depression, anger and total mood disturbance postpartum, regardless of the development of postpartum thyroiditis (Groer 2013). Similar to risks for the child associated with hypothyroidism and hypothyroxinaemia, children born to mothers with thyroid autoimmunity have been shown to be at risk of adverse neurodevelopmental outcomes. Elevated concentrations of TPO-Ab in women between 16 to 20 weeks of gestation have been shown to be a predictor of poor motor skills and intellectual development in early childhood (Li 2010). Maternal thyroid autoimmunity has also been associated with an increased risk of behavioural problems in childhood, particularly attention deficit and hyperactivity (Ghassabian 2012). Current clinical guidelines outline no specific treatment for women with detected thyroid autoantibodies, however encourage monitoring of serum TSH during pregnancy due to the increased risk of hypothyroidism (Stagnaro-Green 2011). The relevant Cochrane review identified no significant difference for the outcome of pre-eclampsia when levothyroxine treatment was compared with no treatment for women who were TPO-Ab positive and euthyroid during pregnancy, however, noted a reduction in preterm birth and miscarriage with levothyroxine treatment (Reid 2013). The review emphasised that due to the small number of trials contributing data to the review, at a moderate risk of bias overall, there was insufficient evidence to make clear conclusions and to guide clinical practice. Hyperthyroidism 7

11 Hyperthyroidism is characterised by an overactive thyroid gland and the release of excessive amounts of thyroid hormones. Hyperthyroidism during pregnancy is rare with reported incidences ranging from 0.1% to 0.4%, and most women who experience the condition are diagnosed prior to conception and pregnancy (Chang 2013). Causes of hyperthyroidism can be distinguished as immune or non-immune in origin (Negro 2011a), with the autoimmune condition Graves disease accounting for an estimated 85% of cases (Le Beau 2006). Graves disease (in which autoantibodies stimulate the thyroid TSH receptor) is characterised by varied clinical presentation including heat intolerance, shortness of breath, the presence of a goitre, ophthalmopathy (swollen tissue behind the eyes), and rarely, thyroid storm (an acute, life-threatening, hyper-metabolic state induced by excessive release of thyroid hormones) and congestive heart failure. Uncontrolled hyperthyroidism as a result of Graves disease has been associated with an increased risk of perinatal complications, including miscarriage, stillbirth, preterm birth, fetal growth restriction, and pre-eclampsia (Stagnaro-Green 2012). Anti-thyroid drugs (such as propylthiouracil and carbimazole) may be used to treat hyperthyroid women during pregnancy with the goal of achieving a euthyroid state (Stagnaro-Green 2011). A recent Cochrane review (Interventions for hyperthyroidism pre-pregnancy and during pregnancy) however found no completed randomised controlled trials for inclusion addressing management in this area (Earl 2013). The most common cause of non-immune hyperthyroidism is gestational thyrotoxicosis, also referred to as transient gestational hyperthyroidism, caused by elevated concentrations of hcg beyond normal range in early pregnancy. Diagnosis is confirmed by suppressed or very low serum TSH concentrations in the presence of high T4 (Negro 2011a). Gestational thyrotoxicosis is commonly associated with hyperemesis gravidarum (or severe morning sickness) and characterised by severe nausea, early-onset vomiting, and dehydration during the first trimester of pregnancy. Gestational thyrotoxicosis has not been associated with poor obstetric or infant outcomes, however women affected during pregnancy may require hospitalisation for supportive treatment to manage dehydration and other symptoms (Stagnaro-Green 2012). Antithyroid drugs have not been recommended, as serum T4 generally returns to normal concentrations between 14 and 18 weeks gestation (Stagnaro-Green 2011). Description of the intervention Given the prevalence of thyroid disorders in pregnancy, the significance of the short- and long-term adverse outcomes for both the mother and her baby, and the availability of potential management options (dependent on the type of disease and clinical scenario), the early identification of women with thyroid dysfunction prior to or during pregnancy is of great importance (Negro 2011a; Vissenberg 2012). Screening is a strategy used to identify unrecognised disease in individuals; this can include those with pre-symptomatic or unrecognised symptomatic disease. Screening interventions are designed to detect disease early, to enable earlier intervention and management with the ultimate aim of improving health outcomes (NSC 2013). Currently, maternal thyroid disorders are largely detected based on clinical presentation of symptoms and further assessment of thyroid hormone concentrations. Potential screening tests for thyroid dysfunction during pregnancy (such as testing for serum TSH and/or the presence of TPO-Ab) are readily accessible and the improved sensitivity of new generation assays allow for the detection of extremely low serum TSH concentrations, often seen in early pregnancy (Glinoer 2010). Current clinical practice guidelines differ in their recommendations for screening, however, generally advocate for a case finding rather than a universal screening approach (Chang 2013). Universal screening involves screening all pregnant women, whereas case finding involves screening a smaller group of individuals of perceived increased risk. Case finding strategies can also differ, with some guidelines, such as those from the American College of Obstetrics and Gynaecology and from the United States Society for Maternal-Fetal Medicine, recommending thyroid testing only in high-risk pregnant women who are symptomatic, have a personal history of thyroid disorders, have type 1 diabetes or another autoimmune disorder (ACOG 2007; SMFM 2012). Other guidelines such as those of the American Association of Clinical Endocrinologists, American Thyroid Association, and Endocrine Society Task Force recommend a more aggressive case finding approach (De Groot 2012; Garber 2012; Stagnaro-Green 2011), and provide detailed criteria for targeted thyroid disease case finding in newly pregnant women or women planning pregnancy (example criteria: over 30 years; family history of thyroid dysfunction; goitre; personal history of thyroid dysfunction; prior head/ neck irradiation; prior thyroid surgery; symptoms or signs suggestive of dysfunction; thyroid antibodies, primarily TPO-Ab; type 1 diabetes or other autoimmune diseases; infertility; prior miscarriage or preterm birth; iodine-deficient population; medications and iodinated contrast media; morbid obesity (Stagnaro-Green 2011)). Within individual guidelines, recommendations have also been found to differ. The Endocrine Society Task Force highlight in their guideline the lack of agreement reached regarding screening, noting that some members supported a universal screening approach to test for serum TSH abnormalities in pregnancy (prior to the ninth week of pregnancy, or at the initial visit), while other members supported an aggressive case finding approach (De Groot 2012). How the intervention might work It has been suggested that screening based on a case finding approach may fail to detect a large proportion of hypothyroid and hyperthyroid women, whose thyroid dysfunction would thus re- 8

12 main uncontrolled throughout their pregnancies (Chang 2013); subclinical hypothyroidism and thyroid autoimmunity in particular, present with few or no obvious clinical symptoms (Vissenberg 2012). Thus, debate currently ensues surrounding the ideal strategy to identify thyroid dysfunction in pregnancy, particularly regarding the role of universal screening for all pregnant women, versus case finding. A number of studies have assessed the effectiveness of current guidelines that emphasise targeted case finding of women with thyroid dysfunction before or during pregnancy, and their results have provided some support for the consideration of a universal screening approach. In a sample of 400 women, Horacek et al reported that over half (55%) of pregnant women with abnormalities detected in thyroid-related tests would have been overlooked if only high-risk case finding criteria were applied (Horacek 2010). Similarly, Vaidya et al revealed, in a sample of 1560 pregnant women, that specific targeting of only high-risk women would miss an estimated one-third of women with OH or SH (Vaidya 2007). In an assessment of thyroid testing and dysfunction rates at a medical centre in Boston, United States, Chang et al concluded that targeted testing for thyroid dysfunction would have missed approximately 80% of women with hypothyroidism during pregnancy (Chang 2011). While universal screening may have the potential to identify a larger proportion of pregnant women with thyroid dysfunction and therefore facilitate earlier intervention and management, the implications of such an approach must be considered, including significant costs associated with treatment, follow-up and monitoring; and the possibility of misinterpretation of thyroid function tests, leading to over diagnosis/misdiagnosis, and the initiation of inappropriate management strategies (Chang 2013). In regards to the cost-effectiveness of a universal screening approach (compared with case finding), two evaluation studies considering SH (Thung 2009), and autoimmune thyroid disease (Dosiou 2012) in pregnancy both indicated that universal screening would in fact be a cost-effective tool, under a range of circumstances. Observational data from a number of studies have suggested that a large proportion of women with thyroid dysfunction in pregnancy are overlooked when targeted case finding methods are utilised (Chang 2011; Horacek 2010; Vaidya 2007). It is therefore important to conduct this review to assess the effectiveness of different methods of screening for thyroid dysfunction in pregnancy on detection, subsequent management, health outcomes and costs of care. It is plausible that universal screening (as compared with case finding) may facilitate improved diagnosis and early management of thyroid disease in pregnancy, and thus may assist in reducing associated maternal and infant complications. O B J E C T I V E S To assess the effects of different screening methods (and subsequent management) for thyroid dysfunction pre-pregnancy and during pregnancy on maternal and infant outcomes. M E T H O D S Criteria for considering studies for this review Types of studies We planned to include randomised controlled trials, quasirandomised controlled trials and cluster-randomised trials. We planned to exclude cross-over trials. We planned to include studies published in abstract form only, along with those published in full-text form. Why it is important to do this review There is clearly documented evidence of morbidity and mortality associated with thyroid dysfunction (both hyper- and hypothyroidism) in pregnancy; thyroid dysfunction is associated with increased risks of a multitude of adverse outcomes for both the mother and her infant in the short- and long-term. While two Cochrane reviews have assessed interventions for the treatment of thyroid dysfunction pre-pregnancy and during pregnancy (Earl 2013; Reid 2013), no systematic review has assessed the effects of different methods of screening for thyroid dysfunction during prepregnancy and during pregnancy (including universal screening versus case finding), for the identification and subsequent management of thyroid disease. Types of participants Women, either pre-pregnancy or during pregnancy (including both singleton and multiple pregnancies). We excluded women with a pre-existing diagnosis of thyroid dysfunction. Types of interventions We included trials where any screening method (e.g. tool, program, guideline or protocol) for detecting thyroid dysfunction (including hypothyroidism, hyperthyroidism, and/or thyroid autoimmunity) pre-pregnancy or during pregnancy was compared with no screening. We also included trials where two or more methods of screening were compared (e.g. case finding versus universal screening). 9

13 Types of outcome measures Primary outcomes Maternal 1. Diagnosis of thyroid dysfunction (as determined by individual trialists) i) Hypothyroidism (overt; subclinical; isolated hypothyroxinaemia) ii) Hyperthyroidism (Graves diseases; gestational thyrotoxicosis) iii) Thyroid autoimmunity 2. Pre-eclampsia Infant 1. Preterm birth (less than 37 weeks gestation) Infant as child 1. Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/intellectual impairment, at latest time reported) Secondary outcomes Maternal 1. Overall clinical improvement in symptoms of: i) hypothyroidism ii) hyperthyroidism iii) thyroid autoimmunity 2. Pharmacological treatment required to manage thyroid dysfunction i) e.g. levothyroxine treatment for hypothyroidism ii) e.g. propylthiouracil or carbimazole treatment for hyperthyroidism 3. Miscarriage 4. Pregnancy-induced hypertension 5. Gestational diabetes 6. Glucose tolerance measures (e.g. glycated haemoglobin (HbA1c) concentration) 7. Anaemia 8. Congestive heart failure 9. Thyroid storm 10. Mode of birth (normal vaginal birth, operative vaginal birth, caesarean section) 11. Induction of labour 12. Preterm labour 13. Placental abruption 14. Postpartum haemorrhage 15. Weight change (e.g. excessive weight gain/loss in pregnancy) 16. Quality of life 17. Adverse effects associated with the intervention 18. Postpartum thyroid dysfunction 19. Postnatal depression 20. Infertility 21. Maternal death Fetal/neonatal/infant 1. Death (defined as all fetal and neonatal deaths) 2. Fetal death 3. Neonatal death 4. Respiratory distress syndrome 5. Low birthweight 6. Small-for-gestational age (defined as birthweight less that 10th centile) 7. Neonatal intensive care unit (or special care unit) admission 8. Abnormal thyroid function (e.g. neonatal hyperthyroidism; neonatal goitre; cretinism - defined as congenital hypothyroidism resulting in impaired physical and mental development) 9. Other congenital malformations Infant as child 1. Cerebral palsy 2. Blindness: corrected visual acuity worse than 6/60 in the better eye 3. Deafness: hearing loss requiring amplification or worse 4. Developmental delay/intellectual impairment Health services 1. Maternal length of hospital stay 2. Neonatal length of hospital stay 3. Cost of screening 4. Costs of maternal and neonatal/infant care *Unless specified, for all outcomes above, we planned to include outcome data reported according to outcome definitions determined/specified by the trialists Search methods for identification of studies The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group. Electronic searches We searched the Cochrane Pregnancy and Childbirth Group s Trials Register by contacting the Trials Search Co-ordinator (14 July 2015). The Cochrane Pregnancy and Childbirth Group s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from: 10

14 1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); 2. weekly searches of MEDLINE (Ovid); 3. weekly searches of Embase (Ovid); 4. monthly searches of CINAHL (EBSCO); 5. handsearches of 30 journals and the proceedings of major conferences; 6. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central alerts. Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the Specialized Register section within the editorial information about the Cochrane Pregnancy and Childbirth Group. Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. Searching other resources We searched the reference lists of all retrieved studies. We did not apply any date or language restrictions. Data collection and analysis The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group. Selection of studies Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third review author. Data extraction and management We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted the third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy. If information regarding any of the above was unclear, we planned to contact authors of the original reports to provide further details. Assessment of risk of bias in included studies Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor. (1) Random sequence generation (checking for possible selection bias) We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as: low risk of bias (any truly random process, e.g. random number table; computer random number generator); high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); unclear risk of bias. (2) Allocation concealment (checking for possible selection bias) We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); high risk of bias (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth); unclear risk of bias. (3.1) Blinding of participants and personnel (checking for possible performance bias) We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes. We assessed the methods as: low, high or unclear risk of bias for participants; low, high or unclear risk of bias for personnel. (3.2) Blinding of outcome assessment (checking for possible detection bias) We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We assessed methods used to blind outcome assessment as: low, high or unclear risk of bias. (4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data) 11

15 We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re-include missing data in the analyses which we undertook. We assessed methods as: low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups); high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; as treated analysis done with substantial departure of intervention received from that assigned at randomisation); unclear risk of bias. (5) Selective reporting (checking for reporting bias) We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as: low risk of bias (where it is clear that all of the study s prespecified outcomes and all expected outcomes of interest to the review have been reported); high risk of bias (where not all the study s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); unclear risk of bias. (6) Other bias (checking for bias due to problems not covered by (1) to (5) above) We described for each included study any important concerns we had about other possible sources of bias. Assessing the quality of the body of evidence using the GRADE approach We assessed the quality of the evidence using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following outcomes for the review s two comparisons. 1. Diagnosis of thyroid dysfunction (as determined by individual trialists) i) Hypothyroidism (overt; subclinical; isolated hypothyroxinaemia) ii) Hyperthyroidism (Graves diseases; gestational thyrotoxicosis) 2. Pre-eclampsia 3. Preterm birth (less than 37 weeks gestation) 4. Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay/intellectual impairment, at latest time reported) 5. Miscarriage 6. Adverse effects associated with the intervention 7. Death (defined as all fetal and neonatal deaths) We used GRADE profiler (GRADE 2014) to import data from Review Manager 5.3 (RevMan 2014) in order to create Summary of findings tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from high quality by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias. Measures of treatment effect For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals. Continuous data For continuous data, we used the mean difference. We planned to use the standardised mean difference to combine trials that measured the same outcome, but used different methods. (7) Overall risk of bias We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook ( Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. In future updates, we will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis. Unit of analysis issues Cluster-randomised trials We planned to include cluster-randomised trials in the analyses along with individually-randomised trials. In future updates of this review, if we include cluster-randomised trials and if clustering has not been taken into account in the trial s analysis, we plan 12

16 to adjust the trial s sample sizes using the methods described in the Handbook (Higgins 2011) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We also plan to acknowledge heterogeneity in the randomisation unit and plan to perform a sensitivity analysis to investigate the effects of the randomisation unit. Assessment of heterogeneity We planned to assess statistical heterogeneity in each meta-analysis using the Tau², I² and Chi² statistics. We would have regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. If we had identified substantial heterogeneity (above 30%), we planned to explore it by pre-specified subgroup analysis. Assessment of reporting biases In future updates, if there are 10 or more studies in the metaanalysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it. Cross-over trials Cross-over trials were considered inappropriate for this review question. Multiple pregnancies As infants from multiple pregnancies are not independent, we planned to use cluster trial methods in the analyses, if the data allowed, and if multiples made up a substantial proportion of the trial population, to account for non-independence of variables (Gates 2004). Multi-armed studies If we included studies using one or more treatment groups (multiarm studies) where appropriate, we planned to combine groups to create a single pair-wise comparison. We planned to use methods described in the Handbook (Higgins 2011) to ensure that we did not double count participants. Dealing with missing data For included studies, levels of attrition were noted. In future updates, if more eligible studies are included, the impact of including studies with high levels of missing data in the overall assessment of treatment effect will be explored by using sensitivity analysis. For all outcomes, analyses were carried out, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing. Had we included studies where women were recruited preconception, for outcomes relating to pregnancy, we planned to take a pragmatic approach and include in the denominators only those women known to have become pregnant. Data synthesis We carried out statistical analysis using the Review Manager software (RevMan 2014). We planned to use fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we planned to use randomeffects meta-analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. We would have treated the random-effects summary as the average range of possible treatment effects and discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we planned to not combine trials. If we had used random-effects analyses, we planned to present the results as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I². We planned to consider trials screening for specific categories of thyroid dysfunction (i.e. hypothyroidism, hyperthyroidism) versus those trials screening for any thyroid dysfunction. We planned to consider the following comparisons in this review: 1. Any screening method (tool, guidelines, protocol) versus no screening (in this review we compare universal screening versus no screening in pregnancy for hypothyroidism) 2. One method of screening versus a different method of screening, such as case finding versus universal screening - (in this review we compare universal screening versus case finding in pregnancy for any thyroid dysfunction) Subgroup analysis and investigation of heterogeneity If we had conducted meta-analyses, and had identified substantial heterogeneity, we planned to investigate it using subgroup analyses and sensitivity analyses. We planned to consider whether an 13

17 overall summary was meaningful, and if it was, we would have used random-effects analysis to produce it. We planned to carry out the following subgroup analyses, for primary outcomes. 1. gestational age at screening for dysfunction used in the trial (e.g. preconception versus first trimester versus second trimester versus third trimester); 2. type of screening method/protocol used in the trial (e.g. case finding (based on symptoms/history only) versus aggressive case finding (based on a range of risk factors)); 3. baseline risk for thyroid dysfunction of women in the trial (e.g. high risk for thyroid dysfunction (i.e. symptomatic women; women with a family history; other risk factors) versus low risk for dysfunction). However, largely (except for considering baseline risk for thyroid dysfunction as reported in one trial) we were not able to conduct subgroup analyses due to paucity of data. We planned to assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We planned to report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value. Sensitivity analysis We planned to carry out sensitivity analyses to explore the effects of trial quality and trial design on the outcomes. However, planned sensitivity analyses were not conducted due to paucity of data. In future updates of this review, we will carry out planned sensitivity analysis for this review s primary outcomes, if required. We will explore the effects of trial quality assessed by allocation concealment and random sequence generation (considering selection bias), by omitting studies rated as high risk of bias (including quasi-randomised trials) or unclear risk of bias for these components. We will investigate the effects of the randomisation unit (individual versus cluster) on the outcomes, and the impact of including studies with high levels of missing data. We will explore the effects of fixed-effect or random-effects analyses for outcomes with statistical heterogeneity, and the effects of any assumptions made such as the value of the ICC used for cluster-randomised trials. We will restrict this to the primary outcomes. R E S U L T S Description of studies Results of the search The search of the Cochrane Pregnancy and Childbirth Group s Trials Register retrieved four records (see: Figure 1). One record related to an ongoing study (Teng 2013, see Characteristics of ongoing studies). The other three records related to two trials, both of which met the review s pre-defined inclusion criteria. (Lazarus 2012; Negro 2010). One of the three records describes the protocol for ongoing follow-up of children from the Lazarus 2012 trial, which is ongoing. 14

18 Figure 1. Study flow diagram. 15

19 Included studies Two randomised controlled trials were included in this review (Lazarus 2012; Negro 2010). A total of 26,408 women and their babies were involved in the two trials. Settings Both trials recruited pregnant women from hospitals in Europe. Lazarus 2012 recruited women from 10 hospitals in the United Kingdom and one hospital in Italy. Negro 2010 recruited women from two hospitals in Italy. Participants All study participants were pregnant women. Negro 2010 recruited women with a singleton pregnancy, prior to the first 11 weeks of gestation and excluded women with a history of thyroid disease. All women included in this trial were Caucasian, with a mean age of 28.9 and 28.7 years in the case finding and universal screening groups respectively. Lazarus 2012 recruited pregnant women at their first antenatal hospital appointment up to 15 weeks and six days gestation. Women less than 18 years of age, with a twin pregnancy or known thyroid disease were excluded. Baseline maternal characteristics were similar between the screening and no screening group, with a mean maternal age at delivery of 30 and 31 years for each group respectively. Children of women who tested positive for hypothyroidism in both the screening and no screening groups were followed up at three years of age for psychological testing. The median age of children at the time of psychological testing in both groups was 3.2 years (interquartile range of 3.2 to 3.3). Interventions One included trial (Negro 2010) was designed to assess treatment of thyroid dysfunction during pregnancy comparing universal screening to case finding methods. All women had a blood sample taken at their first antenatal visit and discussed any risk factors with an obstetrician. Women were considered high risk if they had any one of the following risk factors: family history for autoimmune thyroid disease, presence of goitre, signs and symptoms suggestive for thyroid dysfunction, personal history for type 1 diabetes or other autoimmune disease, history of neck irradiation, previous miscarriages, or preterm deliveries (included in The Endocrine Society s guidelines for screening high-risk women) (Negro 2010). In the universal screening group, all women had their sera tested immediately for TSH, free T4 (ft4), and thyroid peroxidase antibody (TPO-Ab) status. Women in the case finding group who were considered high risk had their sera tested immediately for TSH, free T4 (ft4), and thyroid peroxidase antibody (TPO-Ab) status. Women in the case finding group who were considered low risk had their sera frozen and assayed postpartum (Negro 2010). For both groups (all women in universal screening group and high-risk women in case finding group) in the Negro 2010 study, women were classified as hypothyroid (TSH greater than 2.5 miu/ litre in TPO-Ab+ women), hyperthyroid (undetectable TSH concentration and elevated ft4), or euthyroid; with hypothyroid and hyperthyroid women referred to an endocrinologist by the 12th gestational week. In women identified as hypothyroid at initial screening, levothyroxine was initiated and titrated during the first trimester to maintain TSH concentration less than 2.5 miu/litre (and less than 3 miu/litre in the second and third trimesters). In women identified as hyperthyroid, treatment was based on clinical judgement - methimazole or propylthiouracil was administered, where necessary, to keep ft4 concentrations around the upper limit or normal, and to avoid undetectable TSH values. All women with thyroid dysfunction had thyroid function tests performed at least once during the second and third trimesters. The second included trial (Lazarus 2012), compared antenatal screening and subsequent treatment for hypothyroidism versus no screening. All women had a blood sample obtained on trial entry. Women in the screening group had their sample assayed for TSH and ft4 immediately, whereas women in the control group (no screening) had their sample frozen, to be assayed for TSH and ft4 after birth. Women in the screening group were considered to have screened positive if their TSH concentration was above the 97.5th percentile, their ft4 concentration was below the 2.5th percentile, or both. Women who screened positive for hypothyroidism in this group were treated with levothyroxine, 150 µg per day. Concentrations of TSH and ft4 were checked six weeks after the start of levothyroxine therapy and at 30 weeks gestation with adjustment of the dose as necessary (target TSH concentration was 0.1 to 1.0 miu/litre). All women in both the screening and control groups received routine care. Women who received positive test results in both groups were advised to visit their family physician after birth to determine if levothyroxine should be continued or initiated. Outcomes The primary outcome for one trial (Negro 2010) was obstetric and neonatal complications (composite outcome). Adverse obstetric and neonatal complications were obtained from a review of medical records and included: miscarriage, hypertension, pre-eclampsia, gestational diabetes, placental abruption, thyroid storm, caesarean birth, congestive heart failure, preterm labour, respiratory distress, neonatal intensive care unit admission, low birthweight, 16

20 high birthweight, preterm (34 to 37 weeks) or very preterm (less than four weeks) birth, Apgar score of three or less at five minutes, perinatal/neonatal death, and other (intraventricular haemorrhage, umbilical artery blood ph less than 7.0, necrotising enterocolitis or major malformations). The primary outcome for the second trial (Lazarus 2012) was intelligence quotient (IQ) at three years of age, and IQ of less than 85 in children of women who tested positive for hypothyroidism. IQ was assessed using the Weschsler Preschool and Primary Scale of Intelligence (Wechsler 2003) by psychologists who visited the children at home. Child behaviour was also assessed at three years of age with the Child Behaviour Checklist (Achenbach 2000) and Brief-P (Gioia 2003) resources. Maternal psychological status was assessed with the Beck Depression Inventory II (Beck 1996). Excluded studies We did not exclude any trials from this review. Risk of bias in included studies Overall, the two trials were judged to be of low risk of bias (see Figure 2; Figure 3). Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies. 17