The Impact of Hyperthyroidism on Fertility, Maternal, Foetal and Perinatal Outcomes in the Era of Iodine Fortification

Abstract

Graves’ disease and nodular toxic thyroid disease are the leading causes of hyperthyroidism. Iodine fortification (IF) among mild-to-moderate iodine deficiency populations is associated with transient increase in incident thyrotoxic nodular disease that may last up to 10 years. A rise in incident Graves’ disease and other autoimmune thyroid conditions has also been associated with IF. Epidemiological studies from different geographical settings around the globe suggest increased incidence even among reproductive age groups in affected populations. Recurrent iodine deficiency in iodine replete populations in developed countries may also predispose them to a similar phenomenon. The prevalence and consequences of hyperthyroidism in pregnancy may be higher than previously reported. We intend to describe the aetiopathology and epidemiology of hyperthyroidism, the mechanisms through which hyperthyroidism predisposes to infertility; the impact of hyperthyroidism on fertility treatment, pregnancy in general and among women with infertility; as well as the effects of hyperthyroidism or agents used in the treatment of hyperthyroidism on perinatal outcomes and adult life for those exposed in utero.

1. Introduction

Thyroid hormones control the metabolism of all nucleated cells and hence are vital for the various processes involved in gametogenesis, fertilisation, embryogenesis, implantation, foetal development and growth in utero [1, 2]. Hyperthyroidism is a pathological state characterised by excessive production of thyroid hormones and subsequent elevation of serum levels of thyroxine (T4) and triiodothyronine (T3) and diminution of serum thyroid-stimulating hormone levels [3]. The different aetio-pathological mechanisms leading to hyperthyroidism as well as the various treatment modalities can potentially have a negative impact on male and female fertility, conception, foetal and maternal well-being, as well perinatal and adult life of foetuses exposed in utero [2, 4, 5]. Previously hyperthyroidism was reported as having a low prevalence of less than 1%, mainly affecting middle-aged and elderly populations [6]. Recent epidemiological surveys suggest the prevalence rates of up to 1.6% in populations recovering from endemic iodine deficiency following universal iodisation of salt, mainly presenting as toxic thyroid nodules, not only among the elderly but including persons in the age range 20–49 years [7, 8, 9]. Pedersen et al. [7] reported an increase of prevalence of hyperthyroidism of 160% in the 20–39 age group in Denmark following food fortification with iodine. In Ghana, following 20 years of universal iodization of salt, Sarfo-Kantanka et al. [8] reported an increase in the incidence of thyroid diseases-related hospital admissions 213 to 538/100,00 admissions. Toxic nodular goitre was the second most common presentation with a percentage of 22.5%, affecting mainly women (female: male ratio of 8.3:1) age range of 27–42 years. This increase in hyperthyroidism following improved access to iodine nutrition although transient but can last up to 10 years [10, 11]. This is followed by a decline in the prevalence of hyperthyroidism in countries that attain and maintain optimal iodine nutrition [7, 9, 12]. It is not clear whether excessive iodine intake in formerly iodine deficiency endemic populations, or recurrent exposure to iodine deficiency in pregnancy like, has been reported in some European countries [13, 14] can lead to prolong the ‘transient increase’ in hyperthyroidism secondary to iodine fortification. One study from south China reported that pregnancy not only predisposes to hypertrophy of pre-existing nodules, also but to the formation of new nodules with biochemical milieu close to subclinical hyperthyroidism [15].

Some of the increase in prevalence of hyperthyroidism among younger people following fortification of food with iodine has been attributed to thyroid autoimmune disorders. This is in addition to thyroid nodules that were previously reported to be more common among middle aged and the elderly populations that are also increasingly prevalent among people in reproductive years [10, 16]. Graves’ disease that has been traditionally reported to be more prevalent in developed iodine-sufficient countries has also been reported in recent studies done in countries recovering from endemic iodine deficiency [17]. This has in part been attributed to an epidemiological transition, or better diagnostic capacity in recent times with many cases remaining undiagnosed in the past.

With an estimated 1.88 billion people at risk of mild-to-moderate iodine deficiency in both developed and developing world and concerted effort to improve iodine nutrition through food fortification [18, 19], the incidence of transient hyperthyroidism at population level secondary to improved iodine nutrition is likely to lead to higher prevalence of hyperthyroidism secondary to nodular thyroid and Graves’ disease. Hence, the incidence of hyperthyroidism in developing both developing and developed countries undergoing iodine supplementation due to endemic or recurrent mild-to-moderate iodine deficiency may be higher than previously reported. This not only requires a better understanding of the effect of hyperthyroidism on pregnancy, but also on fertility, and on neonatal and adult life of those exposed to hyperthyroidism and various treatments in utero.

In this chapter we intend to

• Describe the aetiopathology and epidemiology of hyperthyroidism

• Outline the mechanisms through which hyperthyroidism may predispose to infertility

• Explore the impact of hyperthyroidism on fertility treatment

• Explore the impact of hyperthyroidism on foetal and maternal well-being

• Highlight the impact of hyperthyroidism on post-partum maternal health, perinatal and childhood and adult life of children exposed in utero

2. Aetiology and pathogenesis

Hyperthyroidism has a female predilection (sex ratio of 5:1), and a life time risk of 2–5% with a modal age of presentation among females is 20 and 40 years [20]. More than 99% of all patients with hyperthyroidism are as a result of pathological processes within the thyroid gland leading to hyperactivity and excessive secretion of T3 and T4 [20]. Excessive secretion of TSH from the pituitary is an uncommon cause.

Graves’ disease, an autoimmune disorder in which stimulatory serum IgG antibodies bind to TSH receptors in the thyroid leading to excessive output of T3 and T4 secretion from the thyroid gland into the circulation, is the leading cause in iodine-sufficient regions of the world [20]. Graves’ disease tends to affect the young- and middle-aged people [20, 21] and it thought to result from molecular mimicry following infection with bacteria such as Escherichia coli and Yersinia enterocolitica that possess TSH-binding sites [22]. Other risk factors of Graves’ disease include HLA-mediated genetic predisposition as well as smoking [20, 23].

Toxic nodular thyroid lesions are the second most frequent cause of hyperthyroidism and the leading cause in iodine-deficient areas [24]. Previously, toxic thyroid disease associated with iodine deficient was reported to be more prevalent in the elderly [25]. The aetiology of thyroid glandular lesions leading to hyperthyroidism is related to the degree of iodine nutrition of the population [26]. Following the implementation of universal iodization of salt (USI) globally, studies from formerly iodine deficiency endemic areas reported an increased incidence of both Graves’ disease and toxic nodular thyroid disease also affecting not only the elderly populations, but also segments of the population in the reproductive age [8, 9, 11]. Like Graves’ disease, females are more prone to solitary toxic nodules than males with F:M ratio > 4.8 [8]. Toxic nodular thyroid disease compared to Graves’ disease is more prone to resurgence of thyrotoxicosis after achieving euthyroid state with antithyroid drugs [27].

Among populations with low levels of dietary iodine intake, the thyroid gland tries to ensure adequate hormonal production through increased activity of the thyroid follicular cells. Prolongation of this compensatory hyperactivity due to persistent iodine deficiency results into autonomous growth and function of clusters of follicular cells [25]. The increase in dietary iodine intake following the advent of USI implemented in various countries with low-to-moderate severe iodine deficiency results in excessive output of thyroid hormones from the autonomous follicular clusters resulting into nodular toxic thyrotoxicosis [26]. This increased incidence in hyperthyroidism including people of reproductive age requires a concerted effort aimed at preconception diagnosis and management of hyperthyroid disease in people of reproductive age and in early pregnancy so as to mitigate the short- and long-term foetal, perinatal, maternal and adult life complications associated with uncontrolled hyperthyroidism and its treatment.

Gestational hyperthyroidism also known as gestational transient thyrotoxicosis (GTT) is a transient elevation of serum thyroid hormone levels in pregnant women without evidence of thyroid autoimmunity. GTT affects 1–5% of pregnant women early in pregnancy. This form of thyrotoxicosis usually resolves spontaneously by the end of the first or early second trimester of pregnancy. This is attributed to the physiological elevation of serum HCG, which peaks in the first 8 to 11 weeks of pregnancy, decreasing thereafter, and remaining in plateau up to term [28, 29, 30, 31]. GTT has a short and self-limiting course and does not usually require specific treatment. Milder forms are likely to remain unrecognised. Free T4 levels tend to return to normal in the second trimester; hence, supportive management is generally all that is needed [4]. However, in severe form GTT presents as hyperemesis gravidarum, with significant weight loss and thyrotoxicotic features such as tachycardia, hyperreflexia, hand tremors but without goitre or orbitopathy usually associated with Graves’ disease [4].

3. Differential diagnosis

Differential diagnoses of hyperthyroidism are conditions that predispose to thyrotoxicosis without intrinsic hyperactivity of the thyroid gland. These include thyroid pathology that leads to destruction of the follicular cells and consequential release of the preformed T3 and T4 leading to transient thyrotoxicosis. Examples include post-partum thyroiditis, silent thyroiditis and sub-acute painful thyroiditis. Others include iatrogenic T4 administration, medications such as lithium, interferon α and amiodarone, as well as metastatic thyroid carcinoma and thyroid hormone-producing tumours such as struma ovarii [3] and trophoblastic diseases that produce excessive β-HCG that is not only structurally similar to thyroid-stimulating hormone but has accentuated stimulation of the thyroid follicular cells than the normal hCG [32].

4. Hyperthyroidism and reproduction

Thyroid dysfunction is the most commonly found endocrine problem in females of reproductive age [33]. Hyperthyroidism (both clinical and subclinical) can affect both males and females of reproductive age, by producing variable degrees of gonadal dysfunction [33, 34]. In the general population, it affects 1.5% of reproductive age females and 2.3% of the infertile group [35]. It is associated with infertility, though this is not well established due to limited evidence [36]. According to WHO, infertility is failure to achieve successful pregnancy after 12 months or more of appropriate, timed, unprotected intercourse [37]. Although there is no evidence of improved ovulation rates, treatment of both clinical and subclinical hyperthyroidism is advisable to improve pregnancy adverse outcomes, including early pregnancy loss [35, 36].

4.1 Effect of hyperthyroidism on the hypothalamic, pituitary gonadal axis

Thyrotoxicosis in females is associated with increased GnRH sensitivity, though most women will still have ovulatory cycles [36, 37]. Other hormonal changes in a female include an increase in the production of sex hormone-binding globulin (SHBG) and oestrogen with decreased oestrogen clearance. Thyrotoxicosis is also associated with the increased production of androgens such as androstenedione and testosterone that are subsequently converted to estrone [34, 38].

Hyperthyroidism is associated with delayed puberty [32]. Post-puberty hyperthyroidism may be associated with hypomenorrhea, polymenorrhea, oligomenorrhea and hypermenorrhea [34]. These menstrual disturbances are found in about 22% of women with hyperthyroidism compared to 8% of healthy controls [39].

Hyperthyroidism in males is associated with increased incidence of gynecomastia, as well as decreased libido which is attributed to increased levels of free oestrogen [34]. Hyperthyroidism causes oligozoospermia, asthenozoospermia and teratozoospermia, the mechanisms by which these adverse effects come about is poorly understood [40].

4.2 Autoimmune thyroid disease (AITD) and fertility

Thyroid autoimmune is present in up to 25% of the general population [35]. AITD is associated with poor outcomes pregnancy outcomes among women in reproductive age who are euthyroid, especially those who are undergoing assisted reproduction [35]. The thyroid is affected by autoimmune disease via T cells, commonly causing to Graves’ disease and Hashimoto’s thyroiditis accompanied with hyperthyroidism or hypothyroidism [30]. Most common antibodies include thyroid peroxidase antibodies, thyroglobulin antibodies and thyroid-stimulating hormone receptor antibodies. Thyroid-stimulating antibodies are central to the pathogenesis of Graves’ disease, while other antibodies are produced as a response to thyroid injury leading to hypothyroidism. Thyroid-stimulating antibodies have a limited effect on fertility, but have a role in foetal and neonatal hyperthyroidism [30].

The radioactive iodine treatment commonly used for hyperthyroidism, especially Grave’s disease does not have an effect on gonadal function but pregnancy should be postponed by at least 6 months after treatment because of teratogenic effect [31, 35].

5. Preconception care

The best maternal and prenatal outcomes are expected from women who are healthy at the onset of pregnancy [41]. Pregnancy among women with hyperthyroidism faces a two-pronged challenge: potential complications from metabolic derangements secondary to excessive thyroid hormones and circulating auto-antibodies among women with Graves’ disease; and the adverse effects of the varied treatment remedies aimed at the control thyroid function close to the normal state [4]. The principles of preconception care for women with hyperthyroidism are to use effective contraception until the patient achieves a sustained euthyroid state [42]. This will reduce the complications associated with the deranged metabolic state due to excessive thyroid hormones in the circulation.

In order to reduce the risk of teratogenicity, women who have attained a euthyroid state preconceptionally when treated with carbimazole or methimazole should be switched to propylthiouracil till a stable euthyroid state is maintained before attempting to conceive [43]. Treatment with propylthiouracil should be continued until organogenesis is deemed complete at the end of the first trimester.

Since pregnancy is associated with diminution of cell-mediated immunity and reduced risk of relapse, an alternative strategy for euthyroid women with Graves’ disease with TSH receptor antibodies (TRab) below cut-off level, on minimum doses of antithyroid drugs is to withhold the antithyroid drugs at the inception of pregnancy. Then, they are to be followed closely with prompt reinstatement of treatment in case of relapse [43, 44]. Women who still desire pregnancy but are at high risk of relapse due to high-circulating levels of TRab titres should be counselled for the option of total thyroidectomy and thyroid hormone replacement [44].

6. Thyroid physiology in pregnancy

The thyroid gland produces T3 and T4 which are essential for normal maternal and foetal metabolism. The hypothalamic-pituitary-thyroid axis is important for this control [45]. Increase in oestrogen concentration in pregnancy results in elevated hepatic synthesis of thyroid-binding globulin (TBG) necessitating increased T3and T4 output from the thyroid gland. This coupled with relative iodine deficiency due to increased maternal glomerular excretion, and transplacental transfer of iodine to the foetus combined with high levels of HCG leads to maternal thyroid hyperstimulation [46]. This increases the serum T4 and T3 levels between 6 and 12 weeks of gestation reaching a plateau at 20 weeks which through negative feedback reduces TSH secretion from the pituitary [46, 47]. In early pregnancy, there is transplacental transfer of maternal T4 but not TSH which is essential for foetal metabolism and normal neurological development. In the second trimester, there is placental metabolism of maternal thyroid hormones and the foetal thyroid takes over thyroid hormone synthesis using iodine obtained through transplacental transfer from the mother [29].

The normal range of thyroid function tests in pregnancy varies according to iodine dietary content and ethnicity, and fluctuations across the trimesters of pregnancy [48]. Total T4 (tT4) has been found to be more reliable for measurement during pregnancy compared with fT3 and fT4. To adjust for the general increase of tT4 in pregnancy compared to non-pregnancy state, it is recommended that the levels should be multiplied by 1.5. As an option fT4 index may also be used in pregnancy, as it corrects tT4 according to the TBG levels [48].

6.1 Hyperthyroidism and interpretation of results in pregnancy

HCG, which is structurally similar to TSH molecule, has a weak stimulatory effect on the thyroid cells resulting in elevated T4 and T3 [28, 29]. A negative feedback effect of the elevated thyroid hormones on the anterior pituitary results in low levels of TSH [48]. This reduction is estimated to be about 0.1–0.2 mU/L for the lower limit and 0.5–1.0 mU/L for the upper limit compared to non-pregnant state [41]. HCG levels decrease in the second trimester; therefore, TSH level rises again [48]. The use of trimester-specific TSH reference values is necessary in pregnancy due to these physiological changes that result in modification of the normal reference ranges of serum thyroid-stimulating hormone. Free serum T4 (FT4) estimates are unreliable during pregnancy compared to TSH that remains sensitive in pregnancy despite the effects of HCG (human chorionic gonadotropin) (Table 1) [41].

Test	Non-pregnant state	First trimester	Second trimester	Third trimester
TSH	0.3–4.2	0.1–2.5 mIU/L	0.2–3.0 mlU/l	0.3–3.0mlU/L
fT4 (pmol/l)	9.0–26.0	10-16 pmol/l	9.5–15.5 pmol/l	8–14.5 pmol/l
fT3 (pmol/l)	2.6–5.7	3-7 pmol/l	3–5.5 pmol/l	2.5–5.5 pmol/l

Table 1.

Comparison of serum thyroid hormone levels in pregnancy and non-pregnant state.

Refs. [41, 48].

6.2 Clinical features of hyperthyroidism pregnancy

The clinical features of hyperthyroidism overlap with those of pregnancy and hence may make diagnosis difficult especially for a patient who develops incident hyperthyroidism in the first trimester of pregnancy [49]. These include palpitations dyspnoea, fatigue, sweating and haemic murmurs. If these features become severe in addition to nervousness and hyperactivity, it is prudent to exclude thyrotoxicosis with its underlying cause.

Although graves’ disease has traditionally been reported in the young adults, and nodular toxic thyrotoxicosis in older people, it is worthwhile to consider both conditions in addition to gestational thyrotoxicosis when presented with a symptomatic pregnant woman [10, 16]. This is informed by the increased prevalence of both autoimmune and nodular thyroid disease with iodine fortification coupled with recurrent migration within and between countries and continents [15].

Some features that can help distinguish between the three commonest underlying causes of thyrotoxicosis in pregnancy are shown in Figure 1 and Table 2 [50, 51, 52].

Figure 1.

Biochemical features of gestational thyrotoxicosis, Graves’ disease and nodular thyroid disease.

Clinical features	GD	GTT	TMG &TA
Symptoms pre-dating pregnancy	++	—	+/−
Symptoms during pregnancy	+/+++	+/−	+/−
Nausea/vomiting	−/+	+++++	+/−
Persistence of symptoms	May subside	Subsides in second half	May worsen
Goitre	+	—	+
Orbitopathy	+	—	—

Table 2.

Differentiating clinical features of Graves’ disease, gestational thyrotoxicosis and toxic nodular disease.

6.3 Effect of pregnancy on the common underlying entities of thyrotoxicosis

6.3.1 GTT

Since gestational transient thyrotoxicosis is caused by excessive hCG or in heritable TSHR hypersensitivity to hCG, GTT will be self-limiting and most patients will revert to normal thyroid function after the first trimester especially by about 20-week gestation following the natural reduction in serum hCG [51]. However, thyrotoxicosis may persist beyond the first trimester among women with hyper-placentosis such as in multiple pregnancy or among women with heritable TSHR hypersensitivity to hCG. In these patients, toxic nodular goitre need be excluded.

6.3.2 Graves’ disease

Due to the diminishing levels of cell-mediated immunity as pregnancy progresses, serum levels of TRab tend to reduce in the second and third trimester with the consequent reduction in levels of T3 and T4 as well as the symptoms of Graves’ disease [29].

6.3.3 Toxic thyroid nodules

Pregnancy is associated with increase in the size and number of thyroid nodules especially among women of higher parity [15]. This may potentially increase the severity of thyrotoxicosis and the necessity for treatment or increase in doses of ATD or lead to surgical intervention.

6.4 Impact of thyrotoxicosis on pregnancy

Without optimum maternal treatment, hyperthyroidism in pregnancy is associated with maternal and foetal adverse outcomes. This could be secondary to the high metabolic state and specific pathological processes, and ATD [29, 41].

6.4.1 Impact on maternal health

Severe GTT may be associated with hyperemesis gravidarum that in addition to features of thyrotoxicosis will present with weight loss of ≥5%, dehydration and ketonuria [4]. Rather than being a direct complication this may be due to the shared mechanism of high levels or hypersensitivity to circulating hCG.

Maternal nodular goitre can lead to tracheal obstruction. Irrespective of the primary cause, high levels of thyroid hormones T3 and T4 may predispose to maternal arrythmias and cardiac failure, or thyroid storm, miscarriage, abruptio placenta and preeclampsia. Elevated TRAb preconception is a prognostic of risk for relapse of GD, failing ATD or cessation [53].

6.4.2 Maternal complications

Maternal complications of hyperthyroidism include preeclampsia, abruptio placenta, incident diabetes mellitus, thyroid storm, and arrhythmia, congestive heart failure, and cardiovascular disease [4, 41]. In a recent systematic review and meta-analysis, Alves et al. [5] found that the treatment of hyperthyroidism was associated with reduced risk of abruptio placentae, gestational diabetes mellitus and postpartum haemorrhage.

6.5 Management of hyperthyroidism in pregnancy

Optimum management of hyperthyroidism in pregnancy necessitated a multidisciplinary team comprising of an obstetrician, maternal foetal medicine specialist and paediatric endocrinologist, and a neonatologist is necessary, and sometimes adult and paediatric critical care specialists if complications arise [29]. The aim of treatment is to achieve near-euthyroid state without causing adverse effects to the mother and the foetus.

Challenges of treatment include the following:

• Radioiodine crosses the placenta leading to foetal thyroid ablation so is contraindicated in pregnancy.

• Surgery predisposes to pregnancy losses especially in first and third trimester and severe haemorrhage and laryngeal nerve injury to the mother so it is best differed to post-partum period or if unavoidable done in the second trimester [45, 54].

• ATDs cross the placenta, predispose to congenital defects if used in the first trimester, and in high doses predispose to foetal hypothyroidism.

6.5.1 Management of GTT

GTT is usually self-limiting hence symptomatic treatment is usually recommended [49]. If symptoms persist beyond 16 weeks gestation into the second half of pregnancy, or is severe enough to require ATD, the patient should be re-valuated and screened for GD, toxic adenoma or TMN goitre.

6.5.2 Management of thyrotoxicosis among women with GD, toxic adenoma and multinodular goitre in pregnancy

The management includes administration of ATD, beta-blockers and supportive treatment as needed. The mechanism of action of thionamides is to block the synthesis of thyroid hormones; in addition, PTU blocks the peripheral conversion of T4 to more potent T3 [55]. The aim of ATD therapy is to maintain thyroid hormones levels at the upper point of the normal range with the minimum possible dosages of the drugs. PTU should be used in the first trimester as recommended and then later substituted with methimazole in the second trimester to avoid hepatotoxicity associated with it. Adjunctive treatment with beta-adrenergic blockers may be used to reduce tachycardia, palpitations and tremors. Propranolol 20 to 40 mg orally every 8 to 12 hours may be used while awaiting response to the antithyroid medications [4]. Antithyroid medications can and should be tapered as pregnancy progresses [56]. When serum TSH rises to detectable level, this is an indication to reduce ATD.

In patients in with GD in which ATD is discontinued in the third trimester, close monitoring should be done in the postpartum period due to high risk of relapse [56]. The indications for thyroidectomy include severe thyrotoxic orbitopathy, high TRab titres post-radioiodine therapy in GD, obstructive goitre and adverse drug reaction [54].

Since the risk of recurrence of toxic multinodular goitre treated with ATD is more than 95%, patients with thyrotoxic multinodular disease treated with ATD during pregnancy should be considered for thyroidectomy in the in the postpartum period [27].

7. Maternal hyperthyroidism and the foetus

The foetal thyroid gland develops 24-days post-conception and is capable of taking up iodine from 10 to 11 weeks. Foetal thyroid hormone production is controlled by the foetal hypothalamo-pituitary axis beginning 20 weeks after conception. Foetal levels of TSH, T4 and T3 reach adult levels by 36 weeks [55]. Transplacental passage of maternal thyroid-stimulating antibodies or ATD, both of which may disrupt foetal thyroid function have an effect on foetal prognosis [29].

7.1 Effect of TRab on the foetus

The foetus may develop thyrotoxicosis secondary to the maternal receptor antibodies, which having crossed the placenta stimulates the adenylate cyclase in foetal thyrocytes. The foetus of untreated or mothers with poorly controlled GD disease may be complicated by foetal goitre, intrauterine growth retardation, low birth weight and preterm birth or foetal death may occur [4]. These foetal complications have also been observed in pregnancies of some women with Graves’ disease that became euthyroid after surgical or radioiodine treatment that remained with high-serum thyroid receptor antibodies [57]. The detection of TRAbs in pregnancy should result in the foetus being considered at risk of developing thyrotoxicosis and monitored accordingly [58].

7.2 Effects of maternal ATD therapy on the foetal thyroid

All available ATDs (MMI, CM, PTU) cross the placenta and therefore have the potential to cause foetal hypothyroidism [4]. Early exposure in pregnancy to ATD has been associated with birth defects [4]. PTU is associated with less common and less severe teratogenicity than MMI (Table 3) [59]. ATD doses necessary to maintain maternal FT4 in the upper normal to mildly thyrotoxic range are associated with normal foetal thyroid function. Higher doses of ATD predispose to foetal hypothyroidism and goitre [4]. Therefore, it is recommended the lowest effective dose of MMI or PTU to maintain maternal serum FT4/TT4 at or moderately above the upper limit of the reference range should be used.

Carbimazole/methimazole	PTU
Aplasia cutis	Pre-auricular sinus/fistula and cysts
Choanal/oesophageal atresia	Urinary tract abnormalities in males
Hearing loss
Dysmorphic features
Developmental delay
Omphalocele
Omphalomesenteric duct abnormalities

Table 3.

Birth defects associated with ATDs.

Refs. [4, 59].

The ‘Block’ and ‘replace’ treatment method with ATD and levothyroxine (LT4) should be avoided in pregnancy because the transplacental passage of ATD is high, whereas it is negligible for thyroid hormones; hence, addition of LT4 will not protect the foetus from ATD-induced hypothyroidism [60, 61].

7.3 Foetal ultrasound

Mothers with positive Trab should be referred to a maternal foetal medicine specialist for foetal surveillance. This includes foetal ultrasound in the first trimester for dating and nuchal translucency (NT scan), foetal anomaly scan at 18–22 weeks and 2–3 weekly scans to screen for adverse effects of TRab and ATD. Ultrasound features of foetal hyperthyroidism include goitre detected as a solid hyperechogenic vascular neck mass [60], tachycardia, hydrops, polyhydramnios and risk of premature rupture of membranes and preterm labour and foetal growth restriction [4].

Foetal hypothyroidism may be diagnosed by the presence of a large goitre, polyhydramnios and bradycardia. Demonstration of peripheral blood flow on foetal thyroid Doppler ultrasound differentiates goitre due to foetal hypothyroidism from that due to foetal hyperthyroidism, which has both peripheral and central blood flow [62].

7.4 Management of foetal complications

The mainstay of treatment of foetal GD secondary to transplacental maternal TRab regardless of maternal thyroid state is the administration of ATD to the mother and monitoring of reduction of foetal goitre and foetal heart rate. In case maternal hypothyroidism ensues, this is managed with levothyroxine replacement [41].

The approach to foetal hypothyroidism secondary to maternal ATD is to reduce the dose and aim to keep the T4 levels closer to the upper limit of normal [52]. In rare cases where hypothyroidism does not resolve following reduction of maternal ATD doses, invasive therapy with intra-amniotic levothyroxine at a dose of 10mcg/kg/week for several weeks can be given [52].

When foetal goitre persists to time of delivery a planned elective caesarean section should be performed with EX-Utero Intrapartum Treatment (EXIT) procedure to secure the airway with intubation while still maintaining placental circulation [60].

8. Children Born to Mothers with Hyperthyroidism

Since GTT is usually self-limiting [29], children born to mothers with GTT are expected to be healthy at birth. Those born to mothers with Graves and nodular thyrotoxicosis requiring treatment may present with complications secondary to transplacental transfer of ATD [63]. Antithyroid drugs are also transferred into the breast milk and this has been previously thought to put the nursing neonate at risk of hypothyroidism. However, several studies evaluate thyroid function in infants whose mothers breastfed while taking PTU or MMI failed to detect the adverse effects on the newborn [64]. Continuation of breastfeeding is generally now considered safe and should be encouraged in hyperthyroid mothers taking ATD.

About 1–2% of neonates born to mothers with GD develop neonatal hyperthyroidism although some have reported an incidence as high as 5% [65, 66]. Neonatal thyrotoxicosis carries significant morbidity and mortality. In most cases, neonatal thyrotoxicosis is transient and results from the transplacental passage of maternal stimulating TSH receptor antibodies (TRAb) [66, 67]. TRAb may also be transferred to the baby by way of breastmilk and cause neonatal hyperthyroidism, which requires treatment even if the mother is euthyroid [67].

All infants born to mothers with a history of Graves’ disease should undergo careful examination and monitoring to screen for the development of clinical hyperthyroidism and serious complications associated with it [29]. Neonates born to mothers with Graves’ disease with good control on ATD may not have obvious symptoms of hyperthyroidism at birth, which may result in delayed diagnosis and complications [4]. Neonates born to mothers who tested negative for TRAb during the second half of gestation or those that exhibited absence of TRAb in the cord blood are unlikely to develop hyperthyroidism and are considered low-risk patients [68]. However, all neonates of mothers with hyperthyroidism require a focused assessment at birth for potential complications.

8.1 Clinical presentation of neonatal hyperthyroidism

The time of onset and severity of symptoms of hyperthyroidism are variable. Neonates born to mothers who had high TRAb levels (more than three times the upper normal value) and who were not treated with ATDs can exhibit overt hyperthyroidism at birth, while neonates born to mothers treated with ATDs or neonates who receive maternal thyroid receptor blocking antibodies may have normal thyroid function or present with hypothyroidism at birth [69, 70]. Some neonates of mothers with GD on antithyroid medication may be born with the features of hypothyroidism and later after about 2–5 days of life may show signs of hyperthyroidism following subsequent metabolism and excretion of maternal ATDs from their circulation [71].

The neonatal hyperthyroidism may present with a thyroid storm marked by tachycardia, hypertension, hyperthermia, tremors, irritability, restlessness, sweating, difficulty in sleeping, tachypnoea, arrhythmia, supraventricular tachycardia and cardiac failure [72]. Neonates with thyrotoxicosis and cardiac failure have a high mortality rate of up to 20% if not timely and adequately treated [73].

Maternal TRab may remain in the infant circulation for from a month up to 3 months, most neonates with congenital hyperthyroidism respond to ATD therapy within 1–2 months [74]. However, there might be some long-term adverse effects on cognitive development even with the prompt treatment.

Others may present with features such as frontal bossing, triangular face, periorbital oedema, goitre, hyperactivity, failure to thrive despite excessive appetite, reduction in the subcutaneous adipose tissue [68]. The neonate may also present with non-specific clinical features such as diarrhoea, vomiting, fever, sweating, pulmonary hypertension, chylothorax, jaundice, hepatosplenomegaly, prolonged acrocyanosis and sialadenitis. Premature closure of cranial sutures (craniosynostosis) and subsequent microcephaly may be noted in severely affected infants [75].

8.2 Laboratory tests for neonates with hyperthyroidism

It is recommended that neonates born to mothers with TRAb antibodies as well as neonates with a known family history of genetic congenital hyperthyroidism should have their cord blood tested for the TRAb between days 3 and 5 after birth, then at 2 weeks and 3 months [68, 76]. Thyroid function tests performed on the cord blood before the third day of life in neonates tend to reflect intrauterine foetal thyroid status and are poor predictors of neonatal hyperthyroidism. Thyroid function tests start showing biochemical picture in the neonates with hyperthyroidism between days 3 and 15 following birth [77].

High-risk infants with normal initial testing should have repeat blood workup at days 10–14 days of life or when symptoms appear. Hyperthyroidism in the newborn is suggested by high T4 and T3 levels with low TSH (<0.9 mlU/L) [66]. Additional investigations to check for other organ malfunction include AST, ALT and direct bilirubin, blood sugar, and platelets, cardiac and thyroid ultrasonography as well as wrist and hand X-ray for assessment of bone maturation [66].

8.3 Management of neonates with hyperthyroidism

Treatment should be promptly initiated upon clinical and biochemical diagnosis of neonatal hyperthyroidism [76]. Early and appropriate treatment is necessary in order to reduce the risk of heart failure in the acute phase. Adequate hydration should be maintained and airway, breathing and circulatory support should be provided if required [71]. Pharmacological treatment includes adrenergic blockage, inhibition thyroid hormone synthesis, release and peripheral conversion, reduction of preload afterload and regulation of cardiac rhythm and other supportive treatment (Table 4) [71]. Infants with persistent hyperthyroidism despite adequate medical treatment may require thyroidectomy [66].

Pathological state	Targeted action of the medication	Pharmacological agents
Excessive adrenergic stimulation	Adrenergic blockage	Propranolol 0.25–0.75 mg/kg/dose 8hrly
Excessive adrenergic stimulation with cardiac failure	Reduction of preload, afterload, rate and rhythm control	Diuretics and digoxin
Excessive stimulation of the thyroid by TRabs	Blockage of thyroid hormone synthesis	PTU 5–10 mg/kg/day in 3 doses OR; Carbimazole 0.5–1.5 mg/kg/day OR; Methimazole 0.25–1 mg/kg/day in 2–3 divided doses
	Suppression of synthesis and release of thyroid hormones	Potassium 1–2 drops daily; Lugol’s solution 1 drop (8 mg) 8 hourly
Excessive levels of peripheral T3 and T4	Suppress peripheral conversion from T4 to T3; Compensation for thyroid hormone induced hyper-catabolism of endogenous glucocorticoids	Prednisone 2 mg/kg/day
Restlessness and irritability	Supportive care	Sedatives

Table 4.

Treatment options for neonates with congenital hyperthyroidism.

Adapted from Ref. [68].

8.4 Pathogenesis of congenital hypothyroidism among neonates born to mothers with hyperthyroidism

Some neonates of mothers with hyperthyroidism may be born with congenital hypothyroidism which may be central or primary. Primary neonatal hypothyroidism may occur among children born to mothers on ATD, or Graves’ disease secondary to TSHR blocking antibodies transfer across the placenta, which directly suppresses T3 and T4 production in the foetal thyroid (Table 5). Among these patient’s neonatal hypothyroidism tends to be transient due to the clearance of the ATD and antibodies from the neonatal circulation; hence, they may not require treatment [78].

Clinical condition	TSH	T4
Central congenital hypothyroidism	Low / normal or mildly elevated	Low
Primary congenital hypothyroidism	High	Low

Table 5.

Biochemical features of central and primary neonatal hypothyroidism.

Central hypothyroidism arises from downregulation and delayed maturity of the foetal pituitary due to excessive production of thyroid hormones following foetal thyroid stimulation by maternal TRSAB. This tends to be transient in about 70% of the neonates; however, in 30% it may persist requiring lifelong treatment with levothyroxine [66, 79].

8.4.1 Clinical features of neonates with congenital hypothyroidism

Most neonates with congenital hypothyroidism may be asymptomatic; however, symptoms include decreased motor activity, longer spells of sleeping, feeding difficulties, horse cry and prolonged jaundice. The physical examination may reveal enlarged fontanelles, macroglossia, hypotonia, rounded abdomen, umbilical hernia and myxoedema [80].

8.4.2 Management of neonates with congenital hypothyroidism

The recommended treatment should be L-T4 which should be initiated within the first 2 weeks of life at a dose of 10–15 mcg/kg/day according to severity of the disease and dose adjusted according to fT4 and TSH levels [81]. Close follow-up of 1–2 weeks is necessary till TSH levels are established then 1–3 months in the first year and then 2–4 months in the first 3 years. The target is to keep TSH levels within the normal limits according to age and fT4 levels in the upper half of the normal range [81].

9. Postpartum thyroiditis and depression

Postpartum thyroiditis is an autoimmune destructive inflammation of the thyroid gland that manifests within the first 12 months after delivery or miscarriage [82]. A fifth to one quarter of the patients present with the classic biphasic nature of thyrotoxicosis presenting within the first 1–4 months after delivery followed by hypothyroid state in the next 4–8 months. Another quarter present only with thyrotoxicosis, about 50% only with hypothyroid phases [41, 83]. About 80–85% revert to euthyroid state, the rest remaining hypothyroid [41, 83]. While postpartum thyroiditis is associated with a wide range of somatic and psychic symptoms, depression has been more associated with the hypothyroid phase, while anxiety and hyperactivity are more common in the thyrotoxicosis phase of this disease [83]. This may explain the conflicting results reported by different studies that sought to establish the relationship between postpartum thyroiditis and postpartum depression [84, 85] that may have had participants with differing phases of postpartum thyroiditis. Anticipation of the possible incidence of postpartum depression during the hypothyroid phase will help plan appropriate follow-up with consequent early diagnosis and management of women at risk of postpartum depression secondary to postpartum thyroiditis.

An increased incidence of thyroid autoimmunity has been reported following iodine supplementation among populations with mild-to-moderate iodine deficiency [7, 8]. The physiological diminution of cell-mediated immunity during pregnancy may mask the autoimmune thyroiditis, which may manifest as postpartum thyroiditis and with features of depression several months postpartum well past the puerperium period [4, 86]. Hence, it may be prudent to increase surveillance for postpartum thyroiditis and postpartum depression in populations undergoing iodine supplementation due to endemic mild-to-moderate iodine deficiency.

10. Conclusion

Although hyperthyroidism has limited impact on fecundity, if undiagnosed or not effectively controlled, it can greatly reduce fecundability for both fertile women and those on fertility treatment through early pregnancy losses and iatrogenic preterm delivery that may accompany maternal complications. The transient increase in hyperthyroidism secondary to iodine fortification is associated with higher incidence non-toxic and toxic thyroid nodules among women in later half of reproductive age and Graves’ disease among younger women. This may not only increase the incidence of perinatal, congenital and behavioural complications associated with in utero exposure to ATD and TRabs, but also maternal mental and cardiovascular complications. This calls for more studies to further elucidate the epidemiology of hyperthyroidism and other thyroid disease especially in populations with recurrent waves of recurrent iodine deficiency or excess with concurrent iodine fortification as well as increased vigilance during prenatal and postnatal care. Poorly controlled hyperthyroidism in pregnancy is associated with maternal morbidity and mortality. Long follow-up of children born to mothers with hyperthyroidism is crucial as they may present with neurocognitive disorders.

Conflict of interest

The authors declare no conflict of interest.