Primary congenital hypothyroidism: challenges in a low-income country without paediatric endocrinologist and universal newborn screening

Abstract

Due to the lack of public awareness, congenital hypothyroidism (CH) remains an overlooked challenge in Cambodia. This disease should be screened routinely at birth because, though asymptomatic, it can lead to mental retardation in the absence of early treatment. Since 2013, our unit has been the only centre that implements routine screening and provides treatment and follow-up. This case report highlights a long and tough journey of a girl who, after being diagnosed by routine newborn screening, came for follow-up at our centre. Since the screening has yet to be recognised nationally, we want to raise not only awareness of CH but also the difficulties faced by parents because their children are in need of life-long treatment in a low-resource country. Thus, the key to successful management of paediatric patients is their parental involvement, which can be influenced by their educational, cultural, geographical and financial background.

Background

Congenital hypothyroidism (CH) is the most common endocrine disorder, characterised by the deficiency in thyroid hormones in neonates. It is considered to be one of the most common preventable causes of neurodevelopmental disability.¹

Prior to the newborn screening (NBS) era, CH was suspected and diagnosed mostly after clinical manifestations; a 7-year retrospective study in Sweden reported the incidence of the disorder to be 1:6900.² In 1972, the screening for hypothyroidism was first implemented in Quebec, Canada, and the first biggest pilot programme for NBS, conducted in most North American countries, reported the incidence of 1:3684 live births.³ Since then, the incidence of primary CH has been reported to be between 1:2000 and 1:4000.^{4 5}

Most cases of CH are primary and permanent. Eighty-five per cent of the cases, being sporadic, are caused by thyroid dysgenesis (hypoplasia or aplasia), while the other 15% are due to dyshormonogenesis. Commonly found in premature infants, transient hypothyroidism represents about 10% of the cases. Central hypothyroidism, on the other hand, is secondary to hypothalamic-pituitary dysfunction and, therefore, is rare.⁶

It is noteworthy that the majority of infants diagnosed with CH are asymptomatic at birth.⁷ Since thyroid hormone, in addition to its vital role in neurological development, has important effects on metabolism, linear growth and other body functions, its deficiency causes variable, non-specific signs and symptoms. Over several weeks, the absence of hormone replacement will gradually bring about classic clinical features, including constipation, lethargy, prolong jaundice, poor feeding (ie, need to be awakened to be fed), hypotonia, umbilical hernia, mottling or dry skin, abdominal distension, large fontanel (anterior more often than posterior), macroglossia and hypothermia, to name a few.⁸

According to current international guidelines, a newborn with an abnormal screening result should be referred to a specialist centre where confirmatory testing of serum free thyroxine (fT4) and thyroid stimulating hormone (TSH) is performed. Levothyroxine (LT4) should also be initiated immediately if the serum fT4 is below the age-specific reference range and TSH is clearly above the range. However, in countries where laboratory tests are not available, it is recommended to start LT4 when filter paper measurements of TSH concentration are above 40 mU/L (at the moment of screening). The treatment should be initiated before 2 weeks of life. The first follow-up should be arranged 1 or 2 weeks after initiating the treatment to assess clinical progress and maintain TSH within the targeted range. The next follow-up can be arranged for every 2 weeks until TSH returns to the normal range. Once TSH has been normalised, follow-up can then be arranged every 1–2 months during the first year, and every 3–6 months during the next years until expected growth is achieved.⁵

During the 20th century, at the beginning of NBS, the starting dose of 6–8 µg/kg/day was reported to produce good psychometric results with an average score for verbal, performance and full-scale IQ at the age of 6.⁹ However, the American Academy of Pediatrics has increased the starting dose to 10–15 µg/kg/day because recent studies have shown that this higher dose produces better psychomotor outcome in severe CH.^{5 10 11}

Unrecognised CH leads to mental retardation. However, infants treated early have good long-term neurodevelopment outcomes. Using IQ as a means of comparison, we can clearly see that, compared with the infants treated after 2–4 weeks of life, the infants receiving the early treatment showed better outcomes with IQs similar to those of healthy infants.^12–14

Given the aforementioned information, the objective of this case report is to raise the awareness of the commonly overlooked neonatal endocrine disorder and to highlight the important role of parental involvement in providing care to a neonatal and paediatric patient in a low-income country.

Case presentation

Birth history

A female term neonate was born at 40 weeks gestation by vaginal delivery. The amniotic fluid was clear, and the Apgar scores were 8, 9 and 10 at M1, M5 and M10, respectively. The birth weight was 3150 g (30th percentile), while length was 49 cm (34th percentile) and head circumference was 32 cm (3rd percentile).

The mother, gravida 2 para 1, who was in her late 20s, received regular antenatal care visits at her provincial hospital and had no pregnancy-related complications. More specifically, she had no thyroid disease, nor had she been on any medication besides iron-folic acid tablets during pregnancy. Her first child was healthy and met expected growth milestones; however, there was no screening at time of the birth of her first baby.

At well-baby nursery, physical examination was unremarkable except microcephaly. Based on our unit protocol, we did an NBS test at 48 hours of life for G6PD (glucose-6-phosphate dehydrogenase deficiency) and TSH. She was exclusively breast fed and discharged home with her mother.

The results of screening tests were received on day 9 of life:

• Heel-prick TSH (hTSH): 37.6 µU/mL blood (N<9 µU/mL blood).

• G6PD: 4.5 UI/g Hb (N>2.6 UI/g Hb).

In light of the result, the patient’s family was informed and requested to bring the baby back from her province for re-assessment. In 2015, our neonatal intensive care unit (NICU) was still the only centre in Cambodia that had implemented an NBS programme for all neonates born in the centre, and the baby was the third patient. Due to the lack of a national referral centre and paediatric endocrinologists in the country, we assigned one of our neonatologists as the referral doctor to be in charge of CH.

Differential diagnosis

Common causes of CH include central aetiologies (eg, hypothalamic or pituitary dysfunction) and primary causes such as thyroid dysgenesis (thyroid aplasia or hypoplasia), CH with gland in situ, and in rarer cases, transient hypothyroidism due to maternal antithyroid drugs or iodine deficiency. Thyroid dysgenesis and gland in situ can be diagnosed with thyroid ultrasound, whereas transient hypothyroidism seems unlikely owing to the mother’s absence of drug consumption during her pregnancy and the rarity of iodine deficiency in our country. Hypothalamic or pituitary dysfunction can be ruled out in the absence of clinical and laboratory findings that suggest hypopituitarism.

Investigation

During the first follow-up (day 9), physical examination showed no abnormality, and there was no dysmorphic syndrome. The results of investigations were explained to the parents. Further investigations showed:

• Serum T4: 8.87 pmol/L (N: 12–22 pmol/L).

• Serum TSH: >100 mIU/L (N: 0.27–4.2 mIU/L).

• Brain ultrasound: no mass, no bleeding.

• Heart ultrasound: no malformation.

• Thyroid ultrasound: thyroid hypoplasia with

  • Right side: 5×7×8 mm (1.5 g).

  • Left side: 5.5×8×8 mm (1.9 g).

The diagnosis of permanent primary CH due to thyroid hypoplasia was confirmed, and the family were informed of the possible complications, including neurodevelopmental delay, the importance of early hormone supplements, the availability of affordable treatment, the duration of the treatment and a long-term follow-up plan was formulated. However, in spite of the detailed explanation, the parents refused the medication at that time due to three main reasons: the burden of a ‘chronic’ disease, the difficulty of life-long hormonal replacement and the asymptomatic state of their baby.

Treatment

The parents initially hesitated to bring the girl to the centre for further management due to the distance from their hometown (approximately 295 km) and the cost of transportation (about US$30 or 120 000 riels, by shared taxi for a round-trip). On day 13 of life, the family agreed to attend follow-up after many attempts from the medical team to invite the patient for follow-up. After some discussion, they accepted our treatment plan for the first 2 years. LT4 was started once daily with 1 tablet of 25 µg (dosage 7.5µg/kg/day). The preparation of the medication was demonstrated by the nurses to the parents as the medication needed to be crushed before mixing with water. The medication was to be taken 1 hour prior to feeding. Further follow-up was arranged every 2 weeks until the normalisation of TSH, and it was only then that the follow-up appointments could be arranged at less frequent intervals—every 1 or 2 months during the first year of life.

Outcome and follow-up

At the age of 1 month, the baby was brought to the hospital by her mother for the first follow-up after 2 weeks of the treatment. In spite of some minor difficulties, including crushing the tablet, the mother had followed the instructions well. Unfortunately, the syrup formulation was not available in our country. The response to the treatment was significant: TSH 7.15 mIU/L and fT4 of 24.17 pmol/L (figure 1).

Figure 1.

TSH and fT4 timeline (2015–2021). fT4, free thyroxine; TSH, thyroid stimulating hormone.

Follow-up was initially arranged biweekly and adapted as much as possible around family needs and means. In spite of the frequent calls to remind the parents of the follow-up date, we still had to re-arrange our appointment schedule to find common ground between the patient’s family and the attending physician, who spent most of her time in the NICU. There was a total of five successful follow-up visits with a 1-week delay at the most.

Six months later, the infant’s milestones were appropriate for her age with a good catch-up increase of the head circumference to the 50th percentile (figure 2). Her psychomotor development was appropriate. Her mother was happy with her progress. The LT4 titration was based on TSH and fT4 levels during each follow-up, which was planned for every 3–4 months during the first 3 years of life.

Figure 2.

Child’s growth curves.

Two years later, on thyroid replacement at 50µg per day (5µg/kg/day), the girl was thriving well with normal psychomotor development. The dosage was reduced two times based on the TSH level: the active decrease at the age of 4 months and the passive one at the age of 19 months due to a significant weight gain.

Two and a half years later, as the TSH was 0.07 mIU/L with fT4 of 18.6 pmol/L, the LT4 dosage was decreased to approximately 2µg/kg/day for 3 months. However, it was re-increased to 4µg/kg/day after the elevation of TSH to 25.3 mIU/L.

During her early childhood, the girl was brought for follow-up biannually. The growth was appropriate for her age with good communication/cooperation. LT4 was lowered passively to between 3 and 2.5 µg/kg/day in accordance with her weight gain.

Entering her middle childhood, she was growing well and met all educational milestones. Her weight was 17 kg (32nd percentile), height 110 cm (55th percentile)—weight for length of 25th percentile. The TSH and fT4 levels were satisfactory.

Fortunately, as her TSH was within a normal range, the inter-provincial travel restrictions and lockdown of the capital city in 2021 during the COVID-19 outbreak in Cambodia¹⁵ did not affect the patient or our management plan.

Global health problem list

• CH leads to mental retardation, and is often underdiagnosed as neonates are mostly asymptomatic at birth.

• Early detection relies on NBS. The global incidence during the screening era is between 1:2000 and 1:4000.

• There is no national registry of CH incidence in Cambodia as NBS has yet to be established on a nationwide scale.

• NICU at Calmette Hospital (since 2013) is the only centre to routinely screen, treat and follow-up newborns until adulthood. Our unpublished monocentre incidence of CH is about 1 in 2115 (2013–2021).

• Early diagnosis, affordable medication and a good prognosis can be achieved only if an understanding is reached with the parents/guardians of affected children.

Global health problem analysis

Lack of a national registry

CH is often underdiagnosed due to the absence of symptoms at birth.⁸ Even though it leads to poor neurological performance, it still has a good prognosis if diagnosed early with early detection based on screening. NBS is fast, easy and affordable.

To date, NBS is yet to be recognised nationally in Cambodia. Currently, there are neither guidelines nor recommendations. As a result, there is no routine screening in the public sector, not even in referral centres in the cities. Private hospitals, on the other hand, do offer NBS on a case-by-case basis; that is, the decision to test depends on a heterogeneous delivery package for which the cost depends on the type of delivery and the type of NBS tests chosen by prospective parents. Prices vary and can range from US$300 to US$1000. Neonates with abnormal results will be referred to specialist centres. As of today, our NICU remains the only centre to provide routine screening. For these reasons, there is no data recorded in the CH World database for Cambodia.

Our neighbouring countries, on the contrary, showed a worrisome incidence rate of CH: 1 in 3314 in Thailand and 1 in 3678 in the Philippines. The incidence was lower in Laos (1 in 5681), but only 7% of their neonates were reported to have been screened.⁴ There was a retrospective study over a period of 7 years in California showing the disparity of incidence among different races and ethnicities. The incidence was calculated to be about 1:2380 in East Asian communities (Chinese and Vietnamese).¹⁶ The absence or scarcity of data in our country raises a number of hypothetical possibilities: the first most straightforward and least concerning scenario is that we truly do not have a lot of cases. The second scenario is that, as this disease is often asymptomatic in newborns, a failure to screen and diagnose results in a significant underestimation of incidence. The third scenario is that paediatricians might have treated sporadic cases of symptomatic infants without realising that the number of cases is growing and unconsciously forget that it is a preventable disease with a significant prevalence. Reliable national statistical data is crucial to the effective delivery of healthcare.

Involvement of the parents in clinical care

Early diagnosis, affordable medication and understanding factors essential to a good prognosis are the core elements in managing the disease and, more importantly, in convincing the parents to accept our treatment plan. However, the key to success in providing care to a child is the compliance of the parent and guardians whose decisions are influenced by their educational, cultural, geographical and financial backgrounds.

Limited public awareness of heel prick tests and CH delays parents’ decisions, thus lowering the chance of preventing neurological complications. In our case, one of the parents had a healthcare background but even then was not aware of the disease. Thus, both parents were in need of convincing of the importance of treatment. On a national scale, NBS has not been prioritised to improve newborn care. As proven in the Cambodia Demographic and Health Survey (CDHS 2014), we mainly focus on improving mother and child health policies by addressing family planning, pregnant women’s antenatal care, breast feeding, HIV/AIDS and information relating to sexually transmitted diseases. As for children, public health measures focus on infant and child mortality attributable to common diseases such as diarrhoea, pneumonia and predominantly, malnutrition.¹⁷

Our experience is that the social stigma associated with chronic disease and life-long treatment is a disincentive to parents to pursue treatment in-time. Traditionally, the term ‘chronic disease’ is a reminder of diseases such as HIV/AIDS or diabetes which are incurable and require lifetime therapy. Unconscious fears of hopelessness and guilt about their child’s condition and the burden of unspoken discrimination in society or among peers may be distressing. As shown in a questionnaire-based cross-sectional study in which 1005 Cambodian people living with HIV participated, stigma and discrimination are common among people with chronic disease and can lead to mental health issues.¹⁸ Similarly, our experience is that since the initiation of the screening programme, cultural perceptions result in delayed treatment. The first meeting between the attending neonatologist and the parents lasted about 1 hour, during which they discussed the need and the advantages of early diagnosis and treatment in our centre. Even though the parents’ concerns were explored and the advantages of early diagnosis and treatment to avoid neurological complications were explained in detail, the parent initially opted not to pursue treatment.

Geographic background plays a vital role in providing proper care to newborns. The location where the parents live determines their compliance with treatment. In our case, the parents live far in a province. At discharge, we advised them to stay in the capital city for at least 1 month (2–3 follow-up visits) to ensure proper assessment, but they (reasonably) chose not to. First, they did not have any relatives in the city. Second, renting a house was a heavy financial load. Moreover, the husband needed to return to work to earn a living. The best option for them was to come for follow-up from time to time. Another challenge at that time was that we were the only centre to screen, treat and monitor the girl’s condition. In provinces away from the city, there is limited availability of laboratory services for testing and monitoring; and there are also few paediatricians who are familiar with the condition. In spite of the mother’s efforts and our OPD staff’s flexibility in calling to remind them and re-scheduling follow-up dates, the mother always brought her child 1–2 weeks late for follow-up visits. She gave the medicine regularly. Furthermore, we commonly prescribed more tablets than needed to cover the late follow-up.

Finally, the predominant obstacles in handling paediatric patients in low-income and middle-income countries are the socioeconomic concerns of the family. After many almost-missed follow-up appointments, a long interview was conducted when the girl was brought for an appointment at 6 months of life. As described by the mother, during her 3-month maternity leave, the family was struggling financially. Her husband went to work for the whole week. She took care of both children with little recourse for help from family. She was the only one who crushed and fed the LT4 to the girl every morning. No one could help. To her, the medication price is affordable, but the tests (fT4 and TSH) are five times more expensive than a tablet of the drugs. Combined with transportation expense, the situation could not get any worse. To come to each appointment, she paid for a taxi round-trip, and she sometimes needed to stay at a guest house for one night as she had no family in the capital. She always came alone; in the interim, her mother took care of her son, and her husband made a living.

Possible future solutions

The need for a national NBS programme should be recognised to ensure that every newborn is screened. NBS should be implemented in all hospitals, starting from big public ones in the capital to private ones, and to provincial hospitals. However, one or two referral treatment centres would be enough. In 2021, the number of births per year was estimated to be about 321 000 in Cambodia.¹⁹ Most cases of delivery (99%) were assisted by a skilled provider. The country crude birth rate was 20.2 per 1000 people, of which 20.5 in urban area and 20.1 in remote provinces.²⁰ With similar distribution of births between urban and rural regions, by simply building one or two referral centres more in the provinces, we will be able to significantly increase the number of screening in different regions of the country. Moreover, provincial centres can also reduce patients’ expense on transportation and accommodation. In our case, for instance, almost two-thirds of the expense of a bimonthly follow-up would have been saved—that is the travel fee, costing about 240 000 riels (US$60) for two round-trips by a shared taxi, and the hotel fee (approximately US$20) would have been spared. This economic approach will make the hormone replacement more affordable (US$2.8 for a box of LT4 for 1 month), thus increasing the compliance.

Sharing the knowledge through case/data presentation would be a very good start because it can produce ‘snowball effects’, meaning that one case stimulates another; as a result, clinical suspicion for the disease will increase and screening will be performed more frequently. In local regions, ‘Training-of-Trainers’ workshops should be organised to disseminate and enhance knowledge regarding the disease to healthcare providers, including those who are closely involved with mother and child health promotion—obstetricians, paediatricians and midwifes.

We took the first step of routine screening in our maternity unit in 2013 and also conducted a monocentre retrospective observational study for 9 years (2013–2021). During this time, there were 50 positive patients out of 105 732 screened; thus, an incidence was of 1:2115 (Phou K, A single-centre, 9-year retrospective study of congenital hypothyroidism in Calmette Hospital, Phnom Penh, Cambodia; 2022 (unpublished)). It is unexpectedly higher than in Thailand and Philippines, so a larger multicentre study is required.

At an individual level, although NBS is not routinely done, physicians should, first and foremost, routinely explain soon-to-be parents about the importance of screening. We can still do it on a case-by-case basis and refer to the centre that can treat it. Moreover, we do not have to screen all 5, 7 or 10 diseases. Taking our centre as an example, we implemented routine NBS in 2013. Since then, considering the cost-benefit balance, we have been screening only for G6PD and CH. Other rare diseases, particularly congenital adrenal hyperplasia, which had the incidence of 1 in 14 000 to 18 000,²¹ require multidisciplinary team approach, which demands more effort and a larger budget. To this end, we plan to promote more screening in 2025. It is a question of a cost-benefit balance. First, it saves money while reducing the risk of mental delay. Second, we might not have a referral hospital; however, LT4 is affordable and safe. What really matters is not how to treat but how to ensure long-term follow-up. The compliance, in turn, relies on a good and dedicated doctor–patient family relationship. The attending doctor must explain and do follow-up well. Nurses in charge need to be aware of barriers to effective treatment and be prepared to call parents and re-arrange appointments.

Finally, telemedicine might be a better option since it might solve many of our patients’ families’ difficulties. For instance, they can have blood tests done at their hometown and send the results to us to re-adapt the doses. Furthermore, they can also check-up their child’s growth with local paediatricians and send us the report. However, the telemedicine is limited owing to poor digital literacy.

Learning points.

• Congenital hypothyroidism, if untreated, will lead to mental disability; however, it is preventable if the infants are diagnosed early by newborn screening that is fast, easy and affordable.

• We should continuously take a step forward by screening more; it is only then will we be able to decrease the risk of complications.

• The cornerstone to provide successful care to a paediatric patient relies on the involvement of the parents. We need to view the child in their own world, (ie, in their home), surrounded by their family members as primary care givers.

Patient’s mother perspective.

As a midwife, I knew the importance of antenatal care, so I went regularly to my provincial hospital for the check-up. At term, we decided to come to give birth at the biggest tertiary hospital in the capital. We were surprised when they informed us about my girl’s disease. I never heard of it. At first, my husband and I hesitated to accept the treatment as our girl was apparently healthy. It was tough for me. During the first 3 months, I needed to take care of my other young child, and I did not want to bother my mother because she is too old. The nurses called us frequently, but we were always late for the appointment due to our financial concerns. Fortunately, despite the problems, my child is growing well now. Our paediatrician was very gentle and understanding, so were the nurses. We keep coming for follow-up twice per year.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s)