Key points Pregnancy places a metabolic overload on the maternal thyroid, especially in the first trimester, mainly because of the demand imposed by the conceptus. The fetal thyroid becomes functionally mature only around pregnancy week 20. Until then, the fetus depends on the transfer of maternal thyroid hormones (THs). Thyroid hormones are essential for the adequate fetal neurofunctional and cognitive development. Hypothyroidism brings higher risks of obstetric and fetal complications, namely, first-trimester miscarriage, preeclampsia and gestational hypertension, placental abruption, prematurity, low birth weight, and higher perinatal morbidity and mortality. Primary hypothyroidism (involvement of the gland with difficulty in producing and/or releasing TH) is the most common form of disease presentation, with the main etiology of Hashimoto's thyroiditis of autoimmune origin. In about 85%-90% of cases of Hashimoto's thyroiditis, antithyroid antibodies are present; the antithyroperoxidase (ATPO) is the most frequent. Positivity for ATPO is determined when circulating values exceed the upper limit of the laboratory reference. It implies greater risks of adverse maternal-fetal outcomes. Such a correlation occurs even in ranges of maternal euthyroidism. The critical point for the diagnosis of hypothyroidism during pregnancy is an elevation of thyroid-stimulating hormone (TSH). The measurement of free thyroxine (FT4) differentiates between subclinical and overt hypothyroidism. In subclinical hypothyroidism, FT4 is within the normal range, whereas in overt hypothyroidism, FT4 values are below the lower limit of the laboratory reference. Treatment of hypothyroidism is performed with levothyroxine (LT4) replacement with the aim of achieving adequate TSH levels for pregnancy. Some women have a previous diagnosis of hypothyroidism, and may or may not be compensated at the beginning of pregnancy. Even in compensated cases, the increase in LT4 dose is necessary as soon as possible. In the postpartum period, adjustment of the LT4 dose depends on the condition of previous disease, on the positivity for ATPO, and also on the value of LT4 in use at the end of pregnancy. Recommendations In places with full technical and financial conditions, TSH testing should be performed for all pregnant women (universal screening) as early as possible, ideally at the beginning of the first trimester or even in preconception planning. In places with less access to laboratory tests, screening is reserved for cases with greater risk factors for decompensation, namely: previous thyroidectomy or radioiodine therapy, type 1 diabetes mellitus or other autoimmune diseases, presence of goiter, previous history of hypo or hyperthyroidism or previous ATPO positivity. The TSH dosage should be repeated throughout pregnancy only in these cases. The diagnosis of hypothyroidism is made from the TSH value > 4.0 mIU/L. Pregnant women with previous hypothyroidism, overt hypothyroidism diagnosed during pregnancy or those with the above-mentioned higher risk factors for decompensation should be referred for risk antenatal care, preferably in conjunction with the endocrinologist. Overt hypothyroidism in pregnancy is identified when TSH > 10 mIU/L, and treatment with LT4 is readily recommended at an initial dose of 2 mcg/kg/day. TSH values > 4.0 mUI/L and ≤ 10.0 mUI/L require FT4 measurement with two diagnostic possibilities: overt hypothyroidism when FT4 levels are below the lower limit of the laboratory reference, or subclinical hypothyroidism when FT4 levels are normal. The treatment for subclinical hypothyroidism is LT4 at an initial dose of 1 mcg/kg/day, and the dose should be doubled upon diagnosis of overt hypothyroidism. In cases of TSH > 2.5 and ≤ 4.0 mIU/L, if there are complete conditions, ATPO should be measured. If positive (above the upper limit of normal), treatment with LT4 at a dose of 50 mcg/day is indicated. If conditions are not complete, the repetition of the TSH dosage should be done only for cases at higher risk. In these cases, treatment with LT4 will be established when TSH > 4.0 mIU/L at a dose of 1 mcg/kg/day; if needed, the dose can be adjusted after FT4 evaluation. Women with previous hypothyroidism should have their LT4 dose adjusted to achieve TSH < 2.5 mIU/L at preconception. As soon as they become pregnant, they need a 30% increase in LT4 as early as possible. In practice, they should double the usual dose on two days a week. Levothyroxine should be given 30-60 minutes before breakfast or three hours or more after the last meal. Concomitant intake with ferrous sulfate, calcium carbonate, aluminum hydroxide and sucralfate should be avoided. The target of LT4 therapy during pregnancy is to achieve a TSH value < 2.5 mIU/L. Once the therapy is started, monthly control must be performed until the mentioned goal is reached. In the postpartum period, women with previous disease should resume the preconception dose. Cases diagnosed during pregnancy in use of LT4 ≤ 50 mcg/day may have the medication suspended. The others should reduce the current dose by 25% to 50% and repeat the TSH measurement in six weeks. Cases of ATPO positivity are at higher risk of developing postpartum thyroiditis and de-escalation of LT4 should be performed as explained.

Resumo Objetivo Investigar as características das mulheres com parto pré-termo e os respectivos resultados de acordo com a etnia. Métodos Uma análise secundária de umestudo de corte transversalmulticêntrico no Brasil. Mulheres com parto pré-termo foram classificadas por autodefinição como brancas ou não brancas. Dados maternos, clínicos, e da gestação foram coletados por entrevista pós-parto e revisão de prontuários. As características sociodemográficas, obstétricas e clínicas das mulheres, o tipo de parto, e os resultados neonatais dos grupos étnicos foram comparados por análise bivariada. Resultados Das 4.150 mulheres que tiveram parto pré-termo, 2.317 (55,8%) eram não brancas, que com mais frequência: eram menores de 19 anos de idade (razão de prevalência [RP]: 1,05; intervalo de confiança de 95% [IC95%]: 1,01-1,09); não tinham parceiro; eramde baixa renda; tinham baixa escolaridade; tinham ≥ 2 filhos; realizavam trabalho extenuante; provinhammais do Nordeste do que do Sul; tinham histórico de ≥ 3 partos; tinham intervalo interpartal<12 meses; e tiveram complicações gestacionais como aborto, parto pré-termo, rotura prematura de membranas pré-termo (RPM-PT) e baixo peso ao nascimento; iniciaram as consultas de pré-natal no segundo ou terceiro trimestres; comparecerama um número inadequado de consultas; viviam sob contínua exaustão; fumaram no primeiro e segundo ou terceiro trimestres; e tiveram anemia e hipertensão gestacional. Os resultados maternos e neonatais não diferiram entre os grupos, exceto pelamaior taxa de baixo peso ao nascimento (73,7% versus 69,0%) entre as crianças das mulheres não brancas, e e a maior taxa de convulsões (4,05% versus 6,29%) entre as das brancas. Conclusão Condições desfavoráveis foram mais comuns entre não brancas do que entre brancas. Políticas apropriadas são necessárias para diminuir as diferenças, especialmente no contexto da prematuridade, quando mulheres e seus neonatos têm necessidades específicas.

Abstract Objective To investigate the characteristics of women who had preterm birth (PTB) and related outcomes according to ethnicity. Methods A secondary analysis of a multicenter cross-sectional study conducted in Brazil. Women who had PTB were classified by self-report as white and non-white. Clinical, pregnancy, and maternal data were collected through postpartum interviews and reviews of medical charts. The sociodemographic, obstetric and clinical characteristics of the women, as well as the mode of delivery and the neonatal outcomes among different ethnic groups were compared through a bivariate analysis. Results Of the 4,150 women who had PTB, 2,317 (55.8%) were non-white, who were more likely: to be younger than 19 years of age (prevalence ratio [PR]: 1.05; 95% confidence interval [95%CI]: 1.01-1.09); to be without a partner; to live on low income; to have lower levels of schooling; to have ≥ 2 children; to perform strenuous work; to be fromthe Northeastern region of Brazil rather than the from Southern region; to have a history of ≥ 3 deliveries; to have an interpregnancy interval<12 months; to have pregnancy complications such as abortion, PTB, preterm premature rupture of membranes (pPROM), and low birth weight; to initiate antenatal care (ANC) visits in the second or third trimesters; to have have an inadequate number of ANC visits; to be under continuous overexertion; to smoke in the first and second or third trimesters; and to have anemia and gestational hypertension. The maternal and neonatal outcomes did not differ between the groups, except for the higher rate of low birth weight (73.7% versus 69.0%) in infants born to non-white women, and the higher rate of seizures (4.05% versus 6.29%) in infants born to white women. Conclusion Unfavorable conditions weremore common in non-whites than inwhites. Proper policies are required to decrease inequalities, especially in the context of prematurity, when women and their neonates have specific needs.

Resumo Parto prematuro é uma complicação obstétrica de grande impacto para saúde perinatal e neonatal, tendo consequências tambémpara a infância e a vida adulta. Pouco se sabe sobre sua etiologia e fatores determinantes, o que limita osmétodos de rastreamento, predição e prevenção. Esta revisão integrativa traz a discussão sobre o conhecimento atual sobre fatores de risco para parto prematuro espontâneo, as diferenças entre métodos de rastreamento e predição, as limitações das atuais intervenções preventivas, a importância de se aplicar conceitos padronizados para exposição e desfecho na investigação de parto prematuro espontâneo, e porque é importante desenvolver métodos precisos e reprodutíveis para predizer o parto prematuro. Por fim, introduzimos o conceito demetabolômica e da tecnologia envolvida nessa técnica, e discutimos como ela tem se mostrado uma abordagem prosmissora para identificar biomarcadores associados ao parto prematuro espontâneo.

Abstract Pretermbirth is amajormaternal complication that has a great impact on perinatal and neonatal health, with consequences suffered during childhood and adulthood. Little is known about its etiology and development, resulting in poor screening, prediction and preventive methods. The present integrative review discusses the current knowledge regarding some risk factors for preterm birth, the differences between screening and prediction methods, the limitations of some current preventive interventions, the importance of applying standardized concepts for exposures and outcomes, and why it is important to develop more accurate and reproducible methods to predict preterm birth. In addition, the authors introduce the concept of metabolomics and the technology involved in this technique, and discuss about how it has become a promising approach to identify biomarkers for spontaneous preterm birth.

The prediction or early diagnosis of maternal complications is challenging mostly because the main conditions, such as preeclampsia, preterm birth, fetal growth restriction, and gestational diabetes mellitus, are complex syndromes with multiple underlying mechanisms related to their occurrence. Limited advances in maternal and perinatal health in recent decades with respect to preventing these disorders have led to new approaches, and “omics” sciences have emerged as a potential field to be explored. Metabolomics is the study of a set of metabolites in a given sample and can represent the metabolic functioning of a cell, tissue or organism. Metabolomics has some advantages over genomics, transcriptomics, and proteomics, as metabolites are the final result of the interactions of genes, RNAs and proteins. Considering the recent “boom” in metabolomic studies and their importance in the research agenda, we here review the topic, explaining the rationale and theory of the metabolomic approach in different areas of maternal and perinatal health research for clinical practitioners. We also demonstrate the main exploratory studies of these maternal complications, commenting on their promising findings. The potential translational application of metabolomic studies, especially for the identification of predictive biomarkers, is supported by the current findings, although they require external validation in larger datasets and with alternative methodologies.