Congenital Hypothyroidism Can Dictate the Mode of Delivery and Intra-labor Medication Usage

Pregnancy and parturition reflect the complex interaction between physiologic conditions of the mother and her offspring, and fetal health characteristics may affect maternal health throughout pregnancy and delivery. We investigated the characteristics of the mother-infant dyad of term infants detected by the National Newborn Screening Program as having congenital hypothyroidism (CH) (131 out of 108,717; 0.12%). Three years of surveillance in our Pediatric Endocrine Clinic revealed that 65 had transient CH and 66 had permanent CH. A higher proportion of deliveries of CH infants required vacuum assistance, and more infants with CH were born through a cesarean section compared to the general population ( p <0.001). Medication during labor also differed, with higher rates of oxytocin ( p <0.001) and antibiotics ( p =0.008) administered to mothers of CH infants. A multivariate logistic regression model revealed an increased demand for oxytocin administration during the labor of a CH infant in a hypothyroidism severity-dependent manner, expressed as a threefold risk associated with permanent but not transient CH. Our findings of increased utilization of medical interventions during the labor and delivery of CH infants suggest that the prenatal fetal thyroid function affects the development and progress of labor and delivery, in response to oxytocin. of (the lowest SEP) to (the highest an calculation of 14 variables that measure social and economic levels in the of demographics, education, standard of living, and employment (ranging from the lowest -2.797 to the highest 2.590). indicates statistical significance. APGAR appearance (skin color), pulse, grimace (reflex), activity


Introduction
Pregnancy and parturition reflect the complex interaction between the state of health of the mother and her offspring. The Developmental Origins of Health and Disease (DOHaD) hypothesis (formerly "fetal programing") postulated that exposure to maternal conditions affecting the intrauterine environment may have consequences on their offspring's health during infancy, childhood, and even adulthood 1,2 . There is also evidence that fetal health characteristics may affect maternal health outcomes throughout pregnancy and delivery 3 . A better understanding of the bidirectional nature of health characteristics may assist in creating an integrated obstetric medical approach which will take into consideration the mother-infant dyad rather than separate mother and infant.
Neonatal thyroid screening aims to detect infants with congenital hypothyroidism (CH) in order to initiate thyroid hormone replacement therapy as soon as possible and prevent mental retardation 4 . The screen detects infants with anatomic (agenesis or ectopic dysgenesis) or genetic thyroid disorders leading to permanent CH, as well as infants with transient abnormal thyroid function who do not require lifelong thyroid replacement therapy 5,6 . In transient CH, the appropriate maturation of the hypothalamic-pituitary-thyroidal axis may be interrupted by maternal, perinatal, or neonatal factors 7 .
The evolution of environmental, social, and medical influences may have diverse effects on the mother-infant dyad. The past decade has witnessed an increase in the utilization of obstetric interventions, such as assisted reproduction therapy 8 , the number of medications administered during pregnancy and labor, and a rise in the rates of caesarean sections 9 .
Importantly, these medical and surgical interventions may influence the hypothalamicpituitary-thyroidal axis function 7 . In this study, we aimed to investigate characteristics of the mother-infant dyad of infants detected as having CH in order to identify contributing and non-contributing factors.

Patients and methods
Study Population. We conducted a retrospective cohort study of term infants (gestational age ≥37 weeks) delivered liveborn at Lis Maternity and Women's Hospital, Tel-Aviv Sourasky Medical Center (TASMC) between January 1, 2010 and December 30, 2017. Data on maternal, pregnancy, delivery, and perinatal characteristics of the mother-infant dyads were retrieved from the hospital's electronic database that became available from 2010.
Newborn screening for CH among full-term newborns was routinely practiced by a single screen of total T4 (TT4) at 48-72 hours of age, with a subsequent measurement of thyroidstimulating hormone (TSH) when low levels of TT4 were obtained 10  Appropriate birth weight for gestational age (AGA) was defined as corrected birth weight zscores of -1.28 to 1.28, small for gestational age (SGA) as birth weight z-scores <-1.28, and large for gestational age (LGA) as birth weight z-scores >1.28. continuous data between groups were examined using independent-sample t-tests (normally distributed data) or Mann-Whitney U-tests (skewed data). The Chi-squared tests (or Fisher's exact test for small count tables) were used to examine the differences in categorical data.
Stepwise multivariate logistic regression models were used to evaluate the selected factors (including delivery-related and infant characteristics) correlated with the diagnosis of CH and transient vs. permanent CH. A p value of ≤ 0.05 was considered significant.

Results
During the study period, 117,529 infants were liveborn in Lis Maternity and Women's Hospital of TASMC. Excluded from the study were 8810 preterm infants and two infants diagnosed with 21 trisomy. Of 108,717 infants born at term during the study period, 131 Thyroid scintigraphy performed in infants with transient CH revealed normal uptake.
Characteristics of mother-infant dyads with CH compared to the general population are presented in Table 1. The median age of the mothers was 32 years (range 15-50 years), and the median maternal pre-pregnancy weight was 59 kg (range 31-130 kg), with a median weight gain during pregnancy of 13 kg (range 0-40 kg). In addition, 4.9% of the mothers were smokers, and 6.2% were diagnosed with gestational diabetes. There was no significant difference between the groups for any of these parameters. The distribution of mode of delivery differed between groups, with fewer CH infants born by spontaneous vaginal delivery compared to the general population (55.7% vs. 72.2%, p < 0.001). The frequency of maternal medication use during labor differed significantly between groups, with increased administration of oxytocin (43.5% vs. 34.9%, p < 0.001), antibiotics (8.4% vs. 3.9%, p = 0.008), and anesthesia (87.8% vs. 76.3%, p < 0.001) to mothers of CH infants compared to the general population. The CH infants were born at a median GA of 39 weeks (range 37-44), and 51.3% were males. The median birthweight of the infants of the general population was 3.270 kilograms (range 1.165-8.810 kg), and the median birthweight of the CH infants was significantly lower (p = 0.002).
The characteristics of the mother-infant dyads of CH infants stratified according to the diagnosis of transient and permanent CH is presented in Table 2. Maternal age, gravidity, and parity did not differ between the two groups. The median SEP cluster of the cohort was 7 (range 2-10), the index was 0.783 (range -1.305 to 2.667), the vast majority were Jewish, and there were no significant differences in SEP or ethnicity between the transient and permanent CH groups. The mothers did not differ in weight prior to delivery and weight gain during pregnancy, or in their smoking or medical history. Five percent of the pregnancies followed assisted reproductive therapy, most of them after in vitro fertilization treatment. The mode of delivery and extent of medication administration during labor did not differ between the groups. The majority of infants with transient CH were males, while the majority of infants with permanent CH were females, a difference that did not reach statistical significance. The infants with transient CH were born at an earlier GA (p = 0.011). The median birth weight z-scores for all the CH infants were -0.34 (range -2.36 to 2.85), and 7.7% of the infants with transient CH were born SGA vs 18.2% of infants with permanent CH (p = non-significant for all). Infants with permanent CH had lower TT4 levels and higher TSH levels on thyroid screening tests (p = 0.03 and p < 0.001, respectively), and lower FT4 levels and higher TSH levels on confirmatory thyroid testing compared to those with transient CH (p < 0.001 for both).
Multivariate forward logistic regression models to evaluate the factors associated with the diagnosis of any CH, transient and permanent CH in the general population and permanent CH in the CH group are presented in Table 3. The analysis performed on the entire cohort revealed that the administration of oxytocin during labor was associated with the diagnosis of permanent CH (odds ratio [OR]=2.77, p < 0.001), and that none of the neonatal or maternal characteristics were associated with the diagnosis of transient CH. The analysis of the entire CH group revealed that birth weight z-scores and screening TSH levels were significantly associated with the diagnosis of permanent CH (OR=1.52, p = 0.05 and OR=0.99, p < 0.001 respectively).

Discussion
The aim of this study was to analyze the characteristics of the mother-infant dyad of CH infants in order to identify contributing and non-contributing factors. The analyses revealed increased utilization of medical intervention during the labor and delivery of the infants with any CH. Although the mothers of CH infants did not differ in age, weight, and obstetric and medical background, the labor process of the CH infants was different than that of the general population. Our findings suggest that the labor and delivery of CH infants required increased utilization of medical intervention. Specifically, the statistical analyses revealed an increased demand for oxytocin administration during the labor of a CH infant in a hypothyroidism severity-dependent manner, and showed a threefold risk in those with permanent CH but not with transient CH. These findings suggest that the prenatal fetal thyroid function has a role in the development and progress of labor and delivery in response to oxytocin.
Maternal characteristics, such as older age 13,14 and obesity 15 , have been linked with various adverse pregnancy outcomes, including complications during pregnancy and delivery leading to increased morbidity in the newborn. In our study, maternal age and maternal parity did not differ, and maternal weight prior to conception and weight gain during pregnancy were similar for mothers of infants with CH as for those in the general population. As such, neither maternal age nor maternal obesity and their implications provided any explanations for the differences in the delivery of infants with CH.
Only 55% of infants with CH were born through a spontaneous vaginal delivery. A higher proportion of CH deliveries required vacuum assistance, and more infants with CH were born by means of a cesarean section compared to the general population. Cesarean delivery has short-and long-term implications upon the health of both mother and infant 16,17 .
Infants born through cesarean delivery may have compromised adaptation to the extrauterine environment manifested by transient CH. This assumption did not hold true in our study, since the rate of cesarean deliveries did not differ between transient and permanent CH, and the type of delivery did not predict transient CH. The mode of delivery determines the acquisition of the newborn's intestinal microbiota, and the beneficial exposure of the newborn to the maternal vaginal microbiota is prevented in cesarean birthing 18,19 . This earlylife experience, which may be influenced by fetal hypothyroidism, may affect development of the early immune system with possible implications upon allergic, autoimmune, and metabolic morbidities during childhood and adulthood [20][21][22] .
The rate and mode of anesthesia utilization differed between the deliveries of CH infants and the general population. Anesthesia was administered to more mothers of CH infants, and a higher proportion underwent spinal anesthesia. This may be attributed to the increased demand for instrumental and surgical deliveries of CH infants. Spinal anesthesia may result in sustained spinal hypotension with the complication of neonatal acidosis 23 . It could be assumed that the acid-base compromise would contribute to the development of transient CH, however, the type of anesthesia did not differ between our transient and permanent CH infants nor was it identified as a predictive factor for transient CH.
The fetal thyroid milieu may play a role in initiating and maintaining uterine contractions during delivery in response to endogenous oxytocin. Fetal hypothyroidism had been found to reduce uterine contractions (amplitude and frequency) in response to oxytocin administration in rat mothers 24 . Another animal study linking oxytocin administration during delivery and maternal thyroid function reported that administration of intravenous oxytocin to rats decreased their TSH, FT4, and FT3 levels 25 . Thus, oxytocin administration may transiently affect the thyroid axis function of the mother and augment a pre-existing maternal condition. However, maternal hypothyroidism is not the explanation for the findings in our study, since all mothers are screened for hypothyroidism during pregnancy and treated appropriately 26 . Moreover, only 7% of the mothers of our CH infants were diagnosed as having thyroid disease, and they were all treated and monitored during the index pregnancy. Noteworthy, we found oxytocin administration during delivery as a predictor solely of permanent CH. Our findings support the role of prenatal fetal hypothyroidism in the abnormal progression of delivery, since oxytocin administration was even more prominent in the deliveries of infant with permanent CH, most of them having an anatomical explanation.
In this study we chose not to include premature infants in order to limit the effects of maternal, obstetric, and infantile medical conditions other than CH on the process of delivery.
Premature infants are overrepresented in the CH screen detection group due to the lack of age-specific thyroid function cutoffs as well as to various medical conditions complicating prematurity 27 . It is plausible that the premature delivery of CH infants will be affected in a distinctive GA-stratified manner by fetal hypothyroidism. Further studies are warranted to characterize the mother-infant dyad of premature CH infants.
Our study is not without limitations. Since the data of the SEP grading and ethnic origin of mothers from the general population was lacking, we could not evaluate the contribution of these factors. Also missing were data on the quantitative thyroid function of infants from the general population, precluding the establishment of thresholds. The major strengths of this large-scale observational study lie in the uniformity of the obstetric approach of a single medical center and the comprehensiveness of data from the Pediatric Endocrine Clinic which enabled drawing conclusions on well-distinguished transient and permanent CH groups.
In conclusion, the investigation of the mother-infant dyads of CH infants revealed that the labor and delivery process of a CH infant is characterized by increased use of instrumentation and medications. The interaction between neonatal fetal thyroid and exogenous oxytocin administration suggests a role for prenatal fetal thyroid function in the development and progression of delivery in response to oxytocin.  [9,9] 9 [9,9] 0.162 5 minutes 10 [10,10] 10 [10,10] 0.455 The data are expressed as number and (percent), median [interquartile range]. Bold indicates statistical significance. APGAR = appearance (skin color), pulse, grimace (reflex), activity (muscle tone) and respiration; kg = kilograms; n = number; y = years. The data are expressed as number and (percent), median [interquartile range] and mean ± standard deviation. Socioeconomic position (SEP) is defined by the cluster of localities of residence, ranging from 1 (the lowest SEP) to 10 (the highest SEP). The SEP index is an adjusted calculation of 14 variables that measure social and economic levels in the domains of demographics, education, standard of living, and employment (ranging from the lowest -2.797 to the highest 2.590). Bold indicates statistical significance. APGAR = appearance (skin color), pulse, grimace (reflex), activity (muscle tone) and respiration; kg = kilograms; n = number; y = years.  1 Multivariate forward logistic regression model included the following parameters: maternal age, number of current pregnancy, number of previous births, weight before pregnancy, weight gain during pregnancy, type of delivery, anesthesia, oxytocin and antibiotics administration, gestational week, and birth weight. 2 Multivariate forward logistic regression model included the following parameters: maternal age, number of current pregnancy, number of previous births, socioeconomic position, weight before pregnancy, weight gain during pregnancy, type of delivery, anesthesia, oxytocin and antibiotics administration, gestational week, birth weight z-score, thyroid screen test (TSH, TT4), and thyroid confirmatory test (TSH, TT4). OR = odds ratio; CI = confidence interval; TSH = thyroid stimulating hormone; TT4 = total thyroxine