|Year : 2020 | Volume
| Issue : 2 | Page : 516-522
Maternal thyroid function with placental hemodynamics and their effect on fetal and maternal outcomes
Abdelhamed E Shahin1, Nasser K Abd El Aal1, Osama A El-Kelany1, Alaa Eldeen F. El Halaby1, Amira M Elsayed2
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Atmeda Hospital, Mansoura, Egypt
|Date of Submission||01-Jan-2020|
|Date of Decision||01-Feb-2020|
|Date of Acceptance||08-Feb-2020|
|Date of Web Publication||27-Jun-2020|
Amira M Elsayed
Source of Support: None, Conflict of Interest: None
To evaluate the relationship between maternal mild fluctuation in thyroid hormones not amounting to hypothyroidism or hyperthyroidism and altered fetoplacental hemodynamic changes allowing early detection of adverse maternal and perinatal outcomes.
Suboptimal placental function is associated with preeclampsia and intrauterine growth restriction. Studies suggested that thyroid hormones play a role in placental development through the effects on trophoblastic invasion.
Patients and methods
A prospective cohort study, included 123 healthy pregnant women recruited from the antenatal care in Obstetrics and Gynecology Department, at Menoufia University Hospital and Damas Central Hospital, from October 2018 till August 2019. Free thyroxine (FT4) concentrations and thyroid-stimulating hormone were measured in early pregnancy (at 9 and 18 weeks). Placental function was measured by Doppler ultrasound measuring umbilical artery pulsatility index and uterine artery resistance index (between 18–23 and 28–32 gestational weeks).
The data of 123 patients were analyzed. Increased FT4 concentration in early pregnancy was associated with higher vascular resistance in the second and third trimesters in both umbilical artery pulsatility index and uterine artery resistance index. These effects on placental function may demonstrate the association of FT4 with pregnancy outcomes, such as preeclampsia and birth weight.
The data shows that increased) FT4 concentration in early pregnancy is associated with placental vascular function during the second and third trimesters. Other pregnancy-associated complications are preeclampsia and low birth weight.
Keywords: placenta, placental hemodynamics, pregnancy, thyroid function
|How to cite this article:|
Shahin AE, Abd El Aal NK, El-Kelany OA, El Halaby AE, Elsayed AM. Maternal thyroid function with placental hemodynamics and their effect on fetal and maternal outcomes. Menoufia Med J 2020;33:516-22
|How to cite this URL:|
Shahin AE, Abd El Aal NK, El-Kelany OA, El Halaby AE, Elsayed AM. Maternal thyroid function with placental hemodynamics and their effect on fetal and maternal outcomes. Menoufia Med J [serial online] 2020 [cited 2020 Sep 20];33:516-22. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/516/287796
| Introduction|| |
Adequate placental function is essential for an uncomplicated pregnancy and optimal fetal development as the placenta enables fetal nutrient supply, respiratory gas exchange, and elimination of metabolic waste products. Furthermore, the placenta produces hormones that are crucial for maintaining pregnancy including human chorionic gonadotropin hCG, estrogen, progesterone, and prostaglandins. Suboptimal placental function is associated with pregnancy complications, including preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs fetal blood supply), fetal growth restriction, and premature delivery, which are major causes of maternal and perinatal morbidity and mortality worldwide.
Thyroid hormone (TH) transporters and receptors are expressed in the trophoblast cells, and optimal TH concentrations are necessary to ensure appropriate placentation. Placentation is a compound process that requires proper interstitial invasion of fetal trophoblast cells into maternal decidua and endovascular trophoblast invasion into maternal spiral arteries. This is, in part, regulated by proangiogenic and antiangiogenic factors and cytokines. TH regulates the secretion of several growth factors and cytokines that are critical for endovascular trophoblast invasion and angiogenesis of fetal and maternal placental vessels, including angiogenin, angiopoietin 2, vascular endothelial growth factor-A, interleukin 10, and tumor necrosis factor alpha. Furthermore, TH attenuates epidermal growth factor-initiated trophoblastic proliferation, motility, and invasion.
A low thyroid function has been associated with premature delivery and a high thyroid function has been associated with preeclampsia, and fetal growth restriction,, which are adverse pregnancy outcomes that could be arising from impaired placentation in early gestation, given that the placental tissue is responsive to TH,.
The aim of this study is to evaluate the relationship between maternal mild fluctuation in THs not amounting to hypothyroidism nor hyperthyroidism and altered fetoplacental hemodynamic changes allowing early detection of subsequent adverse maternal and perinatal outcomes.
| Patients and Methods|| |
A prospective cohort study, which included 123 healthy pregnant women recruited from the antenatal care in Obstetrics and Gynecology Department, at Menoufia University Hospital and Damas Central Hospital, from October 2018 till August 2019 after obtaining an approval of the Medical Ethics Committee for Human Research. An informed consent was obtained from all selected patients after explanation of the methods and goal of the study.
The participants (N = 123) were divided into three groups according to the estimated free thyroxine (FT4):
- Participants with low–normal thyroid function, FT4 level 0.89: 1.09 ng/dl
- Participants with high–normal thyroid function FT4 level 1.2: 1.76 ng/dl
- Participants with normal thyroid function, FT4 level 1.1: 1.19 ng/dl.
The inclusion criteria of the current study included the following:
- Women in the age group of between 18 and 40 years
- Singleton pregnancy
- During early pregnancy (<18 weeks) by last menstrual period and early ultrasound scan
- Pregnant women with normal thyroid function, thyroid-stimulating hormone (TSH) value (0.4: 4 mIU/ml) and FT4 value (0.89:1.76 ng/dl).
The exclusion criteria:
- Overt hyperthyroidism and hypothyroidism
- Multiple gestations
- Chronic disease (diabetes mellitus, cardiac disease, and renal disease).
History and clinical examination
Careful history taking and clinical examination to ensure fulfillment of the selection criteria.
- Personal history: this included name, age, and parity
- Past history: this included medical diseases such as heart, liver, renal disease, and surgical history of any operations
- Menstrual history: for last menstrual period. Obstetric history: number of pregnancies, deliveries (normal or cesarean section).
This included vital data such as blood pressure, pulse, and temperature together with the presence of abnormal complexion such as pallor, jaundice, or cyanosis.
Fundal level, Fetal Head Station (FHS).
Samples of maternal serum were obtained in early pregnancy (range, 9–18 weeks). Plain tubes were centrifuged and serum was stored at −80°C. TSH and FT4 concentrations in maternal serum samples were determined using chemiluminescence assays (Vitros ECi; Ortho Clinical Diagnostics, Milan, Italy). Euthyroidism was defined according to the 2.5–97.5th percentile reference range for the study population.
Placental function measurements
Measurements of placental vascular resistance used as a reflection of placental function and measure of the placentation success. Placental vascular resistance was evaluated with recorded flow-velocity waveforms from the umbilical (representing the fetal vascular compartment) and uterine (representing the maternal vascular compartment) arteries in the second trimester (between 18 and 23 weeks) and the third trimester (between 28 and 32 weeks), with an interval of 10 weeks between the two measurements. A raised umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) indicate increased placental vascular resistance which is a sign of placental insufficiency that may be due to impaired placental development. Umbilical artery PI was measured in a free-floating loop of the umbilical cord. Uterine artery RI was measured in the uterine arteries near the crossover with the external iliac artery. For each measurement, three consecutive uniform waveforms were recorded by pulsed Doppler ultrasound, during fetal apnea and without fetal movement. The mean of two measurements is used for further analysis.
Outcomes of pregnancy and follow-up
Patients were followed up until delivery for potential adverse maternal and perinatal outcomes such as pregnancy-induced hypertension, preterm labor, and birth weight. Information on birth weight was obtained from hospital registries. Birth weight standard deviation scores adjusted for gestational age were constructed using the Niklasson percentile growth curves. Low birth weight (LBW) was defined as a live birth weight of less than 2500 g.
Premature delivery was defined as a gestational age at birth of less than 37 weeks.
Gestational hypertension was defined as the development of systolic blood pressure more than or equal to 140 mmHg and/or diastolic blood pressure more than or equal to 90 mmHg after 20 weeks of gestation in previously normotensive women. These criteria in addition to the presence of proteinuria (detected when two or more dipstick readings of 2+ or greater, one catheter sample reading of 1+ or greater, or a 24 h.
Technique of ultrasound Doppler examination
Uterine artery color Doppler study
This was performed by an experienced radiologist at Damas Central Hospital in the Department of Radiology (Xario 100, Toshiba America Medical Systems Inc, Tustin, CA, USA).
The uterine artery was detected with color Doppler imaging at the level of its crossing with the external iliac artery. The Doppler gate was placed over the uterine artery (transabdominal) under a less than 60 insonation angle and flow-velocity waveforms were recorded during at least three heart cycles and the waveforms were frozen and measured.
The PI was automatically calculated by software using the formula PI=(peak systolic flow velocity − end diastolic flow velocity)/time average maximum flow velocity.
RI was calculated automatically by software RI=(peak systolic flow − end diastolic flow)/peak systolic flow.
A uterine artery resistant RI of more than 0.7 was considered as the abnormal value.
Umbilical artery Doppler
The uterine contents were scanned to select an area of amniotic cavity with many loops of the umbilical cord. Then using color and pulsed wave Doppler on a free loop of cord, the characteristic sound and shape of the umbilical artery were detected. When at least three consecutive waveforms of similar heights were showed on the screen, the image was frozen and Doppler umbilical artery RI, PI, and systolic/diastolic ratio were measured automatically.
All data were collected, tabulated, and statistically analyzed by the Statistical Package for Social Sciences (SPSS), version 22 (SPSS Inc., Chicago, Illinois, USA).
Two types of statistics were done:
- Descriptive, for example, percentage (%), mean and SD
- Kruskal–Wallis test: it is the nonparametric version of analysis of variance used to collectively indicate the presence of any significant difference between several groups for a not normally distributed quantitative variable
- Post-hoc test is used after one-way analysis of variance (F test) or Kruskal–Wallis test to show any significant difference between the individual groups
- χ2: it is used to compare between two groups or more regarding one qualitative variable. Fisher's exact is used when one of the expected cells is less than 5
- Spearman's correlation analysis: it is used to show the strength and direction of association between two nonparametric variables
- P value: significant difference if P value less than 0.05.
The sample sizing assumes that the expected relations between FT4 and umbilical artery PI be (r = 0.027). To achieve 80% power to detect this result with a significance level of 5%, using the equation of N=[(Zα+Zβ)/C] 2 + 3, where C = 0.5 × ln [(1 + r)/(1 − r)]. The total required sample size would be 123 participants.
| Results|| |
While analyzing the effect of maternal thyroid function with placental hemodynamics and their effect on fetal and maternal outcome, we found that there was significant difference between the studied FT4 hormone groups regarding the age of the participants where the absolute normal level of FT4 hormone was reported to be significant in women with younger age (27.92 ± 6.28) (P = 0.033) but there was no significant difference regarding gestational age or parity (P = 0.604 and 0.096, respectively) [Table 1].
|Table 1: Distribution of the studied free thyroxine groups regarding maternal characteristics |
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There was significant difference between the studied FT4 hormone groups regarding preeclampsia and LBW; they were significantly higher among the high–normal group (18.9 and 22.6%, respectively) (P = 0.015 and 0.007, respectively) [Table 2].
|Table 2: Distribution of the studied free thyroxine groups regarding fetal characteristics|
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We found that PI at the second trimester was significantly lower among the normal FT4 group, while it was significantly lower in the low–normal group at the third trimester than other groups (1.18 ± 0.20 and 1.01 ± 0.15, respectively) (P < 0.001). RI at second and third trimester was significantly lower among the low–normal FT4 group than other groups (0.79 ± 0.11 and 0.70 ± 0.07, respectively) (P < 0.001) [Table 3].
|Table 3: Distribution of the studied groups regarding their pulsatility index and resistance index at second and third trimesters|
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There was significant positive correlation between FT4 and PI and RI, while there was negative correlation with TSH [Table 4].
| Discussion|| |
Maternal thyroid dysfunction during pregnancy is common, with a prevalence of 2–4%. Maternal thyroid dysfunction is associated with many adverse child and maternal outcomes, including miscarriage, prematurity, intrauterine growth restriction, hypertensive disorders, and a decreased child IQ. Hypothyroxinemia, hypothyroidism, Subclinical Hypothyroidisms (SCH), hyperthyroidism, and subclinical hyperthyroidism increased the likelihood of certain adverse outcomes and complications.
During pregnancy, many alterations in thyroid physiology occur to provide sufficient TH to both the mother and the fetus. This is essentially important during early pregnancy because the fetal thyroid begins to produce considerable amounts of TH only from ~20 weeks of gestation, until which time the fetus mainly depends on the maternal supply of TH. This supply of TH to the fetus, as well as raised levels of TH-binding proteins (thyroxine-binding globulin) and degradation of TH by placental type 3 iodothyronine deiodinase necessitate an increased production of maternal TH.
In this prospective study, we studied maternal thyroid function with placental hemodynamics and their effect on fetal and maternal outcome.
We found that there was significant difference between the studied FT4 hormone groups regarding preeclampsia; it was significantly higher among the high–normal group (18.9%) (P = 0.015). These findings are in agreement with the Medici et al. study, which investigated the effects of variation in thyroid function within the population base is calculated by the 2.5–97.5th percentile intervals and revealed an increased risk of preeclampsia in pregnancies with high–normal FT4 concentrations.
The Barjaktarovic et al. study had also investigated the clinical association of maternal thyroid function with placental hemodynamic function and found that the high–normal FT4 concentration was shown to be associated with higher risk of preeclampsia. On the other hand, a decreased risk of preeclampsia in pregnancies with high–normal FT4 concentrations was detected in a recent study by Haddow et al., although these effects were borderline significant and P values were not corrected for multiple testing. A retrospective study with a total of 930 pregnant women with untreated, antibody-negative subclinical hypothyroidism and 7986 controls found that the subclinical hypothyroidism group had an increased risk of hypertensive disorders of pregnancy (odds ratio, 1.476; 95% confidence interval, 1.113–1.923; P = 0.004).
In this study, we found that there was significant difference between the studied FT4 hormone groups regarding LBW; it was significantly higher among the high–normal group (22.6%) (P = 0.007).
This is in agreement with the finding of Medici et al. who studied the relations between normal FT4 and birth weight in Dutch pregnant women with FT4 concentrations within their center-specific reference intervals, showing that high–normal FT4 levels were associated with lower mean birth weights, small for gestational age (SGA), and 2500 g newborns. These results had recently been convincingly replicated in a study by Haddow et al.. A retrospective cohort study with a total of 4504 women were included in the final analysis –3231 were diagnosed as euthyroid; 73 (1.6%) were categorized as having subclinical hyperthyroidism; and 1200 (26.6%) had subclinical hypothyroidism. It has been observed that that subclinical hyperthyroidism correlates with higher rates of extremely LBW of less than 1500 kg. On the other hand, Mannisto et al. studied these relations with both subclinical hypothyroidism and subclinical hyperthyroidism in more detail and found no differences in mean birth weights between these groups.
In this study, we found that there was no significant difference between the studied FT4 hormone groups regarding prematurity. These findings are in agreement with a study by Cleary-Goldman et al., showing that subclinical hypothyroidism (TSH 97.5th percentile and FT4 within the reference interval) was not associated with prematurity, _37 weeks, whereas the effects on earlier premature deliveries were not investigated. In line with this study far fewer data are available on the effects of subclinical hyperthyroidism on premature delivery. In a study in women presenting for antenatal care, subclinical hyperthyroidism (n = 433) was not associated with premature delivery (36, 34, and 32 weeks). Various other studies had also investigated these relations, with conflicting results,,.
This can be partly explained by the fact that few studies included overt and subclinical hypothyroid cases. And some included a fewer number of premature deliveries, whereas others used different TSH cutoff values. Raised TSH concentrations and the risk of prematurity using a population-based 97.5th percentile (4.0 mU/l) and a fixed 2.5 mU/l cutoff.
In this study, we studied the effect of TH on uterine artery RI and umbilical artery PI and found that PI at the second trimester was significantly lower among the normal FT4 group while, it was significantly lower in the low–normal group at third trimester than other groups (1.18 ± 0.20 and 1.01 ± 0.15, respectively) (P < 0.001). There was significant positive correlation between FT4 and PI and RI, while there was negative correlation with TSH. These findings are in agreement with a study by Barjaktarovic et al., a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands which studied the association of maternal thyroid function with placental hemodynamics. A total of 7069 mothers who had an expected delivery date between April 2002 and January 2006 were included in early pregnancy. They found that a raised FT4 concentration during early pregnancy is associated with higher vascular resistance in the second and third trimesters in the fetal and maternal placental compartments.
| Conclusion|| |
The data shows that increased FT4 concentration in early pregnancy is associated with the measurement of placental vascular function, umbilical artery PI, and uterine artery RI during the second and third trimesters. Also, increased FT4 concentration in early pregnancy is associated with pregnancy complications, including preeclampsia, and LBW.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cartwright JE, Fraser R, Leslie K, Wallace AE, James JL. Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders. Reproduction 2010; 140
Fowden AL, Forhead AJ, Sferruzzi-Perri AN, Burton GJ, Vaughan OR. Review: endocrine regulation of placental phenotype. Placenta 2015; 36
Vinnars MT, Papadogiannakis N, Nasiell J, Holmstrom G, Westgren M. Placental pathology in relation to stillbirth and neonatal outcome in an extremely preterm population: a prospective cohort study. Acta Obstet Gynecol Scand 2015; 94
Barber KJ, Franklyn JA, McCabe CJ, Khanim FL, Bulmer JN, Whitley GS, et al
. The in vitro
effects of triiodothyronine on epidermal growth factor-induced trophoblast function. J Clin Endocrinol Metab 2005; 90
Patel J, Landers K, Li H, Mortimer RH, Richard K. Oxygen concentration regulates expression and uptake of transthyretin, a thyroxine binding protein, in JEG-3 choriocarcinoma cells. Placenta 2011; 32
Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010; 31
Vasilopoulou E, Loubiere L, Lash GE, Ohizua O, McCabe CJ, Franklyn JA, et al
. Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner. Hum Reprod 2014; 29
Matsuo H, Maruo T, Murata K, Mochizuki M. Human early placental trophoblasts produce an epidermal growth factor-like substance in synergy with thyroid hormone. Acta Endocrinol (Copenh) 1993; 128
Oki N, Matsuo H, Nakago S, Murakoshi H, Laoag-Fernandez JB, Maruo T. Effects of 3,5,30-triiodothyronine on the invasive potential and the expression of integrins and matrix metalloproteinases in cultured early placental extravillous trophoblasts. J Clin Endocrinol Metab 2004; 89
Sheehan PM, Nankervis A, Araujo Junior E, Da Silva Costa F. Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100
Aggarawal N, Suri V, Singla R, Chopra S, Sikka P, Shah VN, et al
. Pregnancy outcome in hyperthyroidism: a case control study. Gynecol Obstetr Investig 2014; 77
Medici M, Korevaar TI, Schalekamp-Timmermans S, Gaillard R, de Rijke YB, Visser WE, et al
. Maternal early pregnancy thyroid function is associated with subsequent hypertensive disorders of pregnancy: the generation R study. J Clin Endocrinol Metab 2014; 99
Medici M, Timmermans S, Visser W, de Muinck Keizer-Schrama SM, Jaddoe VW, Hofman A, et al
. Maternal thyroid hormone parameters during early pregnancy and birth weight: the generation R study. J Clin Endocrinol Metab 2013; 98
Haddow JE, Craig WY, Neveux LM, Haddow HR, Palomaki GE, Lambert-Messerlian G, et al
. Implications of high free thyroxine (FT4) concentrations in euthyroid pregnancies: the FASTER trial. J Clin Endocrinol Metab 2014; 99
Polyxeni K, Leda C, Emmanouil B, Vasiliki D, Dimitris A, Elias C, et al
. First- and second-trimester reference intervals for thyroid hormones during pregnancy in 'Rhea', Mother-Child Cohort, Crete, Greece. J Thyroid Res 2011; 98
Medici M, de Rijke YB, Peeters RP, Visser W, de Muinck Keizer-Schrama SM, et al
. Maternal early pregnancy and newborn thyroid hormone parameters: the generation R study. J Clin Endocrinol Metab 2012; 9
Campbell S, Griffin DR, Pearce JM, Diaz-Recasens J, Cohen-Overbeek TE, Willson K, et al
. New Doppler technique for assessing uteroplacental blood flow. Lancet 1983; 321
Verburg BO, Jaddoe VW, Wladimiroff JW, Hofman A, Witteman JC, Steegers EA. Fetal hemodynamic adaptive changes related to intrauterine growth: the generation R study. Circulation 2008; 117
Niklasson A, Albertsson-Wikland K. Continuous growth reference from 24th
week of gestation to 24 months by gender. BMC Pediatr 2008; 8
Barjaktarovic M, Korevaar T, Chaker L, Jaddoe V, de Rijke Y, Visser T, et al
. The association of maternal thyroid function with placental hemodynamics. Hum Reprod 2017; 32
Zhou M, Wang M, Li J, Luo X, Lei M. Effects of thyroid diseases on pregnancy outcomes. Exp Ther Med 2019; 18
Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ 2014; 349
Burcu D, Ulku A, Muzaffer T, Emin U. Pregnancy outcomes of antibody negative and untreated subclinical hypothyroidism. J Obstetr Gynaecol Res 2019; 10
Aribib N, Hadar E, Sneh-Arbib O, Wiznitzer A, Gabbay-Benziv R. First trimester thyroid stimulating hormone as an independent risk factor for adverse pregnancy outcome. J Matern Fetal Neonatal Med 2017; 30
Mannisto T, Vaarasmaki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, et al
. Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 2009; 94
Cleary-Goldman J, Malone FD, Lambert-Messerlian G. Matemalthyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112
Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstetr Gynecol 2006; 107
Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, et al
. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab 2011; 96
Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95
Schneuer FJ, Nassar N, Tasevski V, Morris JM, Roberts CL. Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. J Clin Endocrinol Metab 2012; 97
[Table 1], [Table 2], [Table 3], [Table 4]