Associations between hypothyroidism and adverse obstetric and neonatal outcomes: a study of a population database including over 184,000 women with hypothyroidism

Abstract

Background

Maternal hypothyroidism has been associated with multiple adverse pregnancy outcomes. These findings have not been confirmed in a large population database study. Therefore, a large population-based cohort study was established to study the associations between maternal hypothyroidism and pregnancy and perinatal complications.

Methods

This is a retrospective population-based cohort study utilizing data from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) over 11 years from 2004 to 2014. A cohort of all deliveries between 2004 and 2014 inclusive, was created. Within this group, all deliveries to women with hypothyroidism were identified as part of the study group (n = 184,869), and the remaining deliveries were categorized as non-hypothyroidism births and comprised the reference group (n = 8,911,919). The main outcome measures were pregnancy and perinatal complications.

Results

Maternal hypothyroidism is associated with several pregnancy and perinatal complications, including gestational diabetes mellitus (aOR 1.43, 95%CI 1.38–1.47), gestational hypertension (aOR 1.17, 95%CI 1.11–1.22) and preeclampsia (aOR 1.21, 95%CI 1.16–1.27) (all p < 0.001). These patients are more likely to experience preterm premature rupture of membranes (aOR 1.19, 95%CI 1.09–1.29, p < 0.001), preterm delivery (aOR 1.12 95%CI 1.08–1.17, p < 0.001), are more likely to deliver by cesarean section (aOR 1.21, 95% CI 1.18–1.24, p < 0.001), and suffer from postpartum hemorrhage (aOR 1.07, 95%CI 1.01–1.13, p = 0.012), disseminated intravascular coagulation (aOR 1.20, 95%CI 1.00-1.43, p = 0.046), and undergo hysterectomy (aOR 1.42, 95% CI 1.13–1.80, p = 0.003).

As for neonatal outcomes, small for gestational age and congenital anomalies are more likely to occur in the offspring of women with hypothyroidism (aOR 1.20, 95% CI 1.14–1.27 and aOR 1.34, 95% CI 1.22–1.48, both p < 0.001).

Conclusions

Women with hypothyroidism are more likely to experience pregnancy, delivery and neonatal complications. We found an association between hypothyroidism and hypertensive disorders, postpartum hemorrhage, transfusions, infections, preterm delivery and hysterectomy, among other problems. This data from a population sized database confirms the findings of smaller previous studies in the literature.

Keywords:

• Population database
• pregnancy outcome
• obstetric
• delivery
• neonatal
• hypothyroidism

Introduction

Thyroid disorder is common among women of reproductive age and is the most common endocrine disease during pregnancy [1]. Overt, or clinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone (TSH) concentration and a low serum free thyroxine (FT4) concentration, known to affect up to 1–2% of the women [2] and 0.2–0.5% of pregnant women [3]. Subclinical hypothyroidism is defined as elevated TSH whereas the FT4 remains in the normal range and is affecting 2–13.7% of pregnant women [4].

Maternal hypothyroidism, either clinical or subclinical, has been associated with multiple adverse pregnancy outcomes. In a systematic review of clinical impact of thyroid disorders before and during pregnancy, 43 studies were included, in which the number of participants varied between dozens to a couple of hundred [5]. This review and several cited subsequent studies, questioned the association with spontaneous miscarriages [5–7], gestational diabetes mellitus [6,8–12], gestational hypertension or preeclampsia [6,8,9,13,14], placental abruption [15], induction of labor [8], preterm delivery [6,9,15], cesarean section[(7–9,12], low birth weight [11], neonatal intensive care unit admission [9] and fetal death [10]. However, none of the studies exceeded 10,000 participants with hypothyroidism.

In addition, there are some population-based studies in the literature that investigated the association between hypothyroidism and adverse pregnancy outcomes. The largest one was conducted by Turunen et al. and included 16,364 hypothyroid mothers. However, postpartum complications were not evaluated in this study [16]. In another study by Chen et al, 184,611 pregnancies were included, with 7140 women with hypothyroidism (TSH > 4.29). In this study, they found an association to spontaneous abortions and stillbirth, preterm delivery, cesarean section and large for gestational age infants. However, other adverse events, such as pre-eclampsia, gestational diabetes or preterm premature rupture of membranes were not evaluated in this study [17].

The objective of this study, therefore, was to assess the prevalence of a variety of adverse pregnancy and delivery-associated maternal and neonatal outcomes in women with hypothyroidism, in a large database, while accounting for confounding effects.

Materials and methods

We conducted a retrospective population-based study utilizing data from the HCUP-NIS over 11 years from 2004 to 2014, inclusively. The HCUP-NIS is the largest inpatient sample database in the United States of America (USA) and is comprised of hospital inpatient stays submitted by hospitals in 48 states and the District of Columbia. Each year, the database provides information relating to 7 million inpatient stays, including patient characteristics, diagnoses, and procedures. The data are representative of ∼20% of admissions to American hospitals and geographically represent over 96% of the population in the USA.

We evaluated deliveries by using the international classification of diseases, ninth edition, clinical modification (ICD-9-CM) codes for delivery-related discharge diagnoses (650.xx, 677.xx, 651.xx-676.xx where the fifth digit is 0, 1 or 2), and birth-related procedural diagnosis (72.x, 73.x, 74.0–74.2). We limited our study group to the admissions that ended with delivery or maternal death in order to guarantee that multiple admissions in the same pregnancy will be excluded. Within this group, all women with diagnosis of hypothyroidism were identified using ICD-9 diagnostic codes 244 (244.0, 244.1, 244.2, 244.3, 244.8, 244.9), 245.2, 246.1, and the remaining deliveries were categorized as non-hypothyroidism births and comprised the reference group. Women who had a diagnosis of congenital hypothyroidism were excluded from the study.

Hypothyroidism is usually defined as two abnormal TSH (higher than the upper limit of the assay cut offs) with or without abnormal free t3 and free t4. Presently there is controversy over the appropriate upper limit of normal for serum TSH. Some studies have suggested that the upper limit is 2.5 mU/L, whereas others suggested an upper limit of 4.1-4.5 mU/L [18]. In our database, the upper limit was the one that was used in each respective lab.

Baseline clinical characteristics included: patient age, race, income, insurance type, hospital type, previous cesarean section, multiple gestation, smoking history, obesity (body mass index ≥ 30 kg/m2), preexisting hypertension and preexisting diabetes mellitus. Pregnancy outcomes include hypertensive disorders of pregnancy (gestational hypertension and preeclampsia/eclampsia), gestational diabetes mellitus, placenta previa and venous thromboembolism (deep vein thrombosis and pulmonary embolism). Delivery outcomes include preterm premature rupture of the membranes, preterm delivery, placental abruption, cesarean section, maternal infection and chorioamnionitis, and hysterectomy. Postpartum hemorrhage, disseminated intravascular coagulation and blood transfusions were also investigated. Neonatal outcomes included small for gestational age infants, intrauterine fetal death, and congenital anomalies.

Statistical analysis: An initial analysis was performed to identify the prevalence of pregnant women with hypothyroidism over the entire duration of the study. We then compared baseline clinical and demographic characteristics between women with hypothyroidism to those without hypothyroidism. Subsequently, logistic regression analyses were conducted to explore associations between hypothyroidism and obstetrical and neonatal outcomes through the estimation of odds ratio (OR) and 95% confidence intervals (CI). The regression models were adjusted for the potential confounding effects of maternal demographic, pre-existing clinical characteristics, and concurrently occurring characteristics to generate adjusted CIs. A confounder was determined if it was part of the demographics or pre-pregnancy diseases and rates between those with hypothyroidism and the controls gave a p < 0.05. All analyses were performed using SPSS 23.0 (IBM Corporation, Chicago, USA) software for all analyses.

This study used exclusively publicly accessible, anonymized data; therefore, according to Tri-Council Policy Statement (2018), institutional review board approval was not required.

Results

There were 9,096,788 births between 2004 and 2014, inclusively. Of these pregnancies, 184,869 women, or 2.032 per 100 women, had a documented diagnosis of hypothyroidism. Within the 11-year study period, there was a steady rise in the incidence of hypothyroidism, from 1.336 per 100 in 2004 to 3.150 per 100 in 2014 (p < 0.0001). (Figure 1). Baseline demographic characteristics for our study population are summarized in Table 1. Women with hypothyroidism were more likely to be older than 25 years of age and Caucasian, have higher household incomes and private insurance and deliver in an urban teaching hospital, as compared with the non-hypothyroidism obstetrical subjects. Pregnant women with hypothyroidism were also less likely to smoke or use recreational drugs in pregnancy. Women with hypothyroidism were more likely to have chronic hypertension and pre-gestational diabetes, though they were less likely to be obese than the non-hypothyroidism obstetrical population. Women with hypothyroidism were also more likely to have undergone in vitro fertilization treatments and have multi-gestation pregnancies.

Figure 1. Prevalence of Hypothyroidism disease among women who gave birth between 2004 and 2014.

Table 1. Maternal characteristics.

Characteristics	Hypothyroidism N = 184,869	No Hypothyroidism N = 8,911,919	p-value
Age (years)
<25	13.5%	38.5%	<0.001
25–34	56.2%	47.1%
≥35	30.3%	14.4%
Race
White	70.3%	51.9%	<0.001
Black	4.3%	13.9%
Hispanic	12.9%	23.4%
Asian and Pacific	6.7%	5.1%
Native American	0.7%	0.8%
Other	5.0%	4.8%
Income quartiles
Less than 39,000	16.5%	27.6%	<0.001
$39,000-47,999	21.7%	25.5%
$48,000-62,999	26.8%	24.8%
$63,000 or more	35.0%	22.1%
Medical Insurance Plan type
Medicare	0.9%	0.6%	<0.001
Medicaid	20.0%	43.1%
Private including Health Maintenance Organization	74.5%	50.2%
Self-Pay	1.6%	3.2%
No charge	0.1%	0.2%
Other	2.9%	2.7%
Hospital type
Rural	11.9%	14.2%	<0.001
Urban	88.1%	85.8%
Body mass index
Obese (≥30)	3.5%	7.4%	<0.001
Previous cesarean section	20.7%	15.9%	<0.001
In vitro fertilization pregnancy	0.7%	0.1%	<0.001
Chronic hypertension	4.2%	1.8%	<0.001
Pregestational diabetes mellitus	3.6%	0.9%	<0.001
Illicit Drug use	0.7%	1.4%	<0.001
Human immunodeficiency virus	0%	0%	<0.001
Tobacco Smoking	3.4%	4.9%	<0.001
Multiple gestation	3.0%	1.5%	<0.001

The crude and adjusted effect measures for the association between pregnancy and delivery outcomes and their respective prevalence in each cohort are outlined in Table 2. Women with hypothyroidism were more likely to suffer from gestational diabetes mellitus, gestational hypertension, and preeclampsia (all p < 0.001), after controlling for confounding effects of age, race, income level, medical insurance type, obesity, in vitro fertilization use, previous cesarean section, chronic hypertension, pre-gestational diabetes, multiple gestation, tobacco smoking, and illicit drug use. Regarding delivery outcomes, they were more likely to experience preterm premature rupture of membranes (p < 0.001), preterm delivery (p < 0.001), and were more likely to deliver by cesarean section (p < 0.001), after controlling for confounding effects of age, race, income level, medical insurance type, obesity, in vitro fertilization use, previous cesarean section, chronic hypertension, pre-gestational diabetes, multiple gestation, tobacco smoking and illicit drug use, pregnancy-associated hypertension, gestational hypertension, preeclampsia and gestational diabetes mellitus.

Table 2. Pregnancy and delivery outcomes.

Outcomes	Hypothyroidism (%)	No Hypothyroidism (%)	Crude OR (95% CI)	Adjusted OR (95% CI)	Adjusted p-value
Pregnancy outcomes^a
Pregnancy induced hypertension	9.9%	7.4%	1.390 (1.368–1.411)	1.188 (1.150–1.227)	<0.001
Gestational hypertension	4.3%	3.3%	1.315 (1.286–1.346)	1.168 (1.115–1.223)	<0.001
Preeclampsia	4.6%	3.6%	1.308 (1.279–1.337)	1.215 (1.160–1.272)	<0.001
Eclampsia	0.1%	0.1%	0.832 (0.694–0.998)	1.048 (0.689–1.593)	0.827
Preeclampsia and Eclampsia superimposed hypertension	1.1%	0.5%	2.178 (2.083–2.277)	1.058 (0.955–1.173)	0.279
Gestational diabetes mellitus	10.3%	5.7%	1.923 (1.894–1.953)	1.428 (1.383–1.474)	<0.001
Placenta previa	0.8%	0.5%	1.529 (1.453–1.609)	1.154 (1.037–1.285)	0.009
Delivery outcomes^b
Preterm premature rupture of membranes	1.4%	1.1%	1.216 (1.169–1.265)	1.186 (1.091–1.290)	<0.001
Preterm delivery	8.3%	7.2%	1.173 (1.153–1.193)	1.122 (1.077–1.168)	<0.001
Abruptio placenta	1.1%	1.1%	1.028 (0.984–1.074)	1.037 (0.942–1.142)	0.462
Chorioamnionitis	1.7%	1.8%	0.945 (0.912–0.979)	1.088 (1.014–1.167)	0.019
Operative vaginal delivery	6.4%	6.5%	0.989 (0.970–1.007)	1.036 (0.994–1.079)	0.096
Cesarean section	41.8%	32.1%	1.516 (1.502–1.531)	1.206 (1.176–1.236)	<0.001
Spontaneous vaginal delivery	53.5%	62.5%	0.691 (0.685–0.698)	0.847 (0.827–0.867)	<0.001
Hysterectomy	0.1%	0.1%	1.823 (1.610–2.064)	1.424 (1.127–1.799)	0.003
Postpartum hemorrhage	3.1%	2.9%	1.062 (1.034–1.091)	1.072 (1.015–1.131)	0.012
Wound complications	0.5%	0.4%	1.517 (1.424–1.616)	1.113 (0.957–1.295)	0.166
Maternal death	0.0%	0.0%	0.923 (0.521–1.634)	0.708 (0.172–2.921)	0.633
Transfusion	1.1%	1.0%	1.126 (1.078–1.176)	1.122 (1.029–1.224)	0.009
Others
Maternal infection	2.0%	2.2%	0.921 (0.892–0.952)	1.084 (1.015–1.158)	0.017
Deep vein thrombosis	0.1%	0.0%	1.503 (1.250–1.809)	1.353 (0.920–1.991)	0.125
Pulmonary embolism	0.0%	0.0%	1.620 (1.235–2.125)	1.309 (0.743-2.308)	0.352
Venous thromboembolism	0.1%	0.1%	1.545 (1.323–1.804)	1.315 (0.948–1.824)	0.101
Disseminated intravascular coagulation	0.2%	0.2%	1.253 (1.142–1.375)	1.199 (1.003–1.433)	0.046

^aPregnancy outcome: adjust for age, race, medical insurance plan type, obesity, chronic hypertension, illicit drug use, previous cesarean section, tobacco smoking during pregnancy, human immunodeficiency virus, multiple gestation, pregestational diabetes mellitus, in vitro fertilization, hospital type and income.

^bDelivery outcomes: adjust for age, race, medical insurance plan type, obesity, chronic hypertension, illicit drug use, previous cesarean section, tobacco smoking during pregnancy, human immunodeficiency virus, multiple gestation, pregestational diabetes mellitus, in vitro fertilization, hospital type, income, pregnancy induced hypertension, gestational hypertension, preeclampsia, gestational diabetes mellitus and placenta previa.

After controlling for all confounding effects, women with hypothyroidism were more likely to experience chorioamnionitis in labor (p = 0.019), to develop maternal infections in the postpartum period (p = 0.017), postpartum hemorrhage (p = 0.012), disseminated intravascular coagulation (p = 0.047), require blood transfusions (p = 0.009), and hysterectomy (p = 0.012) compared to the control group. However, no association was found between hypothyroidism and placental abruption or venous thromboembolism.

As for neonatal outcomes (Table 3), small for gestational age infants and congenital anomalies were more likely to occur in the offspring of women with hypothyroidism (both p < 0.001).

Table 3. Neonatal outcomes^a.

Outcomes	Hypothyroidism (%)	No Hypothyroidism (%)	Crude OR (95% CI)	Adjusted OR (95% CI)	Adjusted p-value
Small for gestational age infants	2.6%	2.2%	1.213 (1.179–1.249)	1.202 (1.136–1.273)	<0.001
Intrauterine fetal death	0.4%	0.4%	0.968 (0.900–1.040)	1.021 (0.876–1.190)	0.788
Congenital Anomalies	0.8%	0.4%	1.906 (1.808–2.009)	1.342 (1.219–1.477)	<0.001

^aFetal outcomes: adjust for age, race, medical insurance plan type, obesity, chronic hypertension, illicit drug use, previous cesarean section, tobacco smoking during pregnancy, human immunodeficiency virus, multiple gestation, pregestational diabetes mellitus, in vitro fertilization, hospital type, income, pregnancy induce hypertension, gestational hypertension, preeclampsia, gestational diabetes mellitus and placenta previa.

Discussion

The present study involving 184,869 women who had a diagnosis of hypothyroidism, demonstrated that hypothyroidism was associated with a small but significant increased risk of overall adverse pregnancy and delivery outcomes. Multiple smaller studies in the literature have been published in the past, which have assessed the possible increased risk of pregnancy and delivery outcomes in women with hypothyroidism [5,6,16,17]. Similar to these previous publications, we found that pregnancy complications such as preeclampsia and gestational diabetes mellitus are associated with hypothyroidism. Interestingly, a study from Finland on more than 5000 pregnancies reported that overt hypothyroidism predicts the risk of the mother developing diabetes later in life, and not just during pregnancy [hazard ratio 6.0 (95% CI) (2.2–16.4)] [19].

Regarding delivery outcomes, we found a significant association between maternal hypothyroidism and preterm premature rupture of membranes, preterm delivery, chorioamnionitis and cesarean section, excluding placental abruption. A possible explanation could be provided by understanding the physiologic role of thyroid hormone in early placental and embryo development [20–22]. Thyroid hormones are important for trophoblast migration [23] proliferation and invasion [22], and abnormal placentation may represent a direct consequence of inadequate thyroid hormone availability [24]. Abnormal placentation is a well-known contributor to placental-mediated pregnancy complications like those mentioned above [25] and may account for the higher rates of placenta previa that we found in hypothyroid mothers (p = 0.009). These factors may further contribute to the understanding of our findings that hypothyroidism in pregnancy is associated with the occurrence of postpartum hemorrhage, disseminated intravascular coagulation and blood transfusions. In a recent study from Pakistan of 702 women, postpartum hemorrhage was found to be associated with hypothyroidism in the preconception and third trimester, but without discrimination between clinical or subclinical hypothyroidism [22]. As for subclinical hypothyroidism per se, previous studies failed to show similar results while investigating an association between subclinical hypothyroidism and postpartum hemorrhage: Wang et al. found that the incidence of spontaneous abortions in pregnant women with subclinical hypothyroidism was increased, but no other obstetrical complications including postpartum hemorrhage were augmented (n = 756) [26]. In another small study, no difference was found in terms of coagulation parameters and postpartum hemorrhage between euthyroid or subclinical hypothyroid patients with thyroid antibodies (n = 57) and healthy controls (n = 52) [27]. Our findings of increased hematologic complications in hypothyroid mothers may be related to the high rates of preterm premature rupture of membranes, chorioamnionitis and cesarean section that were observed in these subjects. In consequence, it could have a role in the high rates that were observed of hysterectomies in the hypothyroid group.

Finally, we also demonstrated a significantly increased risk of small for gestational age infants in hypothyroid mothers. In the literature, there is a controversy regarding embryo growth and infant birthweight in hypothyroid mothers [5]. Some studies found an increased risk of small for gestational age or low birthweight infants for mothers who suffered from clinical, subclinical, or isolated hypothyroxinemia [6,28–31], whereas other studies showed the opposite [16,17]. Our large study, therefore, farther contributes to the positive relationship between hypothyroidism and small for gestational age infants, which has clinical implication in pregnancy follow-up. Another implication for clinical practice is the increased risk of congenital anomalies which we found in our study (aOR 1.34, 95% CI 1.22–1.48, p < 0.001). This finding correlates with previous studies, but not all. In a Swedish study which included 848,468 women, 9,866 of whom used thyroid hormone, a significantly increased risk of congenital anomalies was found (OR =1.14, 95% CI 1.05–1.26), however for less extent [8]. Another association between maternal hypothyroidism and major congenital anomalies was published in the Finland study (OR 1.14 [CI 1.06–1.22]) [16]. On the contrary, other studies did not show such association [5]. Therefore, farther studies are needed to evaluate and specify this risk.

There are several limitations to our study, the most important being that it was a retrospective analysis with TSH levels and information on presence of thyroid peroxidase antibodies not available. We cannot verify that the diagnosis of hypothyroidism was correctly made in all participants, as such the diagnosis of hypothyroidism may have been inflated although this would only serve to diminish any difference we detected and as such the difference found were likely real. In addition, we cannot distinguish between clinical and subclinical hypothyroidism. This could also result in findings being slightly blunted. However, this would also suggest that any significant findings were likely real. A possible bias can result from including ICD-9 diagnostic code 244.8. This code was given for acquired hypothyroidism. However, it includes secondary hypothyroidism as well, which we could not exclude from our analysis. In addition, odds ratio values were of a small magnitude. These finding highlights that most contribution to pathologies in pregnancy by hypothyroidism are likely mildly elevated in risk. Given that we do not have access to serum TSH levels in pregnancy we cannot be sure that subjects were compliant with their medications. However, this database as such likely reflects the true use of thyroid replacement in the general population and the resultant risks in pregnancy. Given that the database does not list different medications taken, we cannot control for the effect of different thyroid replacement types on outcomes. The fact that most findings in our study confirmed results from publications with smaller samples validates the outcomes of our study. It would have been nice to be able to report the type of neonatal anomalies in the study (i.e. major, minor, genetic) however, this data was unavailable.

One strength of our study is that it is the first truly large study to evaluate the risk of hypothyroidism in pregnancy, which was clearly lacking form the medical literature. Being the first true large population study, which included 9,096,788 births analyzed, and more than 184,000 women with hypothyroidism provides an evaluation of the independent risk of the disease on a variety of adverse pregnancy, delivery, and neonatal outcomes, while being powered to effectively control for confounding effects.

Conclusions

Our large database study, along with previous studies, demonstrated the association between maternal hypothyroidism and obstetrical complications such as preeclampsia and gestational diabetes mellitus, preterm premature rupture of membranes, preterm delivery, chorioamnionitis and cesarean section. In addition, we found that in the postpartum period there is a significant association between maternal hypothyroidism and postpartum hemorrhage, disseminated intravascular coagulation and blood transfusion, which were not previously established. Further studies should be directed to determine if compliance with thyroid replacement minimizes or even eliminates these risks.

Authors contribution

Ranit Hizkiyahu

1. Made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2. Drafted the work or revised it critically for important intellectual content;

3. Approved the version to be published; and

4. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ahmad Badeghiesh

1. Made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2. Drafted the work or revised it critically for important intellectual content;

3. Approved the version to be published; and

4. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Haitham Baghlaf

1. Made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2. Drafted the work or revised it critically for important intellectual content;

3. Approved the version to be published; and

4. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Michael H. Dahan

1. Made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work;

2. Drafted the work or revised it critically for important intellectual content;

3. Approved the version to be published; and

4. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

None

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability Statement

The data that support the findings of this study are publicly available in NIS Database Documentation at https://www.hcup-us.ahrq.gov/db/nation/nis/nisdbdocumentation.jsp.

Additional information

Funding

There is no funding information to declare.