Maternal Hypothyroidism and Adverse Outcomes of Pregnancy

Louise Knøsgaard; Stig Andersen; Annebirthe Bo Hansen; Peter Vestergaard; Stine Linding Andersen

Clin Endocrinol. 2023;98(5):719-729.

Abstract and Introduction

Abstract

Objective: Hypothyroidism has been associated with pregnancy complications, but uncertainty prevail regarding the severity and the role of thyroid autoimmunity. This study aimed to evaluate adverse pregnancy outcomes by exposure to maternal hypothyroidism and thyroid autoimmunity.

Design: Retrospective cohort study.

Patients: 14,744 singleton pregnancies from the North Denmark Region Pregnancy Cohort (2011–2015).

Measurements: Maternal thyroid stimulating hormone (TSH), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab) were retrospectively measured in early pregnancy blood samples (ADVIA Centaur XPT, Siemens Healthineers). Adjusted odds ratio (aOR) with 95% confidence interval (CI) was used to estimate associations between maternal hypothyroidism (TSH cut-offs: 6.0 and 10 mIU/L), thyroid autoimmunity (TPO-Ab cut-off: 60 U/ml, Tg-Ab cut-off: 33 U/ml), and adverse pregnancy outcomes.

Results: Pregnancy outcomes were 93.2% live births, 6.5% spontaneous abortions, and 0.3% stillbirths. The frequency of spontaneous abortion was 6.5% when TSH was below 6.0 mIU/L, 6.5% when above 6.0 mIU/L (aOR 1.0 [95% CI: 0.5–2.0]), and 12.5% when above 10 mIU/L (aOR: 2.0 [95% CI: 0.8–5.2]). For outcome of preterm birth, the frequency was 5.4% when TSH was below 6.0 mIU/L, 7.8% when above 6.0 mIU/L (aOR 1.5 [95% CI: 0.7–2.9]), and 11.4% when above 10 mIU/L (aOR: 2.6 [95% CI: 0.9–7.3]). No association was found between thyroid autoantibodies and spontaneous abortion (TPO-Ab: aOR: 1.0 [0.8–1.3], Tg-Ab: 1.0 [0.8–1.2]) or preterm birth (TPO-Ab: aOR: 1.0 [0.8–1.2], Tg-Ab: 0.9 [0.7–1.2]).

Conclusion: A high frequency of adverse pregnancy outcomes was seen among pregnancies exposed to maternal TSH above 10 mIU/L, whereas no association with thyroid autoantibodies was seen.

Introduction

Hypothyroidism is among the common chronic diseases in pregnant women.^[1] During pregnancy, maternal thyroid hormones are vital for foetal growth and brain development^[2] and a hypothesis of foetal programming by maternal hypothyroidism is biologically plausible.^[3,4] Clinical guidelines unanimously state that overt hypothyroidism in pregnant women should be treated to prevent complications.^[5] On the other hand, no universal screening for maternal overt hypothyroidism is implemented, and the current recommendation is limited to selective screening among pregnant women considered at risk for thyroid disease.^[5]

The role of maternal thyroid hormones and the adverse effects of maternal hypothyroidism when left untreated is evident from experimental findings and from the historical descriptions of cretinism in children born to mothers with severe hypothyroidism caused by iodine deficiency.^[6] Furthermore, the hallmark study by Haddow et al.^[7] substantiated a risk of adverse child outcomes associated with untreated maternal hypothyroidism, which has been corroborated in other reports.^[8] Large studies have substantiated that the frequency of undetected and untreated overt maternal hypothyroidism is around 0.3%,^[9] which is about 10 times more frequent than congenital hypothyroidism revealed by universal newborn screening.^[10] Thus, many criteria for screening^[11] are met when considering overt hypothyroidism, but a critical determinant is on the definition of actual disease and indication for treatment.

Even if more evidence is needed regarding universal screening for overt hypothyroidism in pregnant women, the scientific focus has moved towards subclinical maternal thyroid function abnormalities, isolated changes in free thyroxine (fT4), and thyroid autoimmunity per se.^[6] However, large randomized controlled trials (RCTs) have not shown any effect of treatment.^[6] We recently showed within the North Denmark Region Pregnancy Cohort (NDRPC), that smaller aberrations in maternal thyroid function in early pregnancy thyroid stimulating hormone (TSH) just above the pregnancy-specific reference range) rarely persisted with repeated blood sampling, whereas markedly increased TSH (above 6.0 mIU/L) was likely to reflect persistent hypothyroidism in a pregnant woman.^[12] In our view, a focus on persistent thyroid function abnormalities in pregnant women is needed to inform clinical practice.^[6,12]

In the present study the aim was to identify pregnancies exposed to maternal hypothyroidism in an early pregnancy blood sample and to evaluate the association with adverse outcomes of pregnancy. Furthermore, we aimed to evaluate the role of thyroid autoimmunity per se as reflected by thyroid autoantibodies measured in the early pregnancy blood sample.

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Table 1. Maternal characteristics by thyroid function exposure groups in the main analysis (TSH > 6.0 mIU/L) and in the sub-analysis (TSH > 4.0 mIU/L and thyroid autoantibody positive)
	TSH ≤ 6.0 mIU/L		TSH > 6.0 mIU/L		TSH ≤ 4.0 mIU/L		TSH > 4.0 mIU/La
	n	Freq (%)	n	Freq (%)	n	Freq (%)	n	Freq (%)
All pregnancies	14,621		123		14,374		287
Age
<35 years	12,182	83.3	93	75.6	11,976	83.3	226	78.8
≥35 years	2439	16.7	30	24.4	2398	16.7	61	21.2
Parity
Nulliparous	6822	46.7	44	35.8	6687	46.5	120	41.8
Multiparous	7799	53.3	79	64.2	7687	53.5	167	58.2
Origin^b
Born in Denmark	12,974	88.9	110	89.4	12,753	88.9	260	90.9
Not born in Denmark	1617	11.1	13	10.6	1592	11.1	26	9.1
Diabetes in pregnancy
No	13,326	91.1	101	82.1	13,104	91.2	249	86.8
Yes	1295	8.9	22	17.9	1270	8.8	38	13.2
Known hypothyroidism in pregnancy
No	14,499	99.2	99	80.5	14,273	99.3	246	85.7
Yes	122	0.8	24	19.5	101	0.7	41	14.3
All births	13,669		115		13,444		269
Pre-pregnancy BMI^b
<30 kg/m²	11,481	83.9	78	68.4	11,236	83.9	203	76.0
≥30 kg/m²	2192	16.1	36	31.6	2150	16.1	64	24.0
Smoking in pregnancy^b
No	12,021	88.4	104	91.2	11,811	88.3	250	93.6
Yes	1581	11.6	10	8.8	1567	11.7	17	6.4

Abbreviations: BMI, body mass index; freq, frequency.
^aTSH > 4.0 mIU/L and thyroid autoantibody positive (TPO-Ab > 60 U/ml and/or Tg-Ab > 33 U/ml).
^bMissing values not included: origin (n = 30), BMI (n = 60), and smoking (n = 68).

Table 2. Maternal characteristics by thyroid autoantibody exposure groups
	TPO-Ab negative^a		TPO-Ab positive^a		Tg-Ab negative^b		Tg-Ab positive^b
	n	Freq (%)	n	Freq (%)	n	Freq (%)	n	Freq (%)
All pregnancies	13,196		1548		12,796		1948
Age
<35 years	11,068	83.9	1207	78.0	10,730	83.9	1545	79.3
≥35 years	2128	16.1	341	22.0	2066	16.1	403	20.7
Parity
Nulliparous	6185	46.9	681	44.0	6027	47.1	839	43.1
Multiparous	7011	53.1	867	56.0	6769	52.9	1109	56.9
Origin^c
Born in Denmark	11,739	89.1	1345	87.2	11,419	89.4	1665	85.7
Not born in Denmark	1432	10.9	198	12.8	1352	10.6	278	14.3
Diabetes in pregnancy
No	12,041	91.3	1386	89.5	11,690	91.4	1737	89.2
Yes	1155	8.7	162	10.5	1106	8.6	211	10.8
Known hypothyroidism in pregnancy
No	13,155	99.7	1443	93.2	12,743	99.6	1855	95.2
Yes	41	0.3	105	6.8	53	0.4	93	4.8
All births	12,344		1440		11,963		1821
Pre-pregnancy BMI^c
<30 kg/m²	10,317	83.9	1179	82.3	9985	83.8	1511	83.4
≥30 kg/m²	1975	16.1	253	17.7	1927	16.2	301	16.6
Smoking in pregnancy^c
No	10,832	88.2	1293	90.4	10,428	87.6	1697	93.8
Yes	1453	11.8	138	9.6	1479	12.4	112	6.2

Abbreviations: BMI, body mass index; freq, frequency.
^aCut-off: 60 U/ml.
^bCut-off: 33 U/ml.
^cMissing values not included: origin (n = 30), BMI (n = 60), and smoking (n = 68).

Table 3. Frequency and odds ratio of spontaneous abortion by maternal level of TSH and thyroid autoantibody status in the early pregnancy among all pregnancies ( n = 14,744) and restricted to pregnancies with no treated gestational hypothyroidism ( n = 14,598)
Exposure	All pregnancies								Pregnancies with no treated gestational hypothyroidism
	All n	Spontaneous abortion							All n	Spontaneous abortion
	All n	n	Freq (%)^a	95% CI	OR	95% CI	aOR^b	95% CI	All n	n	Freq(%)^a	95% CI	OR	95% CI	aOR^b	95% CI
TSH ≤ 6.0 mIU/L	14,621	952	6.5	6.1–6.9	Ref.	-	Ref.	-	14,499	946	6.5	6.1–6.9	Ref.	-	Ref.	-
TSH > 6.0 mIU/L	123	8	6.5	2.8–12.4	1.0	0.5–2.0	1.0	0.5–1.9	99	8	8.1	3.5–15.3	1.3	0.6–2.6	1.2	0.6–2.5
TSH ≤ 10 mIU/L	14,704	955	6.5	6.1–6.9	Ref.	-	Ref.	-	14,566	949	6.5	6.1–6.9	Ref.	-	Ref.	-
TSH > 10 mIU/L	40	5	12.5	4.2–26.8	2.1	0.8–5.1	2.0	0.8–5.1	32	5	15.6	5.3–32.8	2.7	1.1–6.7	2.6	1.0–6.9
TPO-Ab negative^c	13,196	852	6.5	6.0–6.9	Ref.	-	Ref.	-	13,155	851	6.5	6.1–6.9	Ref.	-	Ref.	-
TPO-Ab positive^c	1548	108	7.0	5.8–8.4	1.1	0.9–1.3	1.0	0.8–1.3	1443	103	7.1	5.9–8.6	1.1	0.9–1.4	1.1	0.9–1.3
Tg-Ab negative^d	12,796	833	6.5	6.1–7.0	Ref.	-	Ref.	-	12,743	830	6.5	6.1–7.0	Ref.	-	Ref.	-
Tg-Ab positive^d	1948	127	6.5	5.5–7.7	1.0	0.8–1.2	1.0	0.8–1.2	1855	124	6.7	5.6–7.9	1.0	0.8–1.3	1.0	0.8–1.2

Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; freq, frequency; OR, odds ratio; Tg-Ab, thyroglobulin antibodies; TPO-Ab, thyroid peroxidase antibodies; TSH, thyroid stimulating hormone.
^aFrequency within the exposure group.
^bAdjusted model included maternal age (continuous variable), and the categorical variables: parity, origin, and diabetes.
^cCut-off: 60 U/ml.
^dCut-off: 33 U/ml.

Table 4. Frequency and odds ratio of preterm birth and caesarean section by the maternal level of TSH and thyroid autoantibody status in the early pregnancy among all pregnancies with an outcome of live birth ( n = 13,738)
	Live births
	All n	Preterm birth							Caesarean section
	All n	n	Freq (%)^a	95% CI	OR	95% CI	aOR^b	95% CI	n	Freq (%)^a	95% CI	OR	95% CI	aOR^b	95% CI
TSH ≤ 6.0 mIU/L	13,623	734	5.4	5.0–5.8	Ref.	-	Ref.	-	2878	21.1	20.4–21.8	Ref.	-	Ref.	-
TSH > 6.0 mIU/L	115	9	7.8	3.6–14.3	1.5	0.7–3.0	1.5	0.7–2.9	27	23.5	16.1–32.3	1.1	0.7–1.8	0.9	0.6–1.5
TSH ≤ 10 mIU/L	13,703	739	5.4	5.0–5.8	Ref.	-	Ref.	-	2897	21.1	20.5–21.8	Ref.	-	Ref.	-
TSH > 10 mIU/L	35	4	11.4	3.2–26.7	2.3	0.8–6.4	2.7	0.9–7.6	8	22.9	10.4–40.1	1.1	0.5–2.4	1.0	0.5–2.2
TPO-Ab negative^c	12,302	667	5.4	5.0–5.8	Ref.	-	Ref.	-	2596	21.1	20.4–21.8	Ref.	-	Ref.	-
TPO-Ab positive^c	1436	76	5.3	4.2–6.6	1.0	0.8–1.2	1.0	0.8–1.3	309	21.5	19.4–23.7	1.0	0.9–1.2	1.0	0.8–1.1
Tg-Ab negative^d	11,922	652	5.5	5.1–5.9	Ref.	-	Ref.	-	2538	21.3	20.6–22.0	Ref.	-	Ref.	-
Tg-Ab positive^d	1816	91	5.0	4.1–6.1	0.9	0.7–1.1	0.9	0.7–1.2	367	20.2	18.4–22.1	0.9	0.8–1.1	0.9	0.8–1.0

Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; freq, frequency; OR, odds ratio; Tg-Ab, thyroglobulin antibodies; TPO-Ab, thyroid peroxidase antibodies; TSH, thyroid stimulating hormone.
^aFrequency within the exposure group.
^bAdjusted model included maternal age and pre-pregnancy BMI (continuous variables), and the categorical variables: parity, origin, diabetes, and smoking.
^cCut-off: 60 U/ml.
^dCut-off: 33 U/ml.

Table 5. Frequency and odds ratio of outcomes of spontaneous abortion, preterm birth, and caesarean section when stratified by maternal TSH as well as overt and subclinical abnormalities in early pregnancy
	All pregnancies						Live births
	All n	Spontaneous abortion					All	Preterm birth					Caesarean section
	All n	n	Freq (%)^a	95% CI	aOR^b	95% CI	n	n	Freq(%)^a	95% CI	aOR^c	95% CI	n	Freq(%)^a	95% CI	aOR^c	95% CI
TSH ≤ 4.0 mIU/L	14,374	930	6.5	6.1–6.9	Ref.	-	13,399	720	5.4	5.0–5.8	Ref.	-	2828	21.1	20.4–21.8	Ref.	-
TSH > 4.0 mIU/L^d	287	18	6.3	3.8–9.7	0.9	0.6–1.5	269	17	6.3	3.7–9.9	1.2	0.7–2.0	60	22.3	17.5–27.8	1.0	0.7–1.3
Overt^e	89	9	10.1	4.7–18.3	1.4	0.7–2.9	80	4	5.0	1.4–12.3	1.0	0.3–2.7	18	22.5	13.9–33.2	1.0	0.6–1.6
Subclinical^f	198	9	4.5	2.1–8.5	0.7	0.3–1.3	189	13	6.9	3.7–11.5	1.3	0.8–2.4	42	22.2	16.5–28.8	1.0	0.7–1.4

Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; freq, frequency; TSH, thyroid stimulating hormone.
^aFrequency within the exposure group.
^bAdjusted model included maternal age (continuous variable), and the categorical variables: parity, origin, and diabetes.
^cAdjusted model included maternal age and pre-pregnancy BMI (continuous variables), and the categorical variables: parity, origin, diabetes and smoking.
^dTSH > 4.0 mIU/L and thyroid autoantibody positive (TPO-Ab > 60 U/ml and/or Tg-Ab > 33 U/ml).
^eAbnormal TSH and free T4 below the pregnancy week and method-specific lower reference limit.
^fAbnormal TSH irrespective of maternal free T4 in early pregnancy.