Table 2 Summary of selected studies on maternal thyroid disorder and postpartum depression

Harris et al. [21]

1992

Prospective Cohort Study

TPO-AB was assessed as a dichotom ous variable The study used a MS-AB assay to assess for TPO-AB status TPO-AB + (≥ 525 U/ml) at 16 weeks gestation

8,12,20, and 28 weeks postpartum

EPDS (≥ 13), HADS (≥ 11), and HAM-D (≥ 15)

145 antibody-positive women and 229 antibody-negative women delivering between August 1987 and December 1989

Not applicable

The estimated antibody prevalence in depressed women was significantly higher (16 1%, 95% confidence interval 12 1 to 19–8) than that in women without depression (9 3%)

Follow up of 110 antibody-positive and 132 antibody-negative women showed significantly greater depression by research diagnostic criteria in antibody-positive women (47%) than antibody-negative women (32%) regardless of thyroid dysfunction. Antibody-positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003)

Depressive symptoms are associated with positive thyroid antibody status in the postpartum period

Pop et al. [22]

1993

Prospecti ve cohort study

To investigate the association s between Anti-TPO-AB and the occurrence of postpartum depression. TPO-AB was assessed as a dichotomous variable The study used a MS-AB assay to assess for TPO-AB status TPO-AB + (any detectable titers of MS-AB at 32 weeks gestation)

Starting at 4 weeks postpartum, and at 6 week intervals until 34 weeks postpartum

.Depression was assessed using the Research Diagnostic Criteria developed by Spitzer et al.,without knowing the results of biochemical thyroid function tests

293 women at 32 weeks' gestation

Tthe incidence of depression developing during the postpartum period of assessment was 20.8% (61 women). Twenty women (6.8%) met the criteria for major depression, and 41 women (13.9%) for minor depression. Of the 27 MsAb positive women at 32 weeks' gestation, 9 subsequently developed depression during the postpartum period, compared to 52 of the 266 MsAb negative women at 32 weeks' gestation

At 32 weeks' gestation there were 27 (9.2%) women with elevated microsomal antibody titres. Compared with microsomal antibody-negative women at 32 weeks' gestation, these women had an RR of 20 for developing postpartum thyroid dysfunction and an RR of 1.7 for developing postpartum depression

Women with elevated microsomal antibody titres during gestation are particularly at risk for postpartum thyroid dysfunction, but only have a slightly increased risk for postpartum depression

Lazarus et al. [23]

1996

Prospective Cohort Study

Anti-TPO was assessed as dichotom ous variable anti-TPO + (≥ 19.6 kIU/l) measured at 16 weeks of gestation

Starting at the first month of postpartum and at monthly intervals for the first year of postpartum

Symptoms of depression were measured by a symptom questionnaire. Starting at the first month of postpartum and at monthly intervals for the first year of postpartum

474 women were recruited from a district hospital in South Wales over a two year period

Not applicable

Significantl y more TPO-AB + women reported depressive symptoms vs. TPOAB(-) women at the first month of postpartum (no data reported; p < 0.007)

Although postpartum thyroiditis (PPT) is usually transient, this condition, and the euthyroid antibody-positive state, may be associated with significant symptomatology, including an increased incidence of minor to moderate

depression

Kent et al. [18]

1999

Cross-sectional Study

Thyroid dysfunction was defined as TSH or fT4 outside the adult reference range (TSH 0,34–4,8 mU/l and fT4 10–19 pmol/l);

Microsomal antibody (MsAb +  > 1: 400;

TPOAb +  > 49 kIU/l;

Thyroid receptor antibodies (TRAb) with TSH < 0,34 mU/l using a reference range < 10 units/l;

Thyroid stimulating antibodies (TSI) < 1,3 units/l)

25 weeks postpartum (Range: 20–41 weeks)

General Health Questionnaire (GHQ28)

(Goldberg & Hillier, 1979);

Composite International Diagnostic Interview (CIDI-A) padronizado e computadorizado (Janca et al., 1994);

DSM-III-R criteria (The American Psychiatric

Association, 1987.)

748 Women who were Caucasian, aged 20–

45 years and 4·5–5·5 months postpartum

The prevalence of PPTD in the participants was 11·5% (95% CI 9·2–13·8%). The percentage of depression for anti-type positive women was not evaluated

The 6 month point prevalence rates of depression, generalized anxiety disorder and panic disorder and/or agoraphobia were 9·4%, 1·4% and 3·1%, respectively

No relationship was found between PPTD status and the diagnosis of current depression or between thyroid antibody status and current depression. In women

who were diagnosed as anxious at the time of assessment, the number of anxiety symptoms was higher in the PPTD group (P < 0·05)

This study has shown a high prevalence of postpartum thyroid dysfunction but there was no difference in the clinical and psychiatric signs and symptoms between cases and controls

Kuijpens et al. [24]

2001

Prospective Cohort Study

TPO-AB + (> 50 U/ml)

4,12,20,28, 36 weeks postpartum

Syndromal diagnosis for depression (major or minor) using the RDC diagnostic criteria

310 Women were recruited from local midwifery practices or at the Obstetrics Department of St. Joseph Hospital in the Netherlands

59% TPOAB + and 38% TPO-AB(-)

TPOAB + group had significantl y more women develop postpartum depression than the TPO-AB(-) group (59% vs. 38%; p = 0.03)

The presence of TPOAbs during gestation is associated with the occurrence of subsequent depression during the postpartum period and as such can be regarded as a marker for depression

Ruschi et al. [19]

2009

Cross-sectional Study

TSH, free T4, anti-TPO

Between 31^st and 180^th postnatal days

EPDS, 11/12 cutoff point

292 women from Public Health Units in the city of Vitória/ES in Brazil

115 (39.4%) women with PPD Group with changes thyroid: 36%

There was no statistically significant difference in the PPD frequency between patients with and without thyroid disorder (x² = 0.131; p = 0.717)

The frequency of PPD was high, with no association between PPD and thyroid changes

Lambrinoudaki et al. [20]

2010

Cross-sectional Study

Free T4, free T3, TSH, anti-TG, and anti-TPO measured at admission until the 4th postpartum day

Admission up to 6 weeks postpartum

PQB, on admission and on Days 1 to 4 postpartum

EPDS, on Day 4 and at 6 weeks postpartum

57 native Greek women from a Hospital at Aretaieion University with gestational ages of 35 to 38 weeks

Not applicable

Free T3 and free T4 in the prepartum period were negatively correlated with PBQ scores in the first postpartum week. As for thyroid antibodies, no association was found with mood scores

The findings indicate an association between the occurrence of postpartum mood disorders and prenatal thyroid function. Lower levels of free T3 and free T4 are associated with an increased incidence of mood disorders in the first postpartum week

Albacar, et al. [17]

2010

Cross-sectional Study

Free T4, TSH, anti-TPO, PCR analyzed 48 h postpartum

Between 24–48 h postpartum, 8 weeks and 32 weeks postpartum

EPDS, cutoff point 9/10

1053 women of Spanish origin in the postpartum period and with no previous history of depression

Among the 1053 women, 87 (8.3%) were depressed. Although 152 women (14.4%) had high levels of anti-TPO and slightly elevated TSH concentrations with normal free T4

No association was found between thyroid function and PPD. Thyroid dysfunction was not associated with CRP concentrations that were outside normal levels. Although thyroid function was not associated with PPD, when the entire study population was considered, it was observed that women with anti-TPO + had an increased risk of hypothyroidism (OR 5.54)

It was concluded that thyroid function at 48 h postpartum does not predict the risk of PPD. However, it may be that the anti-TPO positivity observed, together with other hormonal and molecular factors, worsens thyroid function and that subsequently anti-TPO positivity may be associated with PPD

Bergink et al. [15]

2011

Longitudinal Study

Anti-TPO antibodies were quantified as immunological measures of AITD

TSH and free T4 levels were also measured to assess clinical thyroid dysfunction

4 weeks and 9 months postpartum

Structural Clinical Interview for DSM-IV (SCID)

31 primiparous women from the community of the provinces of South Holland, Zealand and North Brabant. Without a psychiatric history diagnosed with postpartum psychosis

In the 4 weeks postpartum 19% of women with postpartum psychosis had AITD compared to controls (13%; OR = 2.78, 95% CI 1.08–7.17), and in 9-month postpartum 29% of women with postpartum psychosis had AITD compared to controls (13%; OR = 2.78, 95% CI 1.08–7.17), respectively

Patients with postpartum psychosis had a significantly higher rate of progression from subclinical AITD to clinical thyroid dysfunction. Specifically, of the patients with AITD at the 9-month follow-up, 67% had thyroid dysfunction compared to only 20% of the control group (OR = 8.00, 95% CI 1.23–52.25)

Women with postpartum psychosis are at higher risk not only for AITD but also for clinical thyroid failure. In addition, AITD represents a potentially strong etiological factor for the development of postpartum psychosis

Le Donne, Settineri and Benvenga [9]

2012

Cross-sectional Study

TSH, free T3, free T4, anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies

3 days postpartum

EPDS, MADRS, and TAS. Cutoff scores of 12 (EPDS), 15 (MADRS) and 61 (TAS) were used

74 Caucasian Italian women from a university hospital. The average age of women was 31.8 (range 20–44, median 31.5)

There is no % of PPD in women with thyroid dysfunction. The rates of women with abnormal EPDS, MADRS and TAS scores were similar (31%, 30% and 28.4%, respectively)

The alexithymitic individuals had lower T4, higher T3, lower T4free/T3free ratio and higher levels of anti-TPO or anti-TGT. Only anti-TPO and anti-TG were significantly higher in women at risk for PPD, but only at the EPDS cutoff values of 13 or 14. TAS was shown to be directly correlated with anti-TPO and FT3, and inversely with the T4free: T3free relationship, while EPDS correlated only with anti-TPO

It was concluded that the risk of PPD and alexithymia is directly associated with thyroid autoimmunity, and its association with serum thyroid hormones and the free T4/free T3 ratio follows opposite directions

Groer e Vaughan [25]

2013

Prospective Cohort Study

Anti-TPO and TSH dosages were performed, in addition to a specific physical examination and a checklist of thyroid symptoms developed by the authors was applied. Anti-TPO +  > 20 IU/ml

During pregnancy and in the postpartum period. Follow-up during the 6 months postpartum

Perceived Stress Scale (PSS) and the Mood States Profile Questionnaire (POMS)

47 anti-TPO positive and euthyroid women agreed to continue the follow-up. A control group of anti-TPO negative women (n = 72) was randomly selected for follow-up

Of the total sample of pregnant women, 48 were diagnosed with PPD (6.8%). During the postpartum period, 13 women in the total sample had scores indicating for clinical PPD. These women were all referred Eight (61.5%) of the 13 were TPO positive

Pregnant women with positive anti-TPO had significantly more depressive symptoms and were more likely to score higher than 20 on the POMS scale than women with negative anti-TPO (p = 0.028). Anti-TPO positive women had significantly higher scores for depression, anger and total postpartum mood disturbance scores than anti-TPO negative women, regardless of the development of postpartum thyroiditis (n = 25)

The results suggest that the presence of positive anti-TPO antibodies in pregnant women and euthyroid mothers increases the possibility of negative dysphoric mood, and especially of depressive symptoms that cannot be explained by stress or demographic factors

Sylvén et al. [26]

2013

Population-based Cohort Study

TSH, free T4 and anti-thyroid peroxidase antibodies (anti-TPO)

Blood samples during EPDS delivery at 5 days, 6 weeks and 6 months after delivery

EPDS-Edinburgh Postnatal Depression Scale), cutoff point of 12 or more

347 Swedish women at Uppsala University Hospital, Sweden

After adjustment for previous psychiatric contact, smoking during pregnancy, prepregnancy BMI and sleep, TSH levels above 4.0 mU/L were associated with an increased risk of depressive symptoms at six months postpartum (OR 11.30 95% CI 1.93–66.11)

Among the 329 samples successfully analyzed for TSH, 21 women (6.4%) had levels above 4.0 mU/L. Anti-TPO was analyzed in 248 samples and nine of the women tested had high levels of anti-TPO (3.6%). There was no significant association between PPD and TSH levels at five days or six weeks postpartum

The study suggests a screening tool to identify individuals at risk of developing PPD. However, other works must test this concept in a prospective scenario

Pedersen et al. [29]

2016

Prospective Cohort Study

17-estradiol, progesterone and thyroxine binding globulin (TBG). Variables of primary interest: total T4, free T4 and TBG, associated with thyroid variables of secondary interest: TSH, total T3, free T3 and uptake of T3 resin (T3U)

4 home visits, 2 during pregnancy (31–33 weeks and 35–36 weeks) and two postpartum (6 and 12 weeks)

EPDS; IDATE; MADRS; Hamilton Anxiety Scale (HRDS); and the modified MINI Plus 5.0.0

A cohort of 199 euthyroid women recruited from a public health antenatal clinic located in North Carolina

There is no % of PPD in women with thyroid dysfunction. Based on MINI-Plus interviews, 22 (11.1%) of subjects met DSM-IV criteria for major depression or RDC minor depression during late pregnancy (35–36 weeks), and 24 (12.1%) met criteria postpartum (week 12)

When analyzed in isolation, the level of free T4 was a less strong but still significant predictor of depression and anxiety (p < 0.05), while TBG levels were a significant or almost significant predictor of most classifications. Total T4, TBG and trauma history were significant individual predictors of syndromic depression during the study period (p < 0.05) in models with a single predictor. In models that combine each with a history of trauma and major depression, free T4 and TBG were not significantly predictive of depression or anxiety, and free T4 was also not a significant predictor of syndromic depression

It was shown that lower concentrations at the end of pregnancy of an endocrine variable sensitive to estrogen, TBG, predict perinatal syndromic depression. This result is particularly significant when there is a history of trauma and major depression

Wesseloo et al. [16]

2018

Prospective Cohort Study

anti-TPO, TSH and free T4. A level > 20 IU/ml was defined as positive anti-TPO

10^th-12^nd weeks of gestation

Self-reported PPD was defined using the following validated cutoff scores in the EPDS: 1^st trimester ≥ 11; 2^nd and 3^rd trimester ≥ 10; postpartum ≥ 13

1075 pregnant women with follow-up during pregnancy until one year postpartum

The cumulative incidence of self-reported depression in the first episode in the first postpartum year was 6.3%

A positive anti-TPO state was associated with an increased risk of self-reported depression of single onset at four months postpartum (adjusted OR 3.8; 95% CI 1.3–11.6), but not in other postpartum periods studied. The prevalence of PPD decreased after four months postpartum in the positive anti-TPO group, but remained constant in the negative group. The association between anti-TPO status and self-reported single-onset. depression at 6 weeks, 8 months and 12 months after delivery was not significant

Women with increased anti-TPO during pregnancy have a higher risk of self-reported depression from the first episode. The longitudinal pattern of self-reported depression in the postpartum group in the positive anti-TPO group was similar to the typical course of anti-TPO in the postpartum. This suggests overlap in the etiology of PPD and autoimmune thyroid dysfunction. It was concluded that thyroid function should be assessed in women with PPD

Zhang et al. [28]

2019

Prospective Cohort Study

Serum measurement of TSH and free T4 at three days (3d) and four weeks (4 s) postpartum

3 days and 4 weeks postpartum

Chinese version of the EPDS to assess postpartum depression at three days (3d) and four weeks (4w) postpartum

96 pregnant women recruited from a single hospital in China

The incidence of depression at 3d and 4w was 14.58% and 7.29%, respectively

There was no significant difference in the occurrence of PPD between TSH groups > 2.5 mUI/L and TSH ≤ 2.5 mUI/L. TSH and free T4 levels did not correlate significantly with EPDS at 3 days or with EPDS at 4 weeks. The incidence of PPD decreased by 4 weeks. In the EPDS follow-up assessment, we found that 10 of the 14 individuals who were initially diagnosed with PPD recovered spontaneously. This shows that TSH > 2.5 with high EPDS scores in 3 days after delivery should not be an indication for prophylactic use of thyroid hormone medication

The prenatal TSH level cannot predict the occurrence of PPD. Just as depression and TSH > 2.5 in three days postpartum should not be an indication for prophylactic use of thyroid hormone medication