Accepted Manuscript

Endocrine Causes of Recurrent Pregnancy Loss

Selma Amrane MD Reproductive Endocrinology and Infertility Fellow ,

Rachel McConnell MD Assistant Professor in Obstetrics and Gynecology

PII: S0146-0005(18)30140-X
DOI: https://doi.org/10.1053/j.semperi.2018.12.004
Reference: YSPER 51105

To appear in: Seminars in Perinatology

Please cite this article as: Selma Amrane MD Reproductive Endocrinology and Infertility Fellow ,
Rachel McConnell MD Assistant Professor in Obstetrics and Gynecology , Endocrine
Causes of Recurrent Pregnancy Loss, Seminars in Perinatology (2018), doi:
https://doi.org/10.1053/j.semperi.2018.12.004

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 ACCEPTED MANUSCRIPT

Endocrine Causes of Recurrent Pregnancy Loss

Selma Amrane, MDa and Rachel McConnell, MDa
a. Columbia University Department of Obstetrics and Gynecology, Division of
Reproductive Endocrinology and Infertility. New York, NY

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Selma Amrane, MD – Reproductive Endocrinology and Infertility Fellow

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Rachel McConnell, MD – Assistant Professor in Obstetrics and Gynecology

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Address: Columbia University Fertility Center
1790 Broadway, PH
New York, NY 10019

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CORRESPONDING AUTHOR/ADDRESS:
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Rachel McConnell, MD – Assistant Professor in Obstetrics and Gynecology

Columbia University Fertility Center

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1790 Broadway, PH

New York, NY 10019

rm3057@cumc.columbia.edu
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Abstract
Objective: To review the available data on endocrine disorders and recurrent pregnancy loss.

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Findings: Our group found that most endocrine disorders do not seem to be correlated with a

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diagnosis of recurrent pregnancy loss. The exception to this is testing for thyroid stimulating

hormone and thyroid antibodies, which is recommended due to a strong correlation with

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recurrent pregnancy loss and positive anti-thyroid peroxidase antibodies.

Conclusion: The available literature supports testing thyroid function and antibodies in women
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with RPL. Testing for other endocrine disorders is only warranted if otherwise clinically

indicated, independent from a history of recurrent pregnancy loss.

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Introduction
In the evaluation of patients with recurrent pregnancy loss, screening for

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endocrinopathies is often performed. However, existing data challenges the association between

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many endocrinopathies and recurrent pregnancy loss. This review aims to examine existing data

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on the link between endocrinopathies and recurrent pregnancy loss.

Thyroid Disease US
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Poorly controlled thyroid disease is known to have negative repercussions on established

pregnancies, such as premature delivery, placental abruption, gestational hypertension, low birth
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weight, lower childhood IQ, congenital anomalies, and fetal death (1-4). However, the link

between some thyroid disease and recurrent pregnancy loss is questionable. For example, overt
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hypothyroidism, which affects 0.2-0.3% of pregnancies (1), may have an increased prevalence in
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patients with recurrent pregnancy loss, although more robust studies are needed to solidify this

link (5-6). For example, Rao et al demonstrate an increased prevalence of hypothyroidism of

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4.29% (7/163) in nonpregnant patients with RPL, as compared to a 0.61% (1/170) rate of

hypothyroidism in nonpregnant women with no history of miscarriage and a history of at least

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one successful pregnancy. However, the study designs for this and other available studies are

suboptimal.

The data on subclincial hypothyroidism (SCH), defined as TSH greater than 2.5 and

normal free thyroxine or free thyroxine index, and increased risk of RPL is conflicting. One

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study by Bernardi et al found an increased prevalence of SCH in an RPL population of 19%,

significantly higher than the prevalence of SCH in the general pregnant population (2-3%) or the

general nonpregnant population (4-8.5%) (7). However, this group detected a similar live birth

rate in women with SCH and euthyroid women [27/39 (69%) versus 104/141 (74%)]. Uchida et

al reported similar miscarriage rates in women with RPL across both SCH and euthyroid groups,

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although a difference may have been detected with a larger study number [29.0% (9/31) versus

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17.9% (24/134), p = 0.16] (8). Two additional studies also report similar miscarriage rates in

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women with RPL with either SCH or euthyroid status (9-10). Therefore, data is conflicting, but

may demonstrate an association between SCH and RPL. Further studies are needed to explore

this association. US
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Numerous studies have investigated the link between anti-thyroid peroxidase antibodies

(TPOAb) and RPL. The incidence of TPOAb in women of reproductive age, independent of
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thyroid status, is 8-14%. Although the presence of TPOAb predisposes to hypothyroidism, the

majority of women with these antibodies are euthyroid (11). One meta-analysis reported an
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increased risk of miscarriage in women with RPL with TPOAb (OR 4.22; 95% CI 0.97-18.44, n
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= 221). In fact, they found that the risk of miscarriage was increased in euthyroid women with

RPL and TPOAb (OR 1.86; 95% CI 1.18-2.94, n = 2753) (12). However, the authors of this
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metaanalysis note unexplained significant heterogeneity of these results. A separate

metaanalysis, including some of the same studies, also concluded that there was increased risk of
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miscarriage in women with RPL with TPOAb (13). Therefore, based on this data, the European

Society for Human Reproduction and Embryology (ESHRE) has issued a strong

recommendation for thyroid screening with thyroid stimulating hormone (TSH) and TPOAb in

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women with RPL. They have also recommended that abnormal TSH and TPOAb levels be

followed up with T4 testing in women with RPL.

Additionally, the presence of anti-thyroglobulin antibody (TGAb) appears to be more

common in women with RPL (22.5% 36/160 versus 5% 5/100, p < 0.05) (14). However, in this

retrospective study, there was no relationship between anti-TSH receptor antibody (TSHrAb) and

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RPL (1.87% 3/160 versus 2% 2/100). Therefore, the available data demonstrates that the

antibodies associated with RPL are TPOAb and TGAb, with the clearest association between

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RPL and TPOAb.

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Although overt hyperthyroidism has been known to cause pregnancy loss sporadically, no

studies were found examining the association between hyperthyroidism and RPL.
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Vitamin D
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The association between vitamin D deficiency and RPL has recently been a popular topic
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of investigation. A meta-analysis of 7 observational studies and 4 clinical studies found that

women with RPL had lower vitamin D levels than controls (15). Additionally, this meta-analysis
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confirmed previous findings that women with RPL have altered immune profiles, which vitamin

D levels may affect. First, two retrospective studies have shown that, in women with RPL with
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low vitamin D levels, there is a different immune profile than in women with RPL with normal

vitamin D levels (16, 17). Ota et al demonstrate that women with RPL with low vitamin D (< 30

ng/dL) have increased autoimmune antibodies, such as anti-nuclear antibody (ANA), single

stranded DNA antibody (anti-ssDNA), and thyroid peroxidase antibodies (TPOAb), compared to

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those with normal vitamin D levels (p < 0.05 for each). Both Ota and Chen demonstrated a

larger number of CD19 B cells and NK cytotoxicity in women with RPL with vitamin D

deficiency, both of which have been implicated in the pathophysiology of RPL (18). Reversal of

these profiles was demonstrated both in vitro (16) and in vivo by Chen (17), suggesting that

vitamin D repletion may be beneficial in patients with RPL.

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The effect of vitamin D on women with RPL has been studied at the level of the

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endometrium. Tavakoli et al examined endometrial biopsies in 8 patients with RPL and 8 age-

matched controls, and found that endometrial cells in women with RPL produced more INF-γ, a

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cytokine implicated in both innate and adaptive immunity, compared to controls (19). They also

found similar conversion rates of vitamin D3 in both groups, suggesting women with RPL do not
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have impaired ability to process vitamin D.

Vitamin D has also been studied in early pregnancy in women with RPL as compared to those
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undergoing pregnancy termination (19-21). An altered immune profile and decreased vitamin D
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receptor and 25-hydroxyvitamin D3-1 α –hydroxylase (CYP27B1) expression were found in

villous and decidual tissues in women with RPL as compared to controls undergoing termination.
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These alterations suggest that vitamin D metabolism may play a role in the pathophysiology of

RPL.
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Overall, vitamin D levels and vitamin D metabolism appear altered in women with RPL.
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However, studies demonstrating a causal link between vitamin D and the pathophysiology of

RPL are required. Despite this, it may be reasonable for reproductive physicians and

gynecologists to screen for and treat vitamin D deficiency, given the prevalence of vitamin D

deficiency and its consequences in ongoing pregnancy, such as preeclampsia, gestational

diabetes, and small for gestational age fetuses.

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Luteal Phase Deficiency

Luteal phase deficiency (LPD) refers to insufficient progesterone exposure to allow for

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normal embryo implantation and growth (22). There is controversy with regards to the clinical

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relevance of this condition, partially due to the difficulty in defining it. Part of this difficulty is

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due to the pulsatile secretion of progesterone, as levels can vary significantly over a short period

of time. Conclusions regarding the relationship between LPD and RPL are difficult to make due

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to the heterogeneity in the definitions of LPD in the existing literature and the lack of controlled
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trials (11).

Despite these difficulties, there are several studies exploring the link between RPL and
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luteal phase deficiency. A prospective study of 197 patients with three consecutive euploid first

trimester spontaneous abortions revealed 19.7% of these had a luteal phase deficiency, defined as
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two endometrial biopsies in the luteal phase with greater than or equal to three days of

maturation delay (24). However, LPD has not been predictive of future spontaneous abortions in
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patients with RPL. In fact, in 197 patients with two or more consecutive spontaneous abortions,
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there was no difference in the percentage of subsequent spontaneous abortions in women with

RPL and LPD, and with RPL and no LPD ( 20.5% of women without LPD and (31/151) and
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15.2% (7/46) of women with LPD had a subsequent spontaneous abortion (26).

A molecular basis for the role of luteal phase defect in RPL has been investigated.

Meresmen et al compared endometrial biopsy samples from women with RPL with LPD (n = 16)

to those from women without LPD (n=21) and found that women with luteal phase deficiency

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had increased expression of caspase-3 (p < 0.005), an apoptotic factor (25). However, this study

uses endometrial histological dating, which has questionable reproducibility and accuracy.

Moreover, further studies are necessary to further elucidate the role of apoptosis in RPL and

LPD.

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Overall, testing for luteal phase defect in women with RPL is likely not worth the

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economic burden, especially since there is no consensus on diagnostic criteria of luteal phase

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deficiency.

Insulin Resistance US
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Insulin resistance is defined by a decreased biological response to normal insulin

concentrations. The homeostasis model assessment of insulin resistance (HOMA-IR) and the
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quantitative insulin sensitivity check index (QUICKI) are indices have been developed to assess

insulin resistance, although their use in the clinical setting varies and remains controversial (27).
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Studies examining RPL and insulin resistance use these models, as well as fasting insulin levels,

and fasting glucose to insulin ratios. Although helpful for assessment at a single time point,
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these methods are limited by the lack of a standard universal insulin assay (28).
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Insulin resistance has been found to be more prevalent in the RPL population. Craig et al

demonstrated that nondiabetic women with RPL more commonly have insulin resistance than
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age-matched, nondiabetic controls in a prospective study using fasting insulin and fasting

glucose to insulin ratios(OR 3.55, 95% CI 1.40-9.01) (29). Maryam et al confirmed an increased

prevalence of insulin resistance in patients with RPL in their prospective case control study when

using fasting insulin as the diagnostic test (OR 4.44, 95% CI 1.21-17.1). Additionally, the RPL

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group was found to have increased insulin resistance as defined by increased fasting glucose to

insulin ratios (p = 0.0248) (30). Although fasting glucose levels alone were not found to be

different across both groups, the subject pool was small (n= 50 in each group), and overall, the

study supports increased insulin resistance in women with RPL. Ipsaiou et al also show

increased HOMA-IR and fasting glucose in RPL women as compared to controls (p < 0.05) (31).

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Although there seems to be a link between RPL and insulin resistance, no studies have

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elucidated whether the relationship between insulin resistance and RPL is causative.

Additionally, Kazerooni et al explored the relationship between PCOS and RPL in a case-control

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study dividing 60 women into four groups: women with RPL and PCOS, women with only RPL,

women with only PCOS, and women without RPL or PCOS. Women with the highest fasting
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insulin (p = 0.015) and the lowest QUICKI sensitivity index score (p =0.024) were those with

RPL and PCOS (31). However, more studies are needed to further explore this relationship, and
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to elucidate if PCOS has a causal role in RPL.

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Prolactin Disorders
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Prolactin is a hormone secreted by the lactotroph cells of the anterior pituitary gland. Its
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role in the establishment of early pregnancies is controversial, although some studies

demonstrate that low or high prolactin levels may confer a higher miscarriage risk.
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Li et al evaluated prolactin levels in 174 patients with recurrent miscarriage. 109 of these

patients conceived again during the study period, and those who had a spontaneous abortion in

the index pregnancy had significantly lower prolactin levels (p < 0.05, OR 0.99, 95% CI 0.97-

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0.99). Based on this finding, the conclusion was made that low prolactin levels are associated

with subsequent pregnancy loss in women with a history of RPL (32).

Elevated prolactin level was found to increase miscarriage risk in women with RPL in a

randomized trial by Hirahara et al (33). 46 patients with RPL who were found to have elevated

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prolactin levels, defined by either elevated basal prolactin levels or levels 30 minutes after TRH

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stimulation, or both findings, were randomized to either receive treatment with bromocriptine

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2.5-5mg/day or no treatment. Increased live birth rates were found in the bromocriptine group

(85.7% versus 52.4%, p < 0.05) and increased prolactin levels in those patients with subsequent

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miscarriage (31.8-55.3ng/mL), as compared to those whose pregnancies ended in live birth (4.6-

15.5ng/mL, p < 0.05). Based on these findings, normal prolactin levels may play an important
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role in establishing early pregnancies.

Although these two studies suggest that abnormally low or high prolactin levels may
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contribute to miscarriage risk in women with RPL, a cross-sectional study of 69 women with
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RPL and 31 fertile women and 30 women with infertility found that the rate of

hyperprolactinemia were similar across all groups, though highest in the infertile group and not
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the RPL group (RPL women: 15/69; 21.7%, infertile women: 13/31; 41.9%, and fertile controls:

5/30; 16.7%) (34).

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Given the above inconsistent study findings with regards to prolactin levels and their
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impact on early pregnancy outcomes, ESHRE recommends against testing prolactin levels in

women with RPL with no other clinical indication for testing (11).

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Disclosure Statement: The authors report no proprietary or commercial interest in any product

mentioned or concept discussed in this article.

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