Thyroid Peroxidase Antibodies and Prospective Live Birth Rate: A Cohort Study of Women with Recurrent Pregnancy Loss

Abstract Study question Can antinuclear antibody (ANA) affect the subsequent live birth rate in patients with recurrent pregnancy loss (RPL) who have no antiphospholipid antibodies (aPLs)? Summary answer ANA did not affect the pregnancy prognosis of RPL women. What is known already The prevalence of ANA is well-known to be higher in RPL patients. Our previous study found no difference in the live birth rates of ANA-positive and -negative patients who had no aPLs. Higher miscarriage rates were also reported in ANA-positive patients compared to ANA-negative patients with RPL. The RPL guidelines of the ESHRE state that “ANA testing can be considered for explanatory purposes.” However, there have been a limited number of studies on this issue and sample sizes have been small, and the impact of ANA on the pregnancy prognosis is unclear. Study design, size, duration An observational cohort study was conducted at Nagoya City University Hospital between 2006 and 2019. The study included 1,108 patients with a history of 2 or more pregnancy losses. Participants/materials, setting, methods 4D-Ultrasound, hysterosalpingography, chromosome analysis for both partners, aPLs and blood tests for ANA and diabetes mellitus were performed before a subsequent pregnancy. ANAs were measured by indirect immunofluorescence. The cutoff dilution used was 1:40. In addition, patients were classified according to the ANA pattern on immunofluorescence staining. Live birth rates were compared between ANA-positive and ANA-negative patients after excluding patients with antiphospholipid syndrome, an abnormal chromosome in either partner and a uterine anomaly. Main results and the role of chance The 994 patients were analyzed after excluding 40 with a uterine anomaly, 43 with a chromosome abnormality in either partner and 32 with APS. The rate of ANA-positive patients was 39.2 % (390/994) when the 1: 40 dilution result was positive. With a 1:160 dilution, the rate of ANA-positive patients was 3.62 % (36/994). The live birth rate was calculated for 798 patients, excluding 196 patients with unexplained RPL who had been treated with any medication. With the use of the 1 40 dilution, the subsequent live birth rates were 71.34 % (219/307) for the ANA-positive group and 70.67 % (347/491) for the ANA-negative group (OR, 95%CI; 0.968, 0.707-1.326). After excluding miscarriages with embryonic aneuploidy, chemical pregnancies and ectopic pregnancies, live birth rates were 92.41 % (219/237) for the ANA-positive group and 92.04 % (347/377) for the ANA-negative group (0.951, 0.517-1.747). Using the 1:160 dilution, the subsequent live birth rates were 84.62 % (22/26) for the ANA-positive group, and 70.47 % (544/772) for the ANA-negative group (0.434, 0.148-1.273). Subgroup analyses were performed for each pattern on immunofluorescence staining, but there was no significant difference in the live birth rate between the two groups. Limitations, reasons for caution The effectiveness of immunotherapies could not be evaluated. However, the results of this study suggest that it is not necessary. Wider implications of the findings The measurement of ANA might not be necessary for the screening of patients with RPL who have no features of collagen disease. Trial registration number not applicable

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Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure

Human Reproduction ◽

10.1093/humrep/dez229 ◽

2019 ◽

Vol 34 (12) ◽

pp. 2340-2348 ◽

Cited By ~ 11

Author(s):

Takeshi Sato ◽

Mayumi Sugiura-Ogasawara ◽

Fumiko Ozawa ◽

Toshiyuki Yamamoto ◽

Takema Kato ◽

...

Keyword(s):

Live Birth ◽

Pregnancy Loss ◽

Birth Rate ◽

Recurrent Pregnancy Loss ◽

Live Birth Rate ◽

Not Given ◽

Recurrent Implantation Failure ◽

Miscarriage Rate ◽

Preimplantation Genetic Testing ◽

Biochemical Pregnancy

Abstract STUDY QUESTION Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)? SUMMARY ANSWER PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups. WHAT IS KNOWN ALREADY PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40–50% and 5–25% in patients with RPL, respectively. STUDY DESIGN, SIZE, DURATION A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35–36, 37–38, 39–40 or 41–42 years) were selected for PGT-A groups. PARTICIPANTS/MATERIALS, SETTING, METHODS All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted. MAIN RESULT AND THE ROLE OF CHANCE There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16–13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28–10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02–0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03–0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients. LIMITATIONS, REASONS FOR CAUTION The sample size was too small to find any significant advantage for improving the live birth rate and reducing the clinical miscarriage rate per patient. Further study is necessary. WIDER IMPLICATION OF THE FINDINGS A large portion of pregnancy losses in the RPL group might be due to aneuploidy, since PGT-A reduced the overall incidence of pregnancy loss in these patients. Although PGT-A did not improve the live birth rate per patient, it did have the advantage of reducing the number of embryo transfers required to achieve a similar number live births compared with those not undergoing PGT-A. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Japan Society of Obstetrics and Gynecology and grants from the Japanese Ministry of Education, Science, and Technology. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A

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Systematic meta-analysis of subsequent pregnancy outcomes in recurrent pregnancy loss couples with parental abnormal chromosomal karyotype

10.22541/au.163424449.91097893/v1 ◽

2021 ◽

Author(s):

Peng-Sheng Zheng ◽

Shan Li ◽

Jing Jing He

Keyword(s):

Live Birth ◽

Pregnancy Outcomes ◽

Pregnancy Loss ◽

Birth Rate ◽

Recurrent Pregnancy Loss ◽

Meta Analysis ◽

Live Birth Rate ◽

Sufficient Evidence ◽

Current Evidence ◽

Miscarriage Rate

Background Parental abnormal chromosomal karyotypes are considered as reasons for recurrent pregnancy loss. Objective This systematic meta-analysis evaluated the current evidence on pregnancy outcomes amongst couples with abnormal versus normal chromosomal karyotypes. Search strategy Two independent reviewers screened titles and abstracts identified in EMBASE and PubMed from inception to January 2021. Selection criteria Studies were included if they provided a description of pregnancy outcomes of parental chromosomal abnormality. Data collection and analysis Random effects meta-analysis was used to compare odds of pregnancy outcomes associated with noncarriers and carriers. Main results A significantly lower first pregnancy live birth rate (FPLBR) was found in carriers than in noncarriers with RPL (OR: 0.55; 95% CI: 0.46-0.65; p<0.00001). Regarding FPLBR between translocation or inversion carriers and noncarriers, a markedly decreased FPLBR was found in translocation (OR: 0.44; 95% CI: 0.31–0.61; p<0.00001) but not inversion carriers. The accumulated live birth rate (ALBR) (OR: 0.96; 95% CI: 0.90–1.03; p=0.26) was similar, while the miscarriage rate (MR) of accumulated pregnancies (OR: 2.21; 95% CI: 1.69–2.89; p<0.00001) was significantly higher in the carriers than in noncarriers with RPL. The ALBR was not significant (OR: 1.82; 95% CI: 0.38–8.71; p=0.45) but the MR (OR: 5.75; 95% CI: 2.57–12.86; p<0.0001) was markedly lower for carriers who choose PGD than natural conception. Conclusions Carriers with RPL had higher risk of miscarriage but obtained a satisfying pregnancy outcome through multiple attempts. No sufficient evidence was found PGD could enhance the ALBR but it was an alternative to decrease the MR.

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P–377 Association between antinuclear antibodies and pregnancy prognosis in recurrent pregnancy loss patients

Human Reproduction ◽

10.1093/humrep/deab130.376 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

H Yoshihara ◽

M Sugiura-Ogasawara ◽

T Kitaori ◽

S Goto

Keyword(s):

Live Birth ◽

Pregnancy Loss ◽

Birth Rate ◽

Recurrent Pregnancy Loss ◽

Live Birth Rate ◽

Negative Group ◽

Birth Rates ◽

Positive Group ◽

Live Birth Rates ◽

Uterine Anomaly

Abstract Study question Can antinuclear antibody (ANA) affect the subsequent live birth rate in patients with recurrent pregnancy loss (RPL) who have no antiphospholipid antibodies (aPLs)? Summary answer ANA did not affect the pregnancy prognosis of RPL women. What is known already The prevalence of ANA is well-known to be higher in RPL patients. Our previous study found no difference in the live birth rates of ANA-positive and -negative patients who had no aPLs. Higher miscarriage rates were also reported in ANA-positive patients compared to ANA-negative patients with RPL. The RPL guidelines of the ESHRE state that “ANA testing can be considered for explanatory purposes.” However, there have been a limited number of studies on this issue and sample sizes have been small, and the impact of ANA on the pregnancy prognosis is unclear. Study design, size, duration An observational cohort study was conducted at Nagoya City University Hospital between 2006 and 2019. The study included 1,108 patients with a history of 2 or more pregnancy losses. Participants/materials, setting, methods 4D-Ultrasound, hysterosalpingography, chromosome analysis for both partners, aPLs and blood tests for ANA and diabetes mellitus were performed before a subsequent pregnancy. ANAs were measured by indirect immunofluorescence. The cutoff dilution used was 1:40. In addition, patients were classified according to the ANA pattern on immunofluorescence staining. Live birth rates were compared between ANA-positive and ANA-negative patients after excluding patients with antiphospholipid syndrome, an abnormal chromosome in either partner and a uterine anomaly. Main results and the role of chance The 994 patients were analyzed after excluding 40 with a uterine anomaly, 43 with a chromosome abnormality in either partner and 32 with APS. The rate of ANA-positive patients was 39.2% (390/994) when the 1: 40 dilution result was positive. With a 1:160 dilution, the rate of ANA-positive patients was 3.62% (36/994). The live birth rate was calculated for 798 patients, excluding 196 patients with unexplained RPL who had been treated with any medication. With the use of the 1: 40 dilution, the subsequent live birth rates were 71.34% (219/307) for the ANA-positive group and 70.67% (347/491) for the ANA-negative group (OR, 95%CI; 0.968, 0.707–1.326). After excluding miscarriages with embryonic aneuploidy, chemical pregnancies and ectopic pregnancies, live birth rates were 92.41% (219/237) for the ANA-positive group and 92.04% (347/377) for the ANA-negative group (0.951, 0.517–1.747). Using the 1:160 dilution, the subsequent live birth rates were 84.62% (22/26) for the ANA-positive group, and 70.47% (544/772) for the ANA-negative group (0.434, 0.148–1.273). Subgroup analyses were performed for each pattern on immunofluorescence staining, but there was no significant difference in the live birth rate between the two groups. Limitations, reasons for caution The effectiveness of immunotherapies could not be evaluated. However, the results of this study suggest that it is not necessary. Wider implications of the findings: The measurement of ANA might not be necessary for the screening of patients with RPL who have no features of collagen disease. Trial registration number Not applicable

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Dysmorphic Uteri: Obstetric Results after Hysteroscopic Office Metroplasty in Infertile and Recurrent Pregnancy Loss Patients. A Prospective Observational Study

Journal of Clinical Medicine ◽

10.3390/jcm9092857 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2857

Author(s):

Mónica Sánchez-Santiuste ◽

Mar Ríos ◽

Laura Calles ◽

Reyes de la Cuesta ◽

Virginia Engels ◽

...

Keyword(s):

Live Birth ◽

Pregnancy Loss ◽

Birth Rate ◽

Recurrent Pregnancy Loss ◽

Live Birth Rate ◽

Obstetric Outcomes ◽

Significant Difference ◽

History Of ◽

The Difference ◽

Infertile Patients

To compare the obstetric results achieved after hysteroscopic office metroplasty (HOME-DU) in infertile and recurrent pregnancy loss (RPL) patients diagnosed with dysmorphic uterus, women hysteroscopically diagnosed with dysmorphic uterus who underwent uterine-enlargement metroplasty were prospectively enrolled from June 2016 until April 2020. Patients were followed up and obstetric outcomes were recorded (pregnancy and live birth rate). Sixty-three women (30 infertile; 33 RPL) were enrolled, of which 48 became pregnant post-HOME-DU, with an overall pregnancy rate of 76.2% (66.7% among infertile participants; 84.9% among those with RPL). Overall, 64.3% (n = 36/63) achieved live birth. Among infertile women, 62.07% (n = 18/29) achieved live birth, as well as 66.7% of women with RPL (n = 18/27). The difference in live birth rates between both cohorts was 4.6% (p > 0.05). The rate of miscarriage amongst infertile patients was 3.3% (n = 1/30) and 12.1% amongst women with RPL (n = 4/33). Office metroplasty via the HOME-DU technique improves obstetric results (namely increasing live birth rate) in patients with dysmorphic uterus and a history of reproductive failure. No significant difference was found in the clinical efficacy of HOME-DU in infertile and RPL patients.

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Effect of Japanese herbal Kampo medicines on live birth rate in women with recurrent pregnancy loss

International Journal of Gynecology & Obstetrics ◽

10.1002/ijgo.13477 ◽

2020 ◽

Author(s):

Daisuke Shigemi ◽

Yohei Hashimoto ◽

Nobuaki Michihata ◽

Hideo Yasunaga

Keyword(s):

Live Birth ◽

Pregnancy Loss ◽

Birth Rate ◽

Recurrent Pregnancy Loss ◽

Live Birth Rate

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Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT

Efficacy and Mechanism Evaluation ◽

10.3310/eme06110 ◽

2019 ◽

Vol 6 (11) ◽

pp. 1-72

Author(s):

Rima K Dhillon-Smith ◽

Lee J Middleton ◽

Kirandeep K Sunner ◽

Versha Cheed ◽

Krys Baker ◽

...

Keyword(s):

Confidence Interval ◽

Thyroid Function ◽

Live Birth ◽

Birth Rate ◽

Live Birth Rate ◽

Thyroid Stimulating Hormone ◽

Thyroid Peroxidase ◽

Controlled Trials ◽

Thyroid Antibodies ◽

Thyroid Peroxidase Antibodies

Background Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy. Objectives The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses. Design This was a randomised, double-blind, placebo-controlled, multicentre study. Setting The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016. Participants Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible. Intervention Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation. Main outcome measures The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at < 24 weeks; clinical pregnancy at 7 weeks; ongoing pregnancy at 12 weeks; gestation at delivery; birthweight; appearance, pulse, grimace, activity and respiration (Apgar) scores; congenital abnormalities; and neonatal survival at 28 days of life. Methods Participants were randomised in a 1 : 1 ratio. Minimisation was implemented for age (< 35 or ≥ 35 years), number of previous miscarriages (0, 1 or 2, ≥ 3), infertility treatment (yes/no) and baseline thyroid-stimulating hormone concentration (≤ 2.5 or > 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time. Results Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome. Conclusions Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies. Limitations Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored. Future work Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism. Trial registration Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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