Reduced levels of plasma kisspeptin during the antenatal booking visit are associated with increased risk of miscarriage

C N Jayasena, A Abbara, C Izzi-Engbeaya, A N Comninos, R A Harvey, J Gonzalez Maffe, Z Sarang, Z Ganiyu-Dada, A I Padilha, M Dhanjal, C Williamson, L Regan, M A Ghatei, S R Bloom, W S Dhillo, C N Jayasena, A Abbara, C Izzi-Engbeaya, A N Comninos, R A Harvey, J Gonzalez Maffe, Z Sarang, Z Ganiyu-Dada, A I Padilha, M Dhanjal, C Williamson, L Regan, M A Ghatei, S R Bloom, W S Dhillo

Abstract

Context: Kisspeptin is a recently identified hormone encoded by the KISS1 gene, playing a critical role in human reproduction. Plasma kisspeptin levels rise dramatically during normal pregnancy due to placental synthesis, which implicates it as a potential tool for assessing risks of pregnancy complications. No previous prospective study has investigated the association between plasma kisspeptin and risk of miscarriage.

Objective: The objective of the study was to determine whether a single plasma kisspeptin or serum human chorionic gonadotropin (hCG) measurement in asymptomatic women attending their booking antenatal visit is associated with miscarriage.

Design: This was a prospective cohort study.

Setting: The study was conducted at a tertiary obstetric center.

Participants: A total of 993 asymptomatic pregnant women with a gestation of 6 weeks or longer attending routine antenatal booking visit were recruited between January 2010 and December 2012.

Main outcome measures: Plasma kisspeptin and serum hCG were measured during the antenatal booking visit. Pregnancy outcome was recorded prospectively.

Results: Plasma kisspeptin correlated with gestation (r(2) = 0.57; P < .0001). Gestational age-corrected (multiples of median) plasma kisspeptin was 60.4% lower (P < .001), and multiples of median-hCG was 36.1% lower (P < .001) in women later diagnosed with miscarriage compared with women without miscarriage. Increased plasma kisspeptin was associated with reduced miscarriage risk, even after adjusting for age, body mass index, gestational age, smoking, and blood pressure [odds ratio 0.13 (95% confidence interval 0.08-0.22), P = .0001]. Kisspeptin had a higher diagnostic performance for miscarriage than hCG (receiver-operator characteristic-area under the curve 0.899 ± 0.025 plasma kisspeptin; 0.775 ± 0.040, serum hCG, P < .01 vs plasma kisspeptin).

Conclusion: Our data suggest for the first time that a single plasma kisspeptin measurement taken during the antenatal booking visit provides a potential novel marker for identifying asymptomatic pregnant women at a gestation of 6 weeks or greater at increased risk of miscarriage.

Figures

Figure 1.
Figure 1.
Plasma kisspeptin and serum hCG have distinct distributions when classified by gestation in women with singleton pregnancy who did not miscarry. A and B, In singleton pregnancy not resulting in miscarriage, the mean plasma levels of kisspeptin during the antenatal booking visit increased progressively with increasing gestation (A) and correlated significantly with gestational age (B). C and D, In singleton pregnancy not resulting in miscarriage, the mean serum hCG during the antenatal booking visit peaked at approximately 8 weeks' gestation and then decreased progressively with increasing gestation (C). Scatter plot of serum hCG vs gestational age is shown with a coarse Lowess plot (dotted line), denoting the overall trend in their relationship (D). Data are mean ± SD. ***, P < .0001.
Figure 2.
Figure 2.
Plasma kisspeptin and serum hCG as markers of miscarriage in asymptomatic women during singleton pregnancy. A and B, MoM levels of plasma kisspeptin (A) and serum hCG (B) were calculated to correct for gestational age at the time of the blood collection in asymptomatic women attending their antenatal booking visit for a singleton pregnancy. Levels of each hormone are presented in asymptomatic women who were and were not later diagnosed with miscarriage. C and D, ROC analysis of diagnostic performances of plasma kisspeptin (C) and serum hCG with respect to miscarriage. Data are mean ± SD. ***, P < .0001. AUC, area under the curve.
Figure 3.
Figure 3.
Time elapsed after the measurement of plasma kisspeptin or serum hCG to the diagnosis of miscarriage. A, Plasma kisspeptin is significantly lower in pregnancies during miscarriage, regardless of the time elapsed between the blood test and the diagnosis of miscarriage. B, Levels of plasma kisspeptin correlated with time elapsed until diagnosis of miscarriage in asymptomatic singleton pregnancy. C, Serum hCG is lower only in pregnancies during miscarriage if the time elapsed between the blood test and diagnosis of miscarriage is less than 21 days. D, Scatterplot of serum hCG vs time elapsed until the diagnosis of miscarriage during asymptomatic singleton pregnancy. *, P < .05; ***, P < .001.

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