Analysis of urinary human chorionic gonadotrophin concentrations in normal and failing pregnancies using longitudinal, Cox proportional hazards and two-stage modelling

Marriott, Lorrae; Zinaman, Michael J.; Abrams, Keith R.; Crowther, Michael J.; Johnson, Sarah

doi:10.1177/0004563216671339

Cited by 8 publications

(6 citation statements)

References 35 publications

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“…Principal findings. This analysis builds on the two-stage model approach implemented by Marriott et al 15 .…”

Section: Discussionmentioning

confidence: 99%

“…It was assumed conception occurred the day after the LH surge 37 . Details of sample collection and storage have been described previously 15 . Additional maternal demographics, menstrual and pregnancy history data were recorded.…”

Section: Description Of Datasetmentioning

confidence: 99%

“…The data utilised in this analysis have been analysed previously using a two-stage model approach 15 . The two-stage model utilises existing modelling techniques by first fitting a linear mixed effects model to the longitudinal data.…”

Section: Statistical Analysesmentioning

confidence: 99%

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Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

Ashra

Marriott²,

Johnson³

et al. 2020

Sci Rep

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Human chorionic gonadotrophin (hCG) is largely used to confirm pregnancy. Yet evidence shows that longitudinal hCG profiles are distinguishable between healthy and failing pregnancies. We retrospectively fitted a joint longitudinal-survival model to data from 127 (85 healthy and 42 failing pregnancies) US women, aged 18-45, who were attempting to conceive, to quantify the association between longitudinally measured urinary hCG and early miscarriage. Using subject-specific predictions, obtained uniquely from the joint model, we investigated the plausibility of adaptively monitoring early pregnancy outcomes based on updating hcG measurements. Volunteers collected daily early morning urine samples for their menstrual cycle and up to 28 days post day of missed period. The longitudinal submodel for log hCG included a random intercept and slope and fixed linear and quadratic time terms. The survival submodel included maternal age and cycle length covariates. Unit increases in log hCG corresponded to a 63.9% (HR 0.36, 95% CI 0.16, 0.47) decrease in the risk of miscarriage, confirming a strong association between hCG and miscarriage. Outputted conditional survival probabilities gave individualised risk estimates for the early pregnancy outcomes in the short term. However, longer term monitoring would require a larger sample size and prospectively followed up data, focusing on emerging extensions to the joint model, which allow assessment of the specificity and sensitivity. Early miscarriage, defined in the UK as loss before week 13, is a frequent complication of pregnancy 1. It affects 12% to 24% of clinically confirmed pregnancies, not counting those losses which occur prior to the date of the missed period-so-called biochemical pregnancies 2. Women who suffer from a miscarriage are more likely to report symptoms associated with depression, with affected women ranging from 20% to a high of 55% 3. Though the majority of losses are self-resolving, those that are not may require diagnostic tests, hospital treatment, surgical intervention and follow-up care 2. This provides an incentive to identify potential early losses as early as possible by exploring more patient-centred monitoring strategies. The recently published priorities for research within miscarriage ranked highest the identification of effective interventions to prevent miscarriage 4. This encompasses the plausibility of using biomarkers to track pregnancy progression through viability or miscarriage. Several potential biomarkers have been identified to predict miscarriage, with human chorionic gonadotrophin (hCG) a strong contender 5. The hormone tends to rise rapidly and reliably in early pregnancy, doubling every 1.5 days in the first 5 weeks post conception and then every 3.5 days from week 7, before plateauing around week 10 5,6. Its use is more prevalent in tracking early pregnancy progress in an in vitro fertilisation (IVF) population and for identifying ectopic pregnancies 7. However, evidence suggests that longitudinal profiles of hCG can be utilised t...

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“…Principal findings. This analysis builds on the two-stage model approach implemented by Marriott et al 15 .…”

Section: Discussionmentioning

confidence: 99%

Section: Description Of Datasetmentioning

confidence: 99%

See 1 more Smart Citation

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

Ashra

Marriott²,

Johnson³

et al. 2020

Sci Rep

View full text Add to dashboard Cite

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“…Most of these failures occur soon after implantation and therefore remain undetected. In a substantial number of early pregnancy losses, hCG concentrations only diverge from those in healthy pregnancies when the miscarriage is in progress ( 114 ), suggesting that an alternative mechanism of tissue breakdown is activated ( Figures 2B,C ). A recent study highlighted that embryonic fitness signals modulate the ability of uNK cells to target and clear senDeC.…”

Section: Implantation: Endometrial Receptivity and Selectivitymentioning

confidence: 99%

The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

Muter

Kong

Brosens

2021

Front. Reprod. Health

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In each menstrual cycle, the endometrium becomes receptive to embryo implantation while preparing for tissue breakdown and repair. Both pregnancy and menstruation are dependent on spontaneous decidualization of endometrial stromal cells, a progesterone-dependent process that follows rapid, oestrogen-dependent proliferation. During the implantation window, stromal cells mount an acute stress response, which leads to the emergence of functionally distinct decidual subsets, reflecting the level of replication stress incurred during the preceding proliferative phase. Progesterone-dependent, anti-inflammatory decidual cells (DeC) form a robust matrix that accommodates the conceptus whereas pro-inflammatory, progesterone-resistant stressed and senescent decidual cells (senDeC) control tissue remodelling and breakdown. To execute these functions, each decidual subset engages innate immune cells: DeC partner with uterine natural killer (uNK) cells to eliminate senDeC, while senDeC co-opt neutrophils and macrophages to assist with tissue breakdown and repair. Thus, successful transformation of cycling endometrium into the decidua of pregnancy not only requires continuous progesterone signalling but dominance of DeC over senDeC, aided by recruitment and differentiation of circulating NK cells and bone marrow-derived decidual progenitors. We discuss how the frequency of cycles resulting in imbalanced decidual subpopulations may determine the recurrence risk of miscarriage and highlight emerging therapeutic strategies.

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“…By day 35 following ovulation, mean urinary concentrations vary between 65 000 pmol/L and 2 700 000 pmol/L . A slower rise in log hCG is associated with early pregnancy loss …”

Section: Introductionmentioning

confidence: 99%

Peri‐implantation urinary hormone monitoring distinguishes between types of first‐trimester spontaneous pregnancy loss

Foo

Johnson²,

Marriott³

et al. 2020

Paediatric Perinatal Epid

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Background Lutenising hormone (LH) and human chorionic gonadotropin (hCG) hormone are useful biochemical markers to indicate ovulation and embryonic implantation, respectively. We explored “point‐of‐care” LH and hCG testing using a digital home‐testing device in a cohort trying to conceive. Objective To determine conception and spontaneous pregnancy loss rates, and to assess whether trends in LH‐hCG interval which are known to be associated with pregnancy viability could be identified with point‐of‐care testing. Methods We recruited healthy women aged 18‐44 planning a pregnancy. Participants used a home monitor to track LH and hCG levels for 12 menstrual cycles or until pregnancy was conceived. Pregnancy outcomes (viable, clinical miscarriage, or biochemical pregnancy loss) were recorded. Monitor data were analysed by a statistician blinded to pregnancy outcome. Results From 387 recruits, there were 290 pregnancies with known outcomes within study timeline. Adequate monitor data for analysis were available for 150 conceptive cycles. Overall spontaneous first‐trimester pregnancy loss rate was 30% with clinically recognised miscarriage rate of 17%. The difference to LH‐hCG interval median had wider spread for biochemical losses (0.5‐8.5 days) compared with clinical miscarriage (0‐5 days) and viable pregnancies (0‐6 days). Fixed effect hCG profile change distinguished between pregnancy outcomes from as early as day‐2 post‐hCG rise from baseline. Conclusions The risk of first‐trimester spontaneous pregnancy loss in our prospective cohort is comparable to studies utilising daily urinary hCG collection and laboratory assays. A wider LH‐hCG interval range is associated with biochemical pregnancy loss and may relate to late or early implantation. Although early hCG changes discriminate between pregnancies that will miscarry from viable pregnancies, this point‐of‐care testing model is not sufficiently developed to be predictive.

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Analysis of urinary human chorionic gonadotrophin concentrations in normal and failing pregnancies using longitudinal, Cox proportional hazards and two-stage modelling

Cited by 8 publications

References 35 publications

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes

The Role of Decidual Subpopulations in Implantation, Menstruation and Miscarriage

Peri‐implantation urinary hormone monitoring distinguishes between types of first‐trimester spontaneous pregnancy loss

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