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If You Have Low Progesterone One Pregnancy Will You Again

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Serum progesterone distribution in normal pregnancies compared to pregnancies complicated past threatened miscarriage from 5 to 13 weeks gestation: a prospective cohort study

BMC Pregnancy and Childbirth volume eighteen, Article number:360 (2018) Cite this article

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Abstruse

Background

Progesterone is a critical hormone in early on pregnancy. A low level of serum progesterone is associated with threatened miscarriage. We aim to found the distribution of maternal serum progesterone in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation.

Methods

This is a single eye, prospective cohort written report of 929 patients. Women from the Normal Pregnancy [NP] cohort were recruited from antenatal clinics, and those in the Threatened Miscarriage [TM] cohort were recruited from emergency walk-in clinics. Women with multiple gestations, missed, incomplete or inevitable miscarriage were excluded from the study. Quantile regression was used to characterize serum progesterone levels in the NP and TM cohorts by estimating the 10th, 50th and 90th percentiles from five to xiii weeks gestation. Pregnancy outcome was determined at sixteen weeks of gestation. Subgroup analysis inside the TM grouping compared progesterone levels of women who later miscarried with those who had ongoing pregnancies at 16 weeks of gestation.

Results

Median serum progesterone concentration demonstrated a linearly increasing tendency from 57.5 nmol/L to fourscore.8 nmol/Fifty from 5 to thirteen weeks gestation in the NP cohort. In the TM cohort, median serum progesterone concentration increased from 41.7 nmol/L to 78.1 nmol/50. Nevertheless, median progesterone levels were uniformly lower in the TM cohort by approximately 10 nmol/L at every gestation calendar week. In the subgroup analysis, median serum progesterone concentration in women with ongoing pregnancy at 16 weeks gestation demonstrated a linearly increasing tendency from 5 to xiii weeks gestation. There was a marginal and non-significant increment in serum progesterone from 19.0 to xxx.iii nmol/L from 5 to 13 weeks gestation in women who eventually had a spontaneous miscarriage.

Conclusions

Serum progesterone concentration increased linearly with gestational historic period from five to 13 weeks in women with normal pregnancies. Women with spontaneous miscarriage showed a marginal and not-significant increase in serum progesterone. This study highlights the pivotal role of progesterone in supporting an early on pregnancy, with lower serum progesterone associated with threatened miscarriage and a subsequent consummate miscarriage at 16 weeks gestation.

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Background

Threatened miscarriage is divers every bit vaginal haemorrhage with or without intestinal hurting and a airtight cervical os in early pregnancy. Information technology affects 15 - twenty% of all pregnancies [1, 2] and is a adventure gene for adverse pregnancy outcomes including preeclampsia, pre-term delivery, intrauterine growth brake, preterm premature rupture of membranes and placental abruption [three]. Amongst women with threatened miscarriage, 15 – 25% progress to spontaneous miscarriage [4] and they are ii.6 times more likely to miscarry as compared to significant women with no bleeding [5, 6]. Women with threatened miscarriage are often extremely anxious about the pregnancy outcome, and this is not aided past the lack of predictive models that prognosticate and triage such women into the high or low risk of miscarriage [4].

Progesterone is a critical hormone during implantation. Information technology sustains decidualization [vii], controls uterine contractility and promotes maternal immune tolerance to the fetal semi-allograft [8]. Lymphocytes, in the presence of progesterone, besides release progesterone-induced blocking factor (PIBF). PIBF is a pivotal mediator in progesterone-dependent immunomodulation [9, x] and has a regulatory office in anti-fetal immune responses during pregnancy [xi]. Ane of the primeval studies on progesterone in pregnancy showed an increasing trend of plasma progesterone from conception to commitment [12]. A more than contempo study past Schock et al farther highlighted this increasing trend throughout pregnancy [thirteen]. However, petty is known about the distribution of serum progesterone in early on pregnancy.

Many studies have shown that low serum progesterone is associated with threatened miscarriage. Our group has validated a single serum progesterone cutoff of 35 nmol/50 taken at presentation with a threatened miscarriage can differentiate women at high or low risk of subsequent miscarriage [fourteen, 15]. Hence, women with normal pregnancies (low risk) with no bleeding may have a different serum progesterone distribution compared to women with threatened miscarriage. In this study, we aim to establish the distribution of maternal serum progesterone in normal pregnancies and pregnancies complicated by threatened miscarriage from 5 to xiii weeks' gestation.

Methods

A total of 929 pregnant women, anile 21 years and above, presenting at the KK Women'southward and Children's Infirmary (KKH) antenatal clinics and 24-hour Women's Clinic from Jan 2013 to December 2016 were recruited. Inclusion criteria were a single intrauterine pregnancy betwixt gestation weeks five to 13 (confirmed and dated by ultrasonography), with pregnancy-related per vagina bleeding were recruited in the Threatened Miscarriage [TM] cohort (n = 479) while those with no pregnancy-related per vagina bleeding were recruited in the low risk of miscarriage (normal pregnancy [NP]) cohort (n = 450). Women with multiple gestations, previous episodes of per vagina bleeding or those treated with progesterone for previous per vagina bleeding in the current pregnancy, or women diagnosed with an inevitable miscarriage, missed miscarriage, blighted ovum or planned termination of pregnancy were excluded.

Maternal blood samples were taken to mensurate serum progesterone level at presentation as previously described [xv]. Blood was collected in plain tubes and centrifuged for 10 min at 3000 g inside 2 hours of collection. Serum progesterone level was measured in the KKH clinical laboratory using a commercial Builder progesterone kit (Abbott, Republic of ireland).

Covariates for the analysis were maternal demographics, health, obstetric and lifestyle factors nerveless by an investigator administered the questionnaire in either English or Chinese (Table 1).

Table 1 Serum progesterone and maternal characteristics at baseline, for low gamble and high risk women with threatened miscarriage

Full size table

Effect measures and follow-upwardly

The chief outcome measured was a spontaneous miscarriage, defined by self-reported uterine evacuation after an inevitable or incomplete miscarriage, or consummate miscarriage with an empty uterus, past the 16th calendar week of gestation. All participants were contacted at the 16th calendar week of pregnancy to verify pregnancy status.

Statistical Methods

Baseline maternal demographics and pregnancy characteristics were statistically compared between two study cohorts: (i) patients with no pregnancy-related per vagina bleeding [NP] and (ii) patients with pregnancy-related per vagina bleeding [TM]. The ii-sample t-examination was used to compare continuous baseline variables and Fisher's verbal test to compare categorical variables.

Quantile regression was used to characterize serum progesterone levels in the NP and TM cohorts by estimating the 10th, 50th and 90th percentiles from 5 to 13 weeks gestation. Pregnancy outcome was determined at 16 weeks of gestation. Subgroup assay was carried out within the TM cohort to compare progesterone levels of women who experienced spontaneous miscarriage [TMM] with those who had ongoing pregnancies at sixteen weeks of gestation [TMO]. The numbers of patients that presented in each gestation calendar week in the different groups (NP, TM, TMM and TMO) were summarized in Additional file 1: Table S1 and Additional file 2: Effigy S1).

This report is funded by the Ministry of Health Industry Alignment Fund Category one research fund.

Results

Miscarriage rates were significantly lower in the normal pregnancy (depression risk) [NP] cohort (five.4%) compared to those who presented with a threatened miscarriage (21.five%) (P < 0.0001). Mean serum progesterone was significantly college in the NP cohort (71.eight ± 27.2 nmol/L) compared to those in the threatened miscarriage [TM] accomplice (53.vi ± 25.2 nmol/L) (P < 0.0001). Women in the NP cohort tend to present later for their booking visit (8.4 ± ii.1 weeks vs 7.three ± ane.iv weeks) (P < 0.0001). There were no differences in maternal age, body mass index (BMI), history of previous miscarriages and smoking, or having comorbidities such as diabetes mellitus (Table 1).

Serum progesterone concentration demonstrated a linearly increasing trend from 57.5 nmol/L to 80.8 nmol/L from v to 13 weeks gestation in the NP cohort, with a median trend gradient of bNP = 2.91 (p = 0.0020) (Fig. 1, Additional file 1: Table S1A and Additional file 2: Figure S1A). In the TM cohort, serum progesterone concentration increased from 41.7 nmol/L to 78.1 nmol/L from v to 13 weeks gestation, with a trend gradient of bTM = iv.55 (p <0.0001) (Fig. 1, Additional file 1: Table S1B and Boosted file 2: Figure S1B). Median progesterone levels were uniformly lower in the TM cohort past approximately 10 nmol/L, converging towards the stop of the first trimester with similar values at 13 weeks gestation (Fig. 1).

Fig. 1
figure 1

Distribution of serum progesterone across gestation weeks 5-xiii amongst women with normal pregnancy [NP] vs threatened miscarriage [TM]

Full size image

In the subgroup analysis, women in the TM cohort were divided into those with ongoing pregnancies at 16 weeks gestation [TMO] compared to those who experienced spontaneous miscarriage before or at 16 weeks gestation [TMM]. Serum progesterone levels in women with ongoing pregnancy at 16 weeks gestation demonstrated a linearly increasing trend from 47.four nmol/L to 75.0 nmol/L from 5 to thirteen weeks gestation, with a tendency gradient of bTMO = 3.45 (p <0.0001) (Fig. 2, Additional file one: Tabular array S1C and Additional file 2: Figure S1C). Insufficiently, there was a non-significant and marginal increment in serum progesterone from 19.0 nmol/L to 30.3 nmol/L from 5 to 13 weeks gestation in women who eventually experienced spontaneous miscarriage before or at 16 weeks gestation, with a tendency gradient of bTMM = 1.41 (p = 0.710) (Fig. two, Additional file 1: Table S1D and Additional file ii: Figure S1D) .

Fig. ii
figure 2

Threatened miscarriage [TM] subgroup analysis of women with ongoing pregnancy vs spontaneous miscarriage

Full size prototype

Discussion

Main Findings

Miscarriage rates were significantly lower in the normal pregnancy (low hazard) [NP] cohort (five.4%) compared to those in the threatened miscarriage [TM] cohort. Mean serum progesterone was significantly higher in the NP accomplice compared to those in the TM cohort. Serum progesterone increased linearly with gestational historic period from 5 to 13 weeks in women with normal pregnancies. Women with spontaneous miscarriage showed a marginal and not-significant increase in serum progesterone.

Strengths and Limitations

This is i of the first prospective cohort studies describing the distribution of serum progesterone in normal pregnancies (low take a chance) compared to pregnancies that is complicated by threatened miscarriage. There are several limitations of this report. Specifically, the mean gestation at presentation for women in the normal pregnancy cohort is 8.4, while that for women in the threatened miscarriage cohort is vii.iii. Women with low gamble pregnancies tend to present subsequently, whereas those with bleeding in early pregnancy will seek medical attention promptly. This may be a potential confounder accounting for the higher mean serum progesterone in the normal pregnancy accomplice. In addition, the distribution of serum progesterone across gestations is non taken from the same patient, and then it may be affected by inherent biological variation amongst patients. Farther studies demand to be conducted to evaluate the underlying pathophysiology of low progesterone and miscarriage, and examine the role of progestogens in the management of women with threatened miscarriage.

Interpretation

Many studies have shown that low serum progesterone is associated with poor pregnancy outcomes [16, 17], and our results lend further weight to the pivotal role of progesterone in early on pregnancy. In the NP accomplice, serum progesterone increased linearly with gestation age from 5 to 13 weeks, with a similar tendency observed in TM cohort who had an ongoing pregnancy at 16 weeks gestation.

Progesterone is secreted past the corpus luteum, which but lasts for 14 days if a pregnancy did non occur. In early pregnancy, beta human chorionic gonadotropin (βhCG) secreted by syncytiotrophoblasts maintains the corpus luteum, which allows it to continue secreting progesterone until the placenta takes over its function at 7 to 9 weeks of gestation. Progesterone causes secretory changes in the endometrium of the uterus and is essential for successful implantation of the embryo [18]. Following implantation, elevated levels of circulating progesterone secreted by the placenta interim through progesterone receptors maintain uterine quiescence [19] and stimulate morphological changes to the neck and other tissues that assistance to maintain pregnancy [20].

Luteal phase deficiency (LPD) is a condition of bereft progesterone to maintain a normal secretory endometrium and allow for normal embryo implantation and growth [21]. This is i of many etiologies associated with early on pregnancy loss [22]. Two mechanisms take been proposed that results in LPD. The commencement and likely more common cause relates to the dumb function of the corpus luteum resulting in insufficient progesterone and estradiol secretion [23]. The impaired function tin can exist the result of improper development of the ascendant follicle destined to get the corpus luteum or aberrant stimulation of a commonly developed follicle, leading to deficiencies in progesterone production. The second machinery suggests an disability of the endometrium to mount a proper response to advisable estradiol and progesterone exposure [24].

Autonomously from LPD, there are other proposed causes of spontaneous miscarriage. More than than half of clinically recognized pregnancy loss have been attributed to chromosomal abnormalities [25, 26]. Chromosomal abnormalities could be associated with changes in progesterone levels [27]. Progesterone was shown to be lower in pregnancies with trisomy 13 and trisomy eighteen [28]. Other causes of spontaneous miscarriage include maternal factors such every bit infections and maternal disease states [29].

In women with threatened miscarriage, serum progesterone concentration also increased linearly with gestation, merely exhibited a downwardly displacement of the graph with lower median progesterone levels at every gestation week compared to the low hazard group, converging towards the cease of the first trimester with similar values at xiii weeks gestation. In women with ongoing pregnancies, vaginal bleeding may be due to disruption of decidual vessels at the maternal-fetal interface [30].

In the subgroup analysis of women with threatened miscarriage, those who experienced a spontaneous miscarriage at or before xvi weeks gestation have a lower serum progesterone level. Many prior studies have shown that the hateful serum progesterone level in not-viable gestations are low, ranging between vi.eight – 12 ng/ml (21.6 – 38.2 nmol/L) [31,32,33], but very few have described the distribution of progesterone in early pregnancy. Interestingly, nosotros plant that in women with spontaneous miscarriage at or before 16 weeks gestation, at that place was only a marginal increase in serum progesterone across gestations, with much lower serum progesterone levels between 20 nmol/L to 30 nmol/L. Unlike normal pregnancies, serum progesterone did not increase significantly regardless of gestation in women with spontaneous miscarriage.

Conclusion

This report highlights the pivotal office of progesterone in supporting an early on pregnancy, where lower serum progesterone is associated with threatened miscarriage and a subsequent complete miscarriage at 16 weeks gestation. This may serve every bit a platform for the development of reference ranges for women who present with low gamble pregnancies or threatened miscarriage to predict the take chances of subsequent spontaneous miscarriages based on their progesterone levels.

Abbreviations

NP:

Normal pregnancy

TM:

Threatened miscarriage

TMO:

Threatened miscarriage with ongoing pregnancies at xvi weeks gestation

TMM:

Threatened miscarriage with spontaneous miscarriage earlier or at 16 weeks gestation

KKH:

KK Women'south and Children'southward Hospital

BMI:

Body mass alphabetize

βhCG:

Beta man chorionic gonadotropin

LPD:

Luteal phase deficiency

DM:

Diabetes mellitus

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Acknowledgements

The authors will like to thank Ms Trish Koon and Ms Doris Ong for their assistance in patient recruitment. We wish to thank all the families who participated in our enquiry and all the dedicated staff from all participating departments.

Funding

This study is funded past the Ministry of Health Manufacture Alignment Fund Category 1 research fund. This facilitated the recruitment of clinical research coordinators who recruited the patients, and also facilitated the analysis and interpretation of data, leading to the writing of the manuscript.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available equally farther research and analysis are being performed on the datasets for future publications simply are available from the corresponding author on reasonable asking.

Author information

Affiliations

  1. Department of Obstetrics and Gynecology, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore, 229899, Singapore

    Chee Wai Ku, Sze Min Lek & Thiam Chye Tan

  2. Duke-National University of Singapore Graduate Medical School, Singapore, Singapore

    John C. Allen Jr & Thiam Chye Tan

  3. Lee Kong Chian School of Medicine, Nanyang Technological Academy, Singapore, Singapore

    Ming Li Chia

  4. Schoolhouse of Biological Sciences, Nanyang Technological University, Singapore, Singapore

    Nguan Soon Tan

  5. Establish of Molecular and Cell Biology, A*STAR, Singapore, Singapore

    Nguan Soon Tan

Contributions

CWK adult the inquiry pattern, analysis strategy, conducted patient recruitment and follow-upward and is the first author of the manuscript. JCAJ contributed to the statistical analyses, interpretation of results and presentation and provided editorial guidance. SML developed the research design, analysis strategy, conducted patient recruitment and follow-up. MLC contributed to the analysis and estimation of results and writing of the manuscript. NST contributed to experimental blueprint for serum progesterone-induced blocking cistron quantitation and analysis strategy, estimation of results and presentation, and provided editorial guidance. TCT contributed to the development of research design, assay strategy, provided editorial back up and is the principal investigator of the Ministry of Wellness Manufacture Alignment Fund Category one research fund. All authors accept reviewed and approved the final version of the paper.

Respective author

Correspondence to Chee Wai Ku.

Ethics declarations

Ethics approval and consent to participate

The institutional review lath at SingHealth (CIRB ref: 2013/320/D) canonical the study. All patients take given verbal and written consent to exist included in this study.

Consent for publication

Not applicative.

Competing interests

The authors declare that they have no competing interests.

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Additional files

Boosted file 1:

Tabular array S1A. Distribution of serum progesterone across gestation weeks 5 – xiii amongst women with low adventure pregnancy [NP]. Tabular array S1B. Distribution of serum progesterone across gestation weeks v – thirteen among women with threatened miscarriage [TM]. Table S1C. Distribution of serum progesterone beyond gestation weeks v – 13 amongst women who presented with threatened miscarriage and had ongoing pregnancy at 16 weeks [TMO]. Table S1D. Distribution of serum progesterone across gestation weeks 5 – 13 amid women who presented with threatened miscarriage and had a spontaneous miscarriage at or before 16 weeks [TMM]. (DOCX 20 kb)

Additional file 2:

Effigy S1A. Distribution of serum progesterone across gestation weeks 5 – 13 among women with low gamble pregnancy [NP]. Figure S1B. Distribution of serum progesterone across gestation weeks 5 – thirteen amidst women with threatened miscarriage [TM]. Figure S1C. Distribution of serum progesterone across gestation weeks v – 13 amid women who presented with threatened miscarriage and had ongoing pregnancy at 16 weeks [TMO]. Effigy S1D. Distribution of serum progesterone beyond gestation weeks five – xiii amongst women who presented with threatened miscarriage and had a spontaneous miscarriage at or before sixteen weeks [TMM]. (ZIP 141 kb)

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Ku, C., Allen Jr, J.C., Lek, S. et al. Serum progesterone distribution in normal pregnancies compared to pregnancies complicated by threatened miscarriage from 5 to 13 weeks gestation: a prospective cohort report. BMC Pregnancy Childbirth 18, 360 (2018). https://doi.org/ten.1186/s12884-018-2002-z

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Keywords

  • Serum progesterone
  • Outset trimester distribution
  • Progesterone nomogram
  • Threatened miscarriage

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