Vaginal Bleeding After Pregnancy: Progesterone Levels and Pregnancy Outcomes in the First Trimester

Vaginal bleeding during the first trimester of pregnancy is a common symptom, often associated with threatened abortion, which occurs in 15-20% of all pregnancies. While multiple marker tests can predict pregnancy outcomes in the first trimester, there is limited research identifying reliable cutoff progesterone values linked to poor prognosis.1,2 Given that placenta formation begins around 8 weeks of gestation, progesterone levels are typically measured between 5-8 weeks of pregnancy. To explore this further, we conducted a retrospective study to analyze progesterone levels in the first trimester, prior to any progesterone therapy, across different pregnancy outcomes. This retrospective cohort study was conducted at Peking University International Hospital (PKUIH). Data were collected from the hospital’s electronic medical records between January 2016 and June 2020. Inclusion criteria were: (1) women who underwent their first progesterone test before 9 weeks of gestation at PKUIH; (2) women who conceived naturally and received regular prenatal care at PKUIH. Exclusion criteria included: (1) prior progesterone therapy; (2) pregnancies achieved through artificial reproductive techniques; (3) multiple gestations; (4) cervical cerclage; and (5) use of any tocolytic medication. A total of 3754 patients were included in the study. Patients were categorized into five groups based on pregnancy outcomes: tubal pregnancy (297 cases), missed abortion (876 cases), threatened abortion (109 cases), preterm delivery (249 cases), and full-term delivery (2223 cases) (Supplementary Fig. 1, https://links.lww.com/MFM/A73). Women with threatened abortion were not included in other pregnancy outcome groups. Serum progesterone levels were measured during the first prenatal visit using venous blood samples. Up to 5 milliliters of blood was collected from the antebrachial vein, centrifuged, and stored at –80°C until analysis. Progesterone concentrations were determined using a chemiluminescent microparticle immunoassay (CMIA) on an Abbott Automatic Immunoanalyzer i2000SR. Statistical analyses were performed using Python (3.7.4) and R (3.5.1), with a P < 0.05 considered statistically significant. Demographic characteristics across pregnancy categories showed no significant differences. Serum progesterone levels across different pregnancy outcomes are summarized in Supplementary Table 1, https://links.lww.com/MFM/A73. The serum progesterone levels for the different pregnancy outcomes were as follows (Supplementary Table 2, https://links.lww.com/MFM/A73): 10.14 ± 8.03 ng/mL (tubal pregnancy), 16.79 ± 12.63 ng/mL (missed abortion), 19.81 ± 24.63 ng/mL (threatened abortion), 22.80 ± 17.55 ng/mL (preterm delivery), and 21.54 ± 15.36 ng/mL (full-term delivery) (Supplementary Table 2, https://links.lww.com/MFM/A73). Notably, the standard deviations of progesterone levels were substantial, particularly for threatened abortions, where the standard deviation exceeded the mean. Furthermore, as illustrated in Supplementary Figs 2–7, https://links.lww.com/MFM/A73, the histograms for the five groups were not normally distributed. Therefore, the interquartile range (IQR) and 95% confidence interval (CI) of progesterone levels for each group are more appropriate for interpreting the relationship between progesterone levels and the various pregnancy outcomes. The medians and IQRs of serum progesterone values for each group were as follows: 8.9 and 11.8 ng/mL (tubal pregnancy), with a 95% CI of 9.22, 11.05; 16.00 and 12.13 ng/mL (missed abortion), with a 95% CI of 15.95, 17.63; 15.8 and 15.1 ng/mL (threatened abortion), with a 95% CI of 15.14, 24.49; 20.4 and 13.2 ng/mL (preterm delivery), with a 95% CI of 20.61, 24.99; and 19.5 and 11 ng/mL (full-term delivery), with a 95% CI of 20.90, 22.18. Progesterone levels in tubal pregnancies at 5 and 6 weeks of gestation were significantly lower than in other pregnancy types during the same period (P < 0.05). At 7 and 8 weeks, progesterone levels in tubal pregnancies were significantly lower than in other pregnancy types, except for missed abortion (P < 0.05). Notably, progesterone levels in both tubal pregnancy and missed abortion at 7 and 8 weeks were significantly lower than in other pregnancy groups. The study found no significant differences in progesterone levels before 9 weeks of gestation among missed abortion, threatened abortion, preterm delivery, and full-term delivery groups, except for tubal pregnancy. This suggests that progesterone testing in early pregnancy may not be useful in distinguishing these four pregnancy outcomes. Progesterone secretion is characterized by significant variability due to its pulsatile release, stimulated by luteinizing hormone (LH) pulses occurring every 90 minutes, which can cause serum levels to fluctuate by 6- to 8-fold. Additionally, the role of progesterone therapy in threatened or recurrent abortion remains controversial3. Therefore, routine progesterone testing in the first trimester, in the absence of symptoms, is not recommended. The study also highlighted that low serum progesterone levels before 9 weeks of gestation are associated with poor prognosis. Specifically, progesterone levels in tubal pregnancies at 5 and 6 weeks were significantly lower than in other pregnancy types. Lower progesterone levels in early pregnancy are often indicative of an increased risk of unfavorable outcomes. Previous studies have demonstrated a strong correlation between low progesterone levels (< 6 ng/mL or 19.1 nmol/L) and adverse pregnancy outcomes.4 For example, women with threatened miscarriage who eventually experienced spontaneous miscarriage had 48% lower progesterone levels compared to those who delivered at full term.5 These findings align with a meta-analysis indicating that a single progesterone measurement in early pregnancy, with a threshold between 3.2 and 6 ng/mL, can predict nonviable pregnancy with a sensitivity of 74.6% and specificity of 98.4%.6 Similarly, Lek et al.2 found that serum progesterone < 10.9 ng/mL could predict miscarriage in women with threatened miscarriage. Lower progesterone levels in early pregnancy are associated with poor prognosis, particularly in cases of tubal pregnancy. While pregnancies with higher progesterone levels are more likely to result in full-term delivery, this is not universally true. Women with lower progesterone levels, especially those experiencing discomfort, should be closely monitored. However, the routine use of progesterone in women with first-trimester bleeding has not been shown to prevent miscarriage, as highlighted by a PRISM trial.3 Treatment decisions for threatened miscarriage should be individualized, considering the risks and benefits based on each woman’s serum progesterone levels.6 In summary, low progesterone levels in early pregnancy warrant caution, particularly for tubal pregnancy, while higher levels may indicate a more favorable outcome, though not definitively. Funding Project supported by Peking University International Hospital Research Grant (No.YN2020QN04). Author Contributions Zhi Li and Huixia Yang conceived and designed the study, and critically revised the manuscript. Zhuo Ren was responsible for data collection, analysis, and the initial drafting of the manuscript. Conflicts of Interest None. Editor Note Huixia Yang is the Editor-in-Chief of Maternal-Fetal Medicine. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and the associated research groups. Data Availability The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.