Serum β-HCG contributes to the diagnosis and prediction of pregnancy, and continuous β-HCG measurement can monitor for abortion or ectopic pregnancy. For women with irregular menstrual periods or ovulation changes, the approximate gestational weeks can be calculated based on the initial β-HCG value. For example, according to the fitting curve of the study, if β-HCG is 2500, the possible gestational age is 5 weeks.
However, the increase curve of β-HCG has not been reported consistently. BarnHart [7] reported that the β-HCG of normal intrauterine pregnancy increases by 1.81, 3.28, and 10.76 at 1, 2, and 4 days respectively, with the lowest increases of 24% and 53% at 1 and 2 days. Seeber [8]reported a minimum β-HCG increase in intrauterine pregnancy of 35% over 48 hours. In this study, for viable pregnancies at weeks 4–9, the predicted β-HCG values were 314, 2444, 17623, 54840, 92086, and 104308 mIU/mL, respectively, with weekly multiplications of 6.76, 6.21, 2.11, and 0.68. The β-HCG peaked at 8 weeks and then gradually decreased.
Despite these variations in reporting, β-HCG is still the best index to diagnose pregnancy and predict continuous pregnancy. In an in vitro fertilization-embryo transfer study [5], the prediction accuracy of HCG was better than that of progestin (P = 0.015). Monitoring of serum β-HCG [9] on the 15th day after the transfer of a cleavage stage embryo (3 days post in vitro fertilization) showed that when β-HCG was <500 mIU/ml, the rates of biochemical pregnancy, ectopic pregnancy, and missed abortion were all higher than when β-HCG was 501–1000 mIU/mL. The number of viable pregnancies was significantly reduced in the low β-HCG group. An additional study demonstrated that a ratio of HCG 48h/0h <11% was related to early pregnancy loss [10], while a ratio >75% was related to 100% surviving pregnancy.
A slow increase or decrease of β-HCG is related to ectopic pregnancy and abortion. In one study, a slow increase was seen in 80% of ectopic pregnancies and 35% of abortions [11]. There was no significant difference in daily HCG increase between the two groups, with (210±30 mIU/ml) in the ectopic pregnancies and (311±55 mIU/ml) in the abortions. The concentration of HCG decreased in the remaining cases, with a significantly greater decrease in the abortions than in the ectopic pregnancies (578±28 vs 270±52 mIU/ml daily).
In this study, the logit model with LHCG as the independent variable to predict viable pregnancy had 85.9% sensitivity, 44.72% specificity, and 70.77% overall accuracy. The predicted value, weekly multiplication, and daily multiplication of β-HCG in different gestational weeks of missed abortion were significantly lower than those of viable pregnancy. The daily β-HCG increases in missed abortion and viable pregnancy at 5–8 weeks were 130% and 97%, 76% and 89%, 14% and 31%, and 1% and 10%, respectively. Due to the low initial β-HCG level, the β-HCG level in the missed abortion group increased by 130% at 5 weeks of pregnancy, but was significantly lower than that in viable pregnancy at 6 weeks, and the β-HCG peak value was also relatively low.
However, the initial β-HCG in viable pregnancy was higher than that in disadvantaged pregnancy. The β-HCG level at 5 weeks in viable pregnancy was 2500 mIU/mL, and the increase rate every two days was 178% (89% per day). The accuracy rate of predicting viable pregnancy was 85.9%, because some patients with missed abortion had a very good HCG increase rate, although the embryo stopped developing. The early pregnancy increase rate of the β-HCG regression curve was relatively high in viable pregnancy, compared to that of the missed abortion regression curve, and the ectopic pregnancy regression curve demonstrated a very small growth rate or even a decrease.
The variation in the regression curves for these groups was found to be clinically important. Even with symptoms of threatened abortion such as minor vaginal bleeding, if β-HCG conformed to the weekly multiplication curve of viable pregnancy, the possibility of viable intrauterine pregnancy was high, and the frequency of ultrasonography could be reduced.
The significance of progesterone to early pregnancy outcomes is controversial. Huang [12] studied the progesterone level during pregnancy weeks 4 to 6. The women were divided into high and low (< 25 ng/mL) progesterone groups. There was no statistical difference in pregnancy outcomes between the two groups. However, Huang’s study may have used a progesterone threshold that was too high. Maged [13]showed that serum progesterone was significantly lower in the abortion group than in the continuous pregnancy group (8.7±1.85 vs 26.3±7.2 ng/ml, P<0.001). Progesterone <11.5 ng/ml predicted abortion with an overall accuracy of 99.8%. Puget [10] found that the sensitivity, specificity, and positive and negative predictive values of a 6.2 ng/ml progesterone level in diagnosing early pregnancy loss were 20%, 100%, 100%, and 65.2%, respectively. Ver Haegen reported that when the threshold was 10 ng/mL [14], the sensitivity for predicting infeasible pregnancy was 66.5%, and the specificity was 96.3%. If the progesterone level was low, the probability of non-viable pregnancy increased to 99.2%. Mehmet found 75% sensitivity and 78% specificity for identifying abnormal pregnancy when progesterone is <15 ng/mL [15]. The sensitivity and specificity of identifying abortion were 91% and 89%, respectively.
The conclusions of this study are similar: with progesterone ≥10 ng/ml, the sensitivity, specificity, and overall accuracy for predicting viable pregnancy are 90.25%, 72.04%, and 83.6%, respectively. With progesterone <10 ng/ml, the sensitivity, specificity, and overall accuracy for predicting ectopic pregnancy and complete abortion are 94.2%, 81.57%, and 81.27%, respectively. Progesterone values in viable pregnancy (26.59±10.69 ng/ml), missed abortion (14.41±8.52 ng/ml), and ectopic pregnancy (4.9±4 ng/ml) were significantly different.
Serum β-HCG in normal intrauterine pregnancy doubles after 48 hours [16], and β-HCG in early tubal pregnancy is significantly lower than in normal intrauterine pregnancy. However, 1–2 weeks after uterine implantation of fertilized eggs, serum β-HCG levels in normal intrauterine pregnancy are similar to those in tubal pregnancy, so other biological indicators are needed to identify ectopic pregnancy[5]. In this study, we showed that progesterone can be a specific indicator of ectopic pregnancy, and is especially accurate when combined with the β-HCG increase curve.
Duan reported [6] that the serum progesterone and HCG values in inevitable abortion (13.76±5.52 ng/ml, 3647±2123 mIu/ml) are lower than those in normal intrauterine pregnancy (31.67±5.86 ng/ml, 13437±6256 mIu/ml) (p<0.001). Progesterone combined with β-HCG can predict inevitable abortion with a diagnostic accuracy of 85.7%.
The current research shows 88.8% sensitivity and 75.2% specificity of the combined P and LHCG model for predicting viable pregnancy. The overall prediction accuracy of 83.8% was superior to HCG alone.
We conclude that when progesterone is ≥10 ng/ml, the amenorrhea time and gestational age can be estimated according to β-HCG. The weekly multiplications in first trimester viable pregnancy weeks 5–8 were 6.76, 6.21, 2.11, 0.68, and 0.13, respectively. If the weekly multiplication of β-HCG conforms to this rule, and progesterone is ≥10 ng/ml, 88.8% of the cases are viable pregnancies. If the weekly multiplication of β-HCG is lower than this rule and progesterone is <10 ng/ml, the possibility of ectopic pregnancy and missed abortion is extremely high. Timely vaginal ultrasound examination should be performed in combination with progesterone level monitoring for early identification of missed abortion or ectopic pregnancy.
One limitation of this study is that there was no assessment of other indicators that may be related to the prediction of pregnancy outcomes, such as estradiol. In future work, a triage model for early pregnancy diagnosis will be developed based on the current research results to minimize the risk to early pregnancy.
Conclusions
The innovative weekly combined examination of βHCG and progesterone in this study summarized the patterns of early β-HCG weekly multiplications, predicted values, and progesterone levels in different pregnancy outcomes. The sensitivity of the three methods (HCG, P, and their combination) were similar in predicting viable pregnancy, but the specificity of HCG alone was low, and the accuracy rate for predicting non-viable pregnancy was 44.72%. The specificity and overall prediction accuracy of HCG and P combined were slightly higher than that of P alone. Therefore, monitoring of P or HCG + P was superior to HCG alone.