Main Findings
Miscarriage rates were significantly lower in the normal pregnancy (low risk) [NP] cohort (5.4%) compared to those in the threatened miscarriage [TM] cohort. Mean serum progesterone was significantly higher in the NP cohort compared to those in the TM cohort. Serum progesterone increased linearly with gestational age from 5 to 13 weeks in women with normal pregnancies. Women with spontaneous miscarriage showed a marginal and non-significant increase in serum progesterone.
Strengths and Limitations
This is one of the first prospective cohort studies describing the distribution of serum progesterone in normal pregnancies (low risk) compared to pregnancies that is complicated by threatened miscarriage. There are several limitations of this study. 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 7.3. Women with low risk pregnancies tend to present later, 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 cohort. In addition, the distribution of serum progesterone across gestations is not taken from the same patient, so it may be affected by inherent biological variation amongst patients. Further studies need 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 pregnancy. In the NP cohort, serum progesterone increased linearly with gestation age from 5 to 13 weeks, with a similar trend observed in TM cohort who had an ongoing pregnancy at 16 weeks gestation.
Progesterone is secreted by the corpus luteum, which only lasts for 14 days if a pregnancy did not 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 acting through progesterone receptors maintain uterine quiescence [
19] and stimulate morphological changes to the cervix and other tissues that help to maintain pregnancy [
20].
Luteal phase deficiency (LPD) is a condition of insufficient progesterone to maintain a normal secretory endometrium and allow for normal embryo implantation and growth [
21]. This is one of many etiologies associated with early pregnancy loss [
22]. Two mechanisms have been proposed that results in LPD. The first and likely more common cause relates to the impaired function of the corpus luteum resulting in insufficient progesterone and estradiol secretion [
23]. The impaired function can be the result of improper development of the dominant follicle destined to become the corpus luteum or aberrant stimulation of a normally developed follicle, leading to deficiencies in progesterone production. The second mechanism suggests an inability of the endometrium to mount a proper response to appropriate estradiol and progesterone exposure [
24].
Apart from LPD, there are other proposed causes of spontaneous miscarriage. More 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 18 [
28]. Other causes of spontaneous miscarriage include maternal factors such as infections and maternal disease states [
29].
In women with threatened miscarriage, serum progesterone concentration also increased linearly with gestation, but exhibited a downward displacement of the graph with lower median progesterone levels at every gestation week compared to the low risk group, converging towards the end of the first trimester with similar values at 13 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 16 weeks gestation have a lower serum progesterone level. Many prior studies have shown that the mean serum progesterone level in non-viable gestations are low, ranging between 6.8 – 12 ng/ml (21.6 – 38.2 nmol/L) [
31‐
33], but very few have described the distribution of progesterone in early pregnancy. Interestingly, we found that in women with spontaneous miscarriage at or before 16 weeks gestation, there 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.