Does Maternal Serum Progesterone Level in Early Pregnancy Predict Placental Dysfunction in Third Trimester ?

Objective

Progesterone, which is necessary for maintenance of pregnancy, is secreted by corpus luteum until 10th gestational week, and is produced from the placenta afterwards. Aim of this study is to investigate the relationship of serum progesterone concentrations ​​measured in 6-8th week and 12th week of pregnancy with the parameters that may demonstrate placental dysfunction in the third trimester.

Methods

Relationship of the progesterone values ​​measured at 6-8th week and 12th week of pregnancy with indicators of placental dysfunction, including hypertensive disorders of pregnancy, intrauterine growth restriction, preterm delivery and low birth weight, were evaluated. Furthermore, based on a previous study, two groups with progesterone levels below and above 11 ng/mL in early pregnancy were formed, and the difference between these groups regarding pregnancy outcomes were investigated.

Results

Progesterone concentrations ​​at 6-8th and 12th weeks were not significantly different between the subgroups with and without pregnancy complications indicating placental dysfunction (p>0.05 for all parameters). As for the two groups due to progesterone cut-off of 11 ng/mL at 6-8th week, significant difference was not found in terms of third trimester complications.

Conclusion

In this study, progesterone values ​​measured at early and late first trimester were not found to be associated with placental dysfunction in the third trimester. Also, a previously suggested threshold to predict pregnancy outcome was not validated. Therefore, routine first trimester progesterone monitoring in guiding pregnancy follow-up may not be approppriate.

Keywords

hypertensive disorders, low birth weight, placental dysfunction, pregnancy complications, progesterone

Introduction

The importance of first trimester value of progesterone, which is necessary for preparation of the endometrium for implantation, support of decidualization required for a healthy maintenance of pregnancy, and development of immune tolerance against the fetus, has been shown in several studies on both single and multiple pregnancies [1, 2, 3]. In some studies emhasizing the role of progesterone in predicting pregnancy prognosis in early pregnancy, maternal progesterone level below 35 nmol/L (11ng/mL equivalent) has been found to be associated with vaginal bleeding and miscarriage [4, 5].  However, there are also studies stating different progesterone threshold values ​​for healthy maintenance of pregnancy in the first trimester [5, 6].
Progesterone, which is secreted from corpus luteum until about 10th gestational week, is produced from the placenta afterwards [7]. Low progesterone level in the first trimester of pregnancy is associated with placental dysfunction. Relation of first trimester progesterone concentrations with third trimester pregnancy complications, such as hypertensive disorders, intrauterine growth restriction, oligohydramnios and preterm delivery, as well as low birth weight, were also investigated in few studies [8, 9, 10]. In a recent study, low serum progesterone concentration during early pregnancy was found to be associated with an increase in hypertensive disorders of pregnancy in univariate analysis, but this relationship was not confirmed in multivariate analysis [8]. This study also demonstrated that low progesterone level in the first trimester is associated with low birth weight [8]. However, results of the few studies on this subject are not consistent. [9, 11]. In addition, it has been reported that age and body mass index (BMI) in the first trimester also affect progesterone levels [9].
The aim of this study is to investigate the relationship of progesterone values ​​measured in 6-8th week and 12th week of pregnancy, as indicators of function of corpus luteum and placenta seperately, with the parameters that may demonstrate placental dysfunction in the third trimester, including hypertensive disorders of pregnancy, intrauterine growth restriction, preterm delivery, and neonatal birth weight. 
 

Methods

This study was carried out prospectively in the Gynecology and Obstetrics department of a tertiary center. Patients who had new diagnose of a single intrauterine pregnancy of 6-8 weeks between April 2018 and April 2020, and who accepted to be included in the study were enrolled. Maternal serum progesterone concentrations at 6-8th and 12th gestational weeks were measured by using a chemiluminescence microparticle immunoassay (ARCHITECT progesterone kit, Abbott, Ireland). Routine follow-up of pregnancy was performed, and pregnancy complications including hypertensive disorders, intrauterine growth restriction and preterm delivery along with delivery week and birth weight parameters of the newborn were evaluated.
Patients with multiple pregnancies, patients who were treated with progesterone due to vaginal bleeding or threatened abortion, who had history of recurrent miscarriages, who achieved pregnancy by assisted reproductive techniques, who were smokers, and who had chronic hypertension or systemic diseases were excluded from the study.
All pregnancy outcomes were recorded. Patients' age, BMI calculated according to height and weight at first maternal visit, progesterone values ​​measured at first visit (6-8th week) and at 12th week, pregnancy outcome as abortion or delivery, presence of hypertensive disorders (gestational hypertension / preeclampsia) occuring after the 20th week of pregnancy, presence of fetal intrauterine growth restriction, presence of preterm delivery, gestational week at delivery and birth weight of the newborn were evaluated.
Spontaneous abortion was defined as loss of pregnancy without intervention before the 20th gestational week [12], gestational hypertension was defined as blood pressure ≥160/100 mmHg or ≥140/90 mmHg in two seperate measurements ​​checked at least 4 hours apart after the 20th gestational week, preeclampsia was defined as gestational hypertension and proteinuria (>300 mg protein in 24-hour urine), or thrombocytopenia (<100000x109/L), renal failure (creatinine> 1.1 mg/dL), impaired liver tests in the absence of proteinuria [13]. Preterm delivery was defined as delivery before 37 weeks of gestation [14], and low birth weight was defined as newborn weight less than 2500 grams [15]. Intrauterine growth restriction was defined as estimated fetal weight less than 10th percentile for gestational age [16].
The relationship of the progesterone values ​​measured at 6-8th week and 12th week of pregnancy with hypertensive disorders of pregnancy, intrauterine growth restriction, preterm delivery and low birth weight were evaluated.
Furthermore, two groups with progesterone levels as below and above 11 ng/mL in early pregnancy were formed, and the difference between these groups in terms of hypertensive disorders of pregnancy, development of intrauterine growth restriction, preterm labor and low birth weight was investigated.
In addition, progesterone values ​​measured in both gestational weeks were compared between patients aged ≤ 21 and > 21 years, as well as between patients with a BMI < 30 and ≥ 30 kg/m2.
Written informed consent was obtained from all patients.
This study was approved by Başkent University Institutional Review Board (Project No. KA18/105).
 
Statistical analysis was performed by using the SPSS software (Version 25.0, SPSS Inc., Chicago, IL, USA).
Based on a previous study, under the assumption that pregnant women with early progesterone levels below 11 ng/mL have a high risk of low birth weight and that the low birth weight rate is 0.30 in pregnant women with progesterone levels above 11 ng/mL [7], to find doubling of this rate (0.60) in pregnant women with low progesterone levels significant with 5% error and 80% power, the minimum sample size was determined as 41 patients per group.
Categorical measurements were summarized by number and percentages, while continuous measurements were defined by mean and standard deviation or median and range (when data was not normally distributed). Mann Whitney U test for data, which was not normally distrubited, was used for comparisons between groups. Chi-square or Fisher exact tests were used to assess the categorical variables between groups. P <0.05 was accepted as statistically significant for all tests. 
 

Results

Of the 164 patients enrolled in the study, 2 patients were terminated during early pregnancy due to fetal anomaly, pregnancy of 8 patients resulted in spontaneous abortion, and the pregnancy follow-ups of the remaining 154 patients were continued in the third trimester (Figure 1).
Of the 154 patients whose pregnancy was continued and resulted in delivery in the third trimester, 107 patients gave birth in our center, while 47 patients were found to have given birth in an external center. Pregnancy and delivery information of the patients who gave birth in external centers was obtained by phone calls.
While 6-8th week progesterone values of all patients were available, 12th week progesterone values were obtained in 97 patients.
The mean age of the patients was 29.6 ± 5.1 years, and the mean BMI was 24.2 ± 3.9 kg/m2. Characteristics of the cohort are shown in Table 1.
Median progesterone value at 6-8th gestational week was 8.90 (5.40-18.30) ng/mL in pregnancies resulting in abortion, while it was 16.5 (6.5-53.2) ng/mL in the remaining of the cohort. Spontaneous abortion occurred before 12th gestational week in 7 of 8 patients. Progesterone levels of the only patient, whose abortion occurred after 12th week, were 15.7 ng/mL and 25.5 ng/mL at 6-8th and 12th weeks, respectively.
When patients were evaluated as two groups according to progesterone levels at 6-8th weeks as below and above 11 ng/mL, significant difference was not found between the two groups in terms of third trimester complications including hypertension, intrauterine growth restriction, preterm delivery and low birth weight (p=1.000, p=0.475, p=1.000, p=1.000 respectively).
Among patients with and without low birth weight babies, no difference was found regarding mean age, BMI, and progesterone values ​​in 6-8th week and 12th week (p>0.05 for all parameters).
Likewise, the mean age, BMI, and progesterone values ​​at the 6-8th and 12th week of patients with and without preterm delivery, with and without hypertensive disorders, and with and without intrauterine growth restriction were not significantly different (p> 0.05 for all parameters). The relation of progesterone values ​​at 6-8th week and 12th week with third trimester pregnancy complications is shown in Table 2.
There were 6 patients at and under 21 years of age in the cohort. It was observed that progesterone values ​​measured in both weeks did not change significantly at and under the age of 21 and above the age of 21 (p=0.483 for 6-8th week, p=0.104 for 12th week) (Table 3).
There were 12 patients with BMI ≥ 30, and these patients had a lower progesterone value than patients with BMI <30. The difference was significant for the progesterone values at 6-8th week (p = 0.006), while statistical significance was not found for the progesterone values at 12th week (p = 0.268) (Table 3).
 

Discussion

There are few studies, in which the relation of first trimester serum progesterone concentrations with third trimester placental function is investigated. In this study, effects of progesterone from corpus luteum and placenta on third trimester were evaluated seperately, however, serum progesterone concentrations measured at 6-8th week and 12th week of pregnancy were not found to be related to the complications associated with placental dysfunction in the third trimester.
Progesterone has been used for many years as a parameter indicating the viability of pregnancy in the first trimester, and different cut-off values ​​have been proposed in several studies for this purpose. Daily et al. reported the mean progesterone values in viable and non-viable pregnancies in the first 8 weeks as 22.1 ng/mL and 10.1 ng/mL, respectively [17]. Al-Sebai et al. reported that a cut-off level of 45 nmol/L (14.13 ng/mL) can determine viable and non-viable pregnancies with 87.6% sensitivity and 87.5% specificity [18]. Elson et al. suggested the progesterone cut-off level for normal viable pregnancy in early weeks as >25 ng/mL [19]. Abdelazim et al. reported that the 20 ng/mL cut-off value was 95.1% sensitive and 98.9% specific in diagnosing a non-viable pregnancy [1]. Duan et al. reported that a progesterone level ≤16 ng/mL (50.7 nmol/L) [20], and Arck et al. reported that a progesterone level ≤12 ng/mL (38.3 nmol/L) was associated with an increased risk of abortion [6]. Ku et al. suggested a cut-off level of 35 nmol/L (11 ng/mL) for spontaneous abortion in patients presenting with vaginal bleeding [4, 5]. However, the study was carried out on pregnant women who applied for vaginal bleeding, which may indicate that an already unhealthy population was selected.
Progesterone is one of the important mechanisms determining trophoblastic structuring in the first trimester. It has been suggested that low serum progesterone level in early pregnancy negatively affects trophoblastic invasion and impairs placentation [8, 21]. Besides, it has been reported that complications such as hypertensive disorders and preterm delivery are more common in the later weeks of pregnancy in patients with first trimester complications such as vaginal bleeding [8, 22]. On the other hand, it is known that progesterone, which originates from the corpus luteum at the beginning of the first trimester, is largely produced by the placenta after 10th week [2, 9]. However, the evaluated progesterone levels were measured in the early period of pregnancy in all studies, which reflects the function of the corpus luteum rather than the placenta.
In a retrospective study, He et al. investigated the relationship of progesterone in early pregnancy with third trimester pregnancy complications and low birth weight, and the threshold value was accepted as 11 ng/mL (35 nmol/L), based on a prior study, evaluating first trimester pregnancy viability, conducted in the same clinic. In this study, He reported that a progesterone level of <11 ng/mL between 5-12th weeks was associated with low birth weight in advanced weeks, while there was no significant difference in other parameters showing placental dysfunction [8].
In our study, progesterone values were examined in two separate weeks considering that progesterone originates mainly from the feto-maternal unit at the end of the first trimester and reflects the function of the placenta much more in this period, therefore, 12th week progesterone measurement may be more appropriate in predicting placental dysfunction in the following weeks. However, in our study, unlike the previous study, progesterone values neither ​​measured at 6-8th week nor at 12th week were found to be associated with complications associated with placental dysfunction including low birth weight.
In a recent study, Shen et al. investigated the relation between progesterone concentration in early pregnancy and risk of preterm delivery in a large population. However, unlike our study, progesterone was mostly measured in risky patients, who had vaginal bleeding, instead of all population, majority of the tests were performed before 9th week, and most of the patients were treated with progesterone in this study. While the outcomes might be affected by inclusion criteria and progesterone treatment, similar to our results, low levels of progesterone was not found to be associated with risk of preterm birth [10].
Besides, progesterone level can be affected by different parameters. It has been shown that the first trimester maternal BMI is inversely proportional to the serum progesterone level. Obesity (BMI ≥ 30 kg/m2), has been associated with lower progesterone levels (<35 nmol/L) [9, 23]. Maternal age between 18-21 has also been found to be associated with low progesterone [9]. Our results are partly consistent with these findings; progesterone level was significantly lower in patients with high BMI at early gestational week, however, low values at 12th week measurements was not found to be significant. Progesterone values ​​did not differ significantly in patients aged 18-21, when compared to patients above 21 years old. However, low number of patients in these subgroups may have affected the results.
The most important limitation of the study is that, pregnancy of some of the patients with low progesterone levels resulted in miscarriage in the first trimester, and the failure of these patients to reach the advanced gestational week led to a lack of data of an important group for whom pregnancy complications could be evaluated. The lack of 12th week-progesterone values of some patients whose progesterone levels were measured at 6-8th week is also a limitation of the study. On the other hand, prospective design, measurement of all progesterone values in the same laboratory, and completion of data on pregnancy complications, albeit by phone calls, are the strengths of the study.
 

Conclusion

Both of the progesterone values ​​measured at the beginning and end of the first trimester were not found to be associated with placental dysfunction in the third trimester. Also, the previously suggested threshold to predict pregnancy outcome was not validated. Therefore, routine first trimester progesterone monitoring in guiding pregnancy follow-up does not seem to be logical. However, these results can be re-evaluated in further studies with larger populations.

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	File/Dsecription
	Figure 1 Flowchart of the cohort
	Table 1 Basal characteristics and third trimester outcomes
	Table 2 Early and late first trimester progesterone values in absence and presence of pregnancy complications in third trimester
	Table 3 Progesterone values according to age and body mass index
	Revised Manuscript Revisions on Manuscript