Association of increased C-Reactive Protein and hypocomplementemia with risk factors for thrombosis in women who have susceptibility for poor gestational outcome;importance of preconceptional counseling

Abstract

This study aimed to investigate the association of increased C-Reactive Protein (CRP) and hypocomplementemia with risk factors for thrombosis such as Factor V Leiden (FVLP) and Prothrombin G20210A polymorphisms (PP), increased Activated Protein C Resistance (APCR) and decreased anti-thrombin III (ATIII) activity in women who have metabolic (MTHFR polymorphisms) and immunological risk factors (autoimmune antibody positivity, autoimmune disorders, and chronic inflammatory diseases). All patients ( $n=$ 197) were evaluated in terms of risk factors for thrombosis including FVLP, PP, increased APCR, and decreased ATIII activity as well as CRP and complement (C) 3 and C4 levels within a framework of preconceptional care program. Patients with high CRP levels together with hypocomplementemia were included to the study group ( $n=$ 13), while women with normal levels of CRP, C3, and C4 were accepted as controls ( $n=$ 184). Decreased ATIII activity was found to be statistically more frequent in the study group compared to controls ( $p=$ 0.036). There were no significant differences between the study and control groups in terms of the presence of FVLP, PP and increased APCR ( $p=$ 0.386, $p=$ 0.462, $p=$ 0.625, respectively). Decreased ATIII activity should be the concern of preconceptional and antenatal care programs in risky patients with increased CRP levels and hypocomplementemia in order to prevent placental inflammation related gestational complications.

Keywords

Obstetrical complications placental inflammation pregnancy C-reactive protein complement thrombosis

1. Introduction

Pregnancy is expected to be a fairy tale but may end as a nightmare. Providing better gestational outcome is the main goal of preconceptional care programs, especially for women with poor obstetric history. Obstetrical complications such as miscarriage, fetal growth restriction (FGR), preterm birth, preeclampsia, and stillbirth are the main causes of poor gestational outcome [1, 2, 3, 4, 5, 6, 7]. Miscarriage is one of the most common complications of pregnancy, and its incidence was reported to be between 10 and 20% [8]. FGR has been described as a pathological deviation in an expected fetal growth and is also one of the reasons for poor pregnancy outcome. The incidence of FGR differs among populations and is six times higher in underdeveloped/developing countries [9]. Despite the existence of many etiological factors, placental inflammation and impaired fetal perfusion compose the most frequent pathological pathways for FGR [3, 10]. Preeclampsia is a common complication during pregnancy and is a cause of 10–20% of maternal morbidity/mortality [11]. Its incidence is 4.6% and varies from 2.7–8.2% from one region to the other [11, 12]. Preeclampsia has a wide spectrum of etiological factors and placental inflammation seems to play an important role in its occurrence [10]. Stillbirth is defined as fetal death prior to delivery and its rate was reported to be 16.3–27.3 per 1000 deliveries in Turkey [7, 13].

We believe the goal of the physician should be to prevent obstetrical complications rather than trying to treat/manage them. Maternal-fetal interface (intervillous space) related disorders play an important role in the development of obstetrical complications (miscarriage, FGR, preterm delivery, preeclampsia, among others) [2, 10]. Placental inflammation and impaired fetal perfusion are most likely attributable to destruction of cellular components of the intervillous space (superficial decidual epithelium, endothelium of spiral veins, syncytiotrophoblast of chorionic villi, and endovascular trophoblasts covering the tips of spiral arteries, among others) by various molecules/agents (autoimmune antibodies, toxic immune-complexes, injured cell degrades, inflammatory cytokines, cellulo toxic amino acids, etc.) [10]. Immunological (autoimmune disorders, chronic inflammatory diseases and autoimmune antibody positivity), metabolic (hyperhomocysteinemia, B12/folate deficiency, etc.) infections, and toxic factors create a micro-environment that is conducive to the development of placental inflammation [14, 15].

C-Reactive Protein (CRP) is a protein made by the liver and its blood level increases in response to inflammatory processes [16, 17]. It is used as a blood test marker for inflammation in the body [16, 17, 18]. On the other hand, the complement system is regulated by mechanisms related to thrombotic events and immunological problems [14, 19]. There are numerous studies also conducted on the relationship with the complement levels and obstetric complications such as recurrent pregnancy loss or preeclampsia [20, 21]. Proteins related to complement cascade are also found in feto-maternal units and were reported to affect the vascular remodeling in early placenta [14, 22].

Pregnancy, inflammation, and immunological and metabolic problems are regarded as risk factors for thrombotic events [10]. These risk factors leading to inflammation and thrombosis are widely studied in terms of obstetrical complications [10, 15, 23]. Additionally, hereditary thrombophilia such as FVLP and PP were also known to be the contributing grounds for adverse pregnancy outcome [24]. Antithrombin III (ATIII) deficiency was reported to be associated with thrombosis and adverse pregnancy outcomes [25, 26]. Furthermore, increased activated protein C resistance (APCR) is another risk factor for thrombotic events and obstetric complications [27].

In this study, we aim to investigate the association of increased CRP levels and hypocomplementemia with risk factors for thrombosis such as Factor V Leiden polymorphism (FVLP), Prothrombin G20210A polymorphism (PP), increased APCR, and decreased ATIII activity in women with poor obstetric history within a framework of a specific preconceptional care program for women with poor obstetric history.

Table 1
Demographic and clinical characteristics of the study population as well as the rate of the presence of risk factors for thrombosis in patients with and without increased CRP and hypocomplementemia

	CRP/C3C4 (–) ( $n=$ 184)	CRP/C3C4 ( $+$ ) ( $n=$ 13)	$P$
Age	33.58 $\pm$ 5.06	33.00 $\pm$ 5.74	0.695 ${}^{\text{1,b}}$
Gravidity	4.08 $\pm$ 2.01	2.69 $\pm$ 1.37	0.015 ${}^{\text{2,a}}$
Parity	1.58 $\pm$ 1.06	1.46 $\pm$ 0.66	0.659 ${}^{\text{2,b}}$
BOI	0.53 $\pm$ 0.36	0.83 $\pm$ 0.41	0.017 ${}^{\text{2,a}}$
Metabolic and immunological factors
MTHFR polymorph. ( $n=$ 64)	62 (33.7)	2 (15.4)	0.322 ${}^{\text{3,b}}$
MTHFR polymorph. $+$ Immune system problems ( $n=$ 113)	103 (56.0)	10 (76.9)
Immune system problems ( $n=$ 20)	19 (10.3)	1 (7.7)
Anti-Thrombin III activity
Decreased	26 (14.1)	5 (38.5)	0.036 ${}^{\text{4,a}}$
Normal	158 (85.9)	8 (61.5)
FV Leiden polymorphism
(–)	161 (87.5)	10 (76.9)	0.386 ${}^{\text{4,b}}$
( $+$ )	23 (12.5)	3 (23.1)
Prothrombin (G20210A)
(–)	173 (94.0)	13 (100)	0.462 ${}^{\text{4,b}}$
( $+$ )	11 (6.0)	0 (0.0)
Activated Protein-C res.
Normal	153 (83.2)	11 (84.6)	0.625 ${}^{\text{4,b}}$
Increased	31 (16.8)	2 (15.4)
Total	184 (100)	13 (100)

${}^{1}$ : Student- $t$ test, ${}^{2}$ : Mann Whitney U test, ${}^{3}$ : Pearson Chi-square, ${}^{4}$ : Fishers exact test, a: $p<$ 0.05, b: $p>$ 0.05.

Table 2

Type of MTHFR polymorphisms in the study population

MTHFR polymorphisms ( $n=$ 177)	CRP/C3C4 (–) ( $n=$ 165) $n$ (%)	CRP/C3C4 ( $+$ ) ( $n=$ 12) $n$ (%)	Total
A1298C homozygous	13 (7.90)	2 (16.7)	15 (8.40)
A1298C heterozygous	42 (25.5)	5 (41.7)	47 (26.6)
C677T homozygous	20 (12.1)	1 (8.3)	21 (11.8)
C677T heterozygous	46 (27.8)	1 (8.3)	47 (26.6)
Compound heterozygous	44 (26.7)	3 (25.0)	47 (26.6)
Total	165 (100)	12 (100)	177 (100)

2. Methods

This study was composed of 197 women with metabolic and/or immunological risk factors which may cause placental inflammation associated with obstetrical complications. All patients were evaluated in terms of risk factors for thrombosis such as FVLP, PP, increased APCR and decreased ATIII activity as well as another laboratory tests including CRP and complement (C) 3 and 4 levels within a framework of a specific preconceptional care program for women with poor obstetric history. Patients with high CRP levels together with hypocomplementemia were included in the study group ( $n=$ 13), while women with normal levels of CRP, C3, and C4 were accepted as controls ( $n=$ 184). Study and control groups were compared in terms of the presence of relevant thrombotic risk factors.

We have evaluated the demographic and clinical information related to these patients including maternal age, gravidity, parity, number of living child and Beksac Obstetric Index (BOI) (Table 1). Previous obstetric history of the patients was compared by BOI which is “[number of living child+( $\pi$ /10)]/gravida” [28].

Metabolic risk factors were defined as methylenetetrahydrofolate (MTHFR) polymorphisms, hyperhomocysteinemia, B12/folate deficiency, while immunological risk factors were designated as autoimmune disorders, chronic inflammatory diseases, autoimmune antibody positivity. Obstetrical complications were defined as miscarriage, FGR, preeclampsia, preterm birth, and stillbirth.

CRP was measured in milligrams of CRP per liter of blood (mg/l) and normal CRP levels were below 3 mg/L. C3 and C4 levels lower than 80 mg/dL and 15 mg/dL respectively were defined as hypocomplementemia according to our laboratory. Hypocomplementemia was defined as low C3 and/or C4 levels. ATIII activity lesser than 75% was defined as decreased ATIII activity according to the reference ranges of our laboratory. Additionally, increased APC resistance was defined as an APC ratio greater than 1.1. The study was approved by the Hacettepe University Ethics Committee with reference number GO 19/1064. Written informed consent was obtained from the patients.

Table 3
Details of immune system problems in study population

Immune system problems ( $n=$ 133)	CRP/C3C4 (–) $n$ , (%)	CRP/C3C4 ( $+$ ) $n$ , (%)	Total $n$ , (%)
Autoantibody positivity	97 (79.5)	3 (27.3)	100 (75.2)
Autoimmune dis. & chronic inf. dis.	25 (20.5)	8 (72.7)	33 (24.8)
Total	122 (100)	11 (100)	133 (100)
Autoimmune dis. & chronic inf. dis.	( $n=$ 25)	( $n=$ 8)	( $n=$ 33)
Ankylosing spondylitis	0 (0.0)	3 (37.5)	3 (9.1)
Asthma	3 (12.0)	0 (0.0)	3 (9.1)
Behcet’s disease	1 (4.0)	0 (0.0)	1 (3.0)
Celiac disease	1 (4.0)	0 (0.0)	1 (3.0)
Hashimoto’s disease	4 (16.0)	1 (12.5)	5 (15.2)
Sjogren’s disease	1 (4.0)	0 (0.0)	1 (3.0)
SLE	13 (52.0)	4 (50.0)	17 (51.6)
Type-1 DM	2 (8.0)	0 (0.0)	2 (6.0)

Autoimmune dis. & chronic inf. dis.: Autoimmune disorders and chronic inflammatory diseases, SLE: Systemic lupus erythematosus.

3. Results

Table 1 shows the demographic and clinical characteristics of the study population. Tables 2 and 3 show the distribution of metabolic and immunological risk factors in the study groups. There were no significant differences between the groups in terms of metabolic and/or immunological risk factors ( $p=$ 0.322). BOI index, which indicates the previous obstetric performance of the patient, was significantly higher in the study group ( $p=$ 0.017) (Table 1). On the other hand, decreased ATIII activity was found to be statistically more frequent in the study group compared to the controls ( $p=$ 0.036). Decreased ATIII activity rate was 14.1% and 38.5% in the control and study groups respectively ( $p=$ 0.036). There were no significant differences between the study and control groups in terms of the presence of FVLP, PP, and increased APCR ( $p=$ 0.386, $p=$ 0.462, and $p=$ 0.625 respectively) (Table 1).

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, version 23). The data was presented as a number, percentage and mean $\pm$ standard deviation. Groups were compared using the Chi-square test or Fischer’s exact test. A $p$ -values $<$ 0.05 were considered statistically significant.

4. Discussion

Poor obstetric history and already existing health disorders necessitate timely preconceptional counseling together with careful medical examinations not to have obstetrical complications and adverse pregnancy outcomes in subsequent pregnancies. Immune system problems, chronic inflammatory diseases and metabolic disorders should especially be the concern of preconceptional and antenatal care programs [1, 6, 10, 14, 23]. It has been reported that various types of immunological and metabolic risk factors may cause placental inflammation associated obstetrical complications such as miscarriage, FGR, preterm delivery, preeclampsia, and stillbirth [1, 2, 10, 11, 14, 15, 29, 30]. Such disorders are also associated with thrombotic events and may create further complications during pregnancy [15, 19, 23, 29, 30]. Miscarriage is one of the most common complications of pregnancy and its incidence was reported to be between 10 and 20% [8]. FGR has been described as a pathological deviation in an expected fetal growth and is also one of the reasons for poor pregnancy outcome [9]. Small fetuses typically have a greater risk of morbidity and mortality, regardless of etiological factors. Diagnosis of these fetuses at the antenatal period and management of their deliveries are crucial means of reducing frequency of adverse outcomes [3, 10]. Preeclampsia is an important complication during pregnancy and has a wide spectrum of etiological factors [10, 11, 12]. Preeclampsia is one of the main reasons of perinatal morbidity and mortality [11, 12]. Stillbirth rate was reported to be 16.3–27.3 per 1000 deliveries and one of the main concerns of perinatal medicine as well as preterm births [3, 7, 13]. For this reason, pre-pregnancy evaluation of woman with poor obstetric history is very important. We believe that preconceptional care programs should concentrate on the presence of risk factors to prevent obstetrical complications and thrombotic events during forthcoming pregnancies not to have adverse pregnancy outcomes.

Pregnancy is a physiological prothrombotic state and risk factors for thrombotic events should also be the focus of preconceptional and antenatal care programs [24, 25, 26, 27]. The natural anticoagulants, APC and its cofactor protein S, are reduced in pregnancy. As pregnancy progresses, tissue factor-dependent thrombin production increases together with factors VII, VII, IX, fibrinogen, prothrombin fragments, and thrombin-antithrombin complexes [27]. Moreover, hereditary thrombophilias such as FVL, PP, and protein C, protein S and ATIII deficiencies are all important in terms of obstetric complications and poor gestational outcomes [24, 25, 26, 27]. FVL accounts almost half of the hereditary thrombophilias and characterized by a resistance to APC leading to the inability of Protein C to cleave Factors Va and VIIIa. The incidence of PP is 1–6% and increases prothrombin and thus more thrombin generation and additionally reduces APC-mediated inactivation of Factor Va [27]. ATIII deficiency might be acquired and inherited. AT inactivates thrombin and factor Xa and therefore its deficiency promotes coagulation [27].

CRP increases in response to inflammatory processes in chronic diseases and immune system disorders [16, 17]. It is used as a blood test marker for inflammation in the body and elevated levels of CRP may be observed in chronic diseases and autoimmune disorders [16, 17, 18]. The complement system is also related to immunological disorders, inflammation, and thrombotic events [14, 19]. It has been reported that complement and the coagulation serine proteinase cascades have been associated with immune and vascular problems [19]. Members of the complement system are designated as “C” and given numbers according to the sequence of reaction. There are different pathways in the activation of complement system designated as classical, alternative and lectin pathways. Determination of levels of C3 and C4 has a great implication in certain clinical circumstances [14]. Additionally, these disorders are associated with poor pregnancy outcomes [1, 2, 10, 11, 14, 15, 29, 30]. In this study, BOI which is used to express the obstetric performance of woman was found to be unexpectedly higher in the study group. On the other hand, we have observed significantly decreased ATIII activity in patients with increased CRP and hypocomplementemia compared to the control group. However, there were no significant differences between the study and control groups in terms of the presence of FVLP, PP, and increased APCR.

Limitations of this case control study are the limited number of patients in the study group and the absence of follow-up results. Further studies are necessary to demonstrate the impact of risk factors such as inflammation and thrombosis on placental inflammation and obstetrical complications.

In conclusion, risk factors for thrombosis such as ATIII activity should be the concern of follow-up protocols (both preconceptional and antenatal) in patients with increased CRP levels and hypocomplementemia to prevent upcoming thrombotic events and placental inflammation-related gestational complications. Preconceptional care programs are especially beneficial for women having immunological and metabolic risk factors for obstetric complications and poor perinatal outcomes.

Funding

There is no financial support for this study

Ethics approval

The study was approved by the Hacettepe University Ethics Committee with reference number GO 19/1064.

Authors’ contribution

MSB: Study Design, Literature research, Manuscript Preparation, Critical Reading

HGD: Data Collection, Statistical analysis, Literature research, Manuscript Preparation.

Footnotes

Conflict of interest

The authors declare that they have no conflict of interest.

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Association of increased C-Reactive Protein and hypocomplementemia with risk factors for thrombosis in women who have susceptibility for poor gestational outcome;importance of preconceptional counseling

Abstract

Keywords

1. Introduction

Table 1 Demographic and clinical characteristics of the study population as well as the rate of the presence of risk factors for thrombosis in patients with and without increased CRP and hypocomplementemia

Table 3 Details of immune system problems in study population

4. Discussion

Funding

Ethics approval

Authors’ contribution

Footnotes

Conflict of interest

References

Table 1
Demographic and clinical characteristics of the study population as well as the rate of the presence of risk factors for thrombosis in patients with and without increased CRP and hypocomplementemia

Table 3
Details of immune system problems in study population