Effect of hypocomplementemia on perinatal outcomes of pregnancies with autoimmune disorders

Abstract

OBJECTIVE:

To demonstrate the effect of preconceptional complement levels on perinatal outcomes of pregnancies with autoimmune disorders.

METHODS:

Pregnant women with autoimmune disorders (autoimmune disease and/or autoimmune antibody positivity) who were screened for complement levels (C3 and C4) prior to their pregnancies were enrolled in a special antenatal care program. These patients were administered low-dose low-molecular-weight heparin (enoxaparine, 1 $\times$ 2000 Anti-XA IU/0.2 mL/day), low-dose salysilic acid (100 mg/day) and low-dose corticosteroid (methylprednisolone, 1 $\times$ 4 mg/day orally) as soon as their pregnancies were confirmed according to the institutional protocol. We have compared hypo- and normocomplement pregnancies with autoimmune disorders in terms of their obstetric and perinatal outcomes. We have also used Beksac Obstetric Index (BOI) which is “[living child $+$ ( $\pi$ /10)]/gravidity” for the comparison of their previous obstetric histories.

RESULTS:

Obstetric and neonatal outcomes showed no significant difference between hypocomplement patients ( $n=$ 38) and control group ( $n=$ 157) ( $p>$ 0.05). “Composite obstetric and perinatal adverse outcome” rates were 26.2% and 27.3% in study and control groups, respectively ( $p>$ 0.05). BOI was significantly lower in hypocomplement patients ( $p$ : 0.002). Then, we have classified hypocomplement patients into 3 subgroups according to the type of complement (C3, C4 or both). Comparison inbetween these groups revealed no statistical significance in any of the analyzed parameters ( $p>$ 0.05).

CONCLUSION:

Low complement levels in pregnant women with autoimmune disorders may be associated with gestational problems and poor obstetric history. Immunomodulatory treatment modalities such as ours may be beneficial for improving the obstetric and neonatal outcomes.

Keywords

Hypocomplementemia complement activation obstetric outcome neonatal outcome immunesuppression

1. Introduction

Pregnancy has an altered physiology that affects nearly all systems including immune system. Pregnancy is a state of immune tolerance to semi-allogenic fetus and this immune tolerance is provided by many complex regulatory mechanisms [32]. This immune tolerance between fetus and mother has been widely studied in the literature and has been identified as a triggering point for many obstetric pathologies and adverse outcomes [6]. Maternal immuno activation and aberrant activation of innate immune system or T-helper cells may induce cytotoxicity in placenta which is accepted as one of the underlying mechanisms for various types of complications like preeclampsia [29].

Immunomodulation occuring during pregnancy is a complex process effecting many cells and receptors such as natural killer (NK) cells, T cells, B cells and NK cell inhibitory receptors [10, 17, 20, 32]. Any discordance between these immunsuppressive and immunoactivator pathways may lead to obstetric complications. Aberrant maternal inflammation is associated with impaired feto-placental perfusion leading to complications such as intrauterine growth retardation (IUGR), preeclampsia or fetal demise [11]. Autoimmune antibodies, complement system activation and “autoimmune disorder related cellular destruction products” may be the reason of placental inflammation taking place at the maternal-fetal interface (injury of intervillous space cellular structures such as endothelial cells of the spiral veins, syncytiotrophoblasts covering the chorionic villi, superficial and glandular epithelial cells of the decidua, endovascular trophoblasts, etc.) which may end up with obstetrical complications [3]. However, the origin of inflammation is usually undetermined, but mostly dedicated to imbalance of anti-inflammatory processes [13].

Previous studies demonstrated the importance of increased immunologic activity in autoimmune diseases and efficacy of immunomodulatuar treatments during pregnancy [10, 17, 28, 35]. Furthermore, it has also been shown that preconceptional immunomodulation has an important role in clinical practice [31].

Complement system is a lytic system which identifies and eliminates foreign and self damaged materials. This system is regulated by strict mechanims that ends up with regular immune response. 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 such as systemic lupus erythematosis (SLE) to determine the course of the disease [9]. There are numerous studies also conducted on the relationship with the complement levels and obstetric complications such as recurrent pregnancy loss or preeclampsia [12, 25]. Proteins related to complement cascade are also found in feto-maternal unit and were reported to affect the vascular remodelling in early placenta [15].

Previous studies demonstrated that the most common reason for abnormal complement activation is circulating autoantibodies [37]. Thus, determining the complement levels for the pregnancies with autoimmune disorders may be beneficial for defining high risk patients and performing any medical interventions. In this study, we aimed to evaluate the obstetric outcomes of patients with low complement levels (C3, C4 or both) and efficacy of an unique immunosuppressive treatment modality.

2. Materials and methods

We have retrospectively evaluated patients with a detected complement level prior to conception between 2009–2019. Complement screening included C3 and C4 and this screening modality was applied to patients with any autoimmune disorders including autoimmune diseases and/or autoantibody positivity. Pregestational evaluation of the patients and immune system screening was performed within 3 months before getting pregnant. C3 and C4 levels lower than 80 mg/dL and 15 mg/dL respectively were defined as hypocomplementemia according to our laboratory. C3 and C4 levels were measured by using nephelometric assays in our institution.

Patients screened within this program were accepted to a special antenatal care program which was described in previous literature [34]. After detection of pregnancy, the patients were administered low-dose low-molecular-weight heparin (LMWH) (enoxaparine, 1 $\times$ 2000 Anti-XA IU/0.2 mL/day), low-dose salysilic acid (coraspirin, 100 mg/day) and low-dose corticosteroid (methylprednisolone, 1 $\times$ 4 mg/day orally).

We retrospectively evaluated maternal age, previous obstetric history including Beksac Obstetrics Index (BOI) which is defined as “[living child $+$ ( $\pi$ /10)]/ gravidity”. BOI gives information about the prior obsteric history of the patients and enables comparison of high risk pregnany groups [5]. We have also evaluated gestational week at delivery, birthweight, APGAR scores and NICU admission. Newborns with an APGAR score lesser than 7 at the first ten minutes were classified as “APGAR score $<$ 7” group. Newborns with a birthweight lesser than 10 percentile according to birthweek were classified as intrauterine growth retardation (IUGR). Any adverse outcomes including stillbirth, newborn exitus, APGAR score $<$ 7, NICU admission, IUGR, newborn exitus, development of preeclampsia or gestational hypertension were evaluated as composite adverse outcome.

We have compared hypo- and normo-complement pregnancies with autoimmune disorders in terms of obstetri and perinatal outcomes. Then, we have classified hypocomplement patients into 3 subgroups according to the type of complement (C3, C4 or both) for further comparisons.

Prior to final statistical analysis, we have excluded cases with prenatally detected genetic/congenital abnormalities and gestational diabetes mellitus (GDM) which may affect obstetric and neonatal outcomes regardless of complement levels.

We have performed visual and quantitative analysis for determination of normality of distribution. Due to lack of normal distribution, the quantitative variables were given as median values and interquartile ranges (IQR), while categoric variables were given as number and rates. We have performed Mann-Whitney U and Kruskal-Wallis test for continuous variables and Chi-square test for categoric variables. All statistical calculations were performed using Statistical Package for Social Sciences (SPSS) for Windows (SPSS version 23) software package.

This retrospective study was approved by the Hacet-tepe University Ethics Committee (Number: GO 19/ 429).

3. Results

This study was consisted of 195 patients with autoimmune disorders. We have defined 38 and 157 patients as study (low C3 and/or C4 levels) and control (normal C3 and C4 levels) groups respectively.

We have summarized the maternal characteristics and obstetric outcomes of all patients at Table 1. Rate of composite adverse outcomes was detected as 27.2%. Three (1.5%) newborns died at postnatal period in which 2 were due to extreme prematurity and IUGR, while 1 was due to respiratory problems. NICU admission rate was found to be 13.8% ( $n=$ 27).

Table 1
Maternal characteristics and obstetric outcomes of the patients

$n=$ 195
Maternal age ${}^{\ddagger}$	33 (7)
Graviditiy ${}^{\ddagger}$	3 (2)
Living child ${}^{\ddagger}$	1 (1)
BOI ${}^{\ddagger}$	0.31 (0.79)
C3 level ${}^{\ddagger}$	115 (31)
C4 level ${}^{\ddagger}$	21 (9)
Hypocomplementemia	38 (19.4%)
MTHFR polymorphisms ${}^{\yen}$	115 (58.9%)
Birthweight ${}^{\ddagger}$	2930 (630)
Birthweek ${}^{\ddagger}$	37 (1)
Birthweight percentile ${}^{\ddagger}$	45 (52)
Newborn exitus ${}^{\yen}$	3 (1.5%)
NICU admission ${}^{\yen}$	27 (13.8%)
APGAR $<$ 7 ${}^{\yen}$	19 (9.7%)
IUGR ${}^{\yen}$	19 (9.7%)
Composite adverse outcome ${}^{\yen}$	53 (27.2%)

${}^{\ddagger}$ : Median (IQR), ${}^{\yen}$ : Number of cases (rate).

Statistical analysis was performed for the comparison of the hypocomplement patients and control group (Table 2). The complement levels were significantly lower in the study group, while the maternal age was comparable between groups ( $p$ : $<$ 0.001, $<$ 0.001, and 0.731; respectively). We have used BOI to compare previous obstetric history and demonstrated that patients with hypocomplementemia had significanlty lower BOI results ( $p$ : 0.002). Data related to obstetric outcomes revealed similar gestational week at birth and birthweight between groups ( $p$ : 0.499 and 0.290; respectively). Other statistical analysis regarding the obstetric outcomes revealed no statistically significant difference between the groups ( $p>$ 0.05 for all). Composite adverse outcome rates were also found as 26.2% and 27.3% for the study group and control group, respectively. Then, we have classified hypocomplement patients into 3 subgroups according to the type of complement (C3, C4 or both). Comparison inbetween these groups revealed no statistical significance in any of the analyzed parameters ( $p>$ 0.05) (Table 3).

Table 2

Comparison of hypocomplement patients with control group in terms of maternal characteristics and obstetric outcomes

	[l]Hypocomplement
group ( $n=$ 38)	[l]Control group
( $n=$ 157)	$p$
Maternal age ${}^{\ddagger}$	32.5 (6)	33 (7)	0.731
BOI ${}^{\ddagger}$	0.18 (0.21)	0.314 (0.28)	0.002
MTHFR Polymorphisms ${}^{\yen}$	24 (63.1%)	91 (57.9%)	0.587
C3 level ${}^{\ddagger}$	89 (37)	118 (27)	$<$ 0.001
C4 level ${}^{\ddagger}$	13 (3)	23 (8)	$<$ 0.001
Birthweight ${}^{\ddagger}$	2880 (560)	2950 (620)	0.579
Birthweek ${}^{\ddagger}$	37 (1)	37 (1)	0.499
Birthweight Percentile ${}^{\ddagger}$	37 (52)	47 (52)	0.290
Newborn exitus ${}^{\yen}$	0	3 (1.9%)	0.390
NICU admission ${}^{\yen}$	4 (10.5%)	23 (14.6%)	0.509
APGAR $<$ 7 ${}^{\yen}$	2 (5.2%)	17 (10.8%)	0.299
IUGR ${}^{\yen}$	5 (13.1%)	14 (8.9%)	0.429
Composite adverse Outcome ${}^{\yen}$	10 (26.2%)	43 (27.3%)	0.894

${}^{\ddagger}$ : Median (IQR) via Mann-Whitney U test; ${}^{\yen}$ : Number of events (rate) and Chi-square test.

Table 3

Comparison of subgroups according to complement levels in terms of maternal characteristics and obstetric outcomes

	[l]C3 low
( $n=$ 8)	[l]C4 low
( $n=$ 25)	[l]Both
complements
low ( $n=$ 5)	$p$
BOI ${}^{\ddagger}$	0.13 (0.22)	0.15 (0.23)	0.314 (0.33)	0.310
Birthweight ${}^{\ddagger}$	2880 (818)	2870 (495)	2970 (605)	0.485
Birthweek ${}^{\ddagger}$	37 (1)	37 (1)	37 (3)	0.887
Birthweight Percentile ${}^{\ddagger}$	55 (70)	34 (44)	36 (52)	0.691
Newborn Exitus ${}^{\yen}$	0	0	0	N/A*
NICU Admission ${}^{\yen}$	2 (25%)	2 (4%)	0	0.281
APGAR $<$ 7 ${}^{\yen}$	1 (12.5%)	0	1 (20%)	0.110
IUGR ${}^{\yen}$	1 (12.5%)	3 (7.5%)	1 (20%)	0.888
Composite Adverse Outcome ${}^{\yen}$	3 (37.5%)	5 (12.5%)	2 (40%)	0.469

${}^{\ddagger}$ : Median (IQR) via Mann-Whitney U test; ${}^{\yen}$ : Number of events (rate) and Chi-square test; N/A: Non-applicable.

4. Discussion

Pregnancy leads to various types of changes at the immune system that prevents the rejection of semiallogenic fetus. It has been reported that these physiological alterations in divergent immunological events might be associated with obstetric problems [22, 24]. Patients with autoimmune disorders or increased immune response are found to be related with adverse obstetric outcomes [33]. Thus, immunomodulator interventions may be necessitated in such patients, both for regulating autoimmune disease itself and modulating pregnancy outcomes [3, 4].

Complement system is a part of immune system which is activated by various types of immune system problems. It enhances the ability of immune system cells to eliminate microorganisms and damaged cells, activates antibodies, promote inflammation and attack cell membranes of targetted pathogens. Different pathways (classical, alternative, lectine, etc) are involved in the activation of complement system [40]. Low levels of complements are reported to be associated with increased immune responses in certain group of patients [41]. Determination of complement levels in these patients must be well interpreted to follow the course of the disease and predict the outcomes. The association between complement system and autoimmune disease flare up or immune system activation is well studied. The activation of complement system via alternative pathways is reported to be the triggering point of many autoimmune disorders [2]. Normalization of complement levels during the course of an autoimmune disorder is also related with a better disease course according to studies regarding SLE [19]. Thus, normal complement levels are associated with a more favorable pregnancy outcome compared to hypocomplement pregnant patients with autoimmune disorders [23].

In this study, we have analyzed the impact of preconceptional complement levels on the pregnancy outcomes of patients with autoimmune disorders. We have evaluated the complement levels prior to pregnancy due to the alterations of complement levels during the pregnancy. It has been reported that complement levels show a gradual increase up to 10–50% during the normal gestation [1]. It has already been shown that it is difficult to evaluate complement consumption during pregnancy as the increased production may lead to false negatives [21]. Hence, we have evaluated complement levels prior to pregnancy and conducted our analysis with the cutoffs determined for normal population.

Our results demonstrated no significant difference between study groups in the most of the variables. That may be explained by the existence of similar risk factors in the control group and the application of immunomodulator therapy all along the pregnancy for both groups. The patients involved in this study are the ones enrolled in a special antenatal care program with a formerly defined immunomodulatory treatment protocol. The defined therapy was previously discussed at the literature at certain groups of pregnant patients [14, 34, 38]. Administration of low dose LMWH is also discussed in literature and in vitro studies demonstrated the immunomodulator actions of LMWH [7]. LMWH was also reported to be affecting and suppressing the inflammatory pathways on complement-dependent and complement-independent pathways [27]. Low dose salysilic acid is also discussed widely in literature and recommended for the prevention of preeclampsia which is a disorder with immunologic background [30]. The administered treatment modality may be the reason for similar obstetric outcomes with hypocomplement patients and control group in our study.

We have classified hypocomplement patients into 3 subgroups according to the type of complement (C3, C4 or both) and performed further statistical analysis for the comparison of these groups. The analysis revealed no significant difference between patients according to whether C3, C4 or both complements are low. Levels of complements differ with classical or alternative pathways [39]. C4 levels seems to be more sensitive, since C3 levels may not get below the limits despite evident complement consumption. Thus, interpretation of the complement levels may be challenging in terms of obstetric outcomes [18, 36]. It has also been reported that the levels of complement consumption products may be used in the evaluation and comparison of pregnancy outcomes [26]. Previous literature also demonstrated that complement activation leads to disruption of angiogenic factors and defective placental development in experimental mouse model [16]. Furthermore, complement activation is demonstrated in the placenta by immunohistochemical studies [8]. Thus, further studies regarding placental inflammation must be conducted for more accurate results.

Our analysis revealed statistically significant difference between groups in terms of BOI ( $p$ : 0.002). This is an important finding as BOI is an easily applicable index for the discrimination of patients in terms of a poor obstetric history. Our results indicated that the patients with hypocomplementemia had a poorer obstetric history compared to normocomplement patients. According to our study, BOI analysis revealed that patients with hypocomplementia seems to be more susceptible to immunological problems and poor obstetric history. We also demonstrated that pregnancy outcomes were similar during the study period under our treatment protocol. Thus, we may conclude that our treatment protocol has improved the obstetric outcomes, especially in hypocomplement patients.

In conclusion, low complement levels in pregnant women with autoimmune disorders may be associated with gestational problems and poor obstetric history. Immunomodulatory treatment modalities such as ours may be beneficial for improving the obstetric and neonatal outcomes.

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Effect of hypocomplementemia on perinatal outcomes of pregnancies with autoimmune disorders

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

2. Materials and methods

3. Results

Table 1 Maternal characteristics and obstetric outcomes of the patients

References

Table 1
Maternal characteristics and obstetric outcomes of the patients