Obstetric outcomes in patients with primary thrombotic and obstetric antiphospholipid syndrome and its relation to the antiphospholipid antibody profile

Abstract

Introduction: Previous studies suggested different obstetric outcomes between patients with thrombotic or obstetric antiphospholipid syndrome, but the data are inconclusive. Aims: To investigate obstetric outcomes and their relation to the antiphospholipid antibody profile in primary thrombotic or obstetric antiphospholipid syndrome patients and compare those to a control population. Materials and methods: A retrospective single-centre study on a cohort of 30 pregnant women with primary antiphospholipid syndrome treated at Karolinska University Hospital Solna, Sweden between 2000 and 2016. The pregnancy outcomes were compared to the outcomes of all pregnancies in Stockholm County during the same period. Results: Preeclampsia (p < 0.001), low birth weight at delivery (p = 0.001), Apgar < 7 at 5 minutes (p < 0.001) and small infants (p < 0.001) were more common in antiphospholipid syndrome patients compared to controls. Obstetric antiphospholipid syndrome patients had a higher incidence of small infants (p = 0.023), lower birth weight (p = 0.013) and infants born with complications (p=0.004) compared to thrombotic antiphospholipid syndrome. Mothers with triple antibody positivity had a higher incidence of preeclampsia (p = 0.03), preterm delivery (p = 0.011), small infants (p=0.002) and infants born with complications (p = 0.012). Conclusions: Patients with primary antiphospholipid syndrome, especially those with obstetric antiphospholipid syndrome and triple antibody positivity, are at higher risk for adverse pregnancy outcomes, even under antithrombotic treatment. More frequent antenatal controls in high-risk patients can further improve outcomes.

Keywords

Antiphospholipid syndrome antiphospholipid antibodies pregnancy preeclampsia small for gestational age birth weight

Introduction

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboembolic episodes and/or obstetric complications in the persistent presence of antiphospholipid antibodies (aPL; i.e. anticardiolipin (aCL), anti-β₂glycoprotein-I (aβ₂GPI) and lupus anticoagulant (LA)). APS can be present as a single clinical entity without other concomitant autoimmune disorders, which is primary APS. It can also be associated with other autoimmune diseases, especially systemic lupus erythematosus (SLE), and is then called secondary APS. Moreover, depending on the initial clinical presentation, APS is divided into two subgroups: thrombotic APS (TAPS) and obstetric APS (OAPS). The adverse pregnancy outcomes constituting the clinical manifestations of OAPS include increased risk of recurrent miscarriage, fetal death, preeclampsia, eclampsia, placental insufficiency, prematurity and giving birth to small, growth-retarded infants.^1–3 The clinical manifestations of TAPS are defined as one or more episodes of venous, arterial or small vessel thrombosis in any tissue or organ.³

Patients can be single to triple positive for aPL and positivity can be expressed from low to high antibody titres. Depending on the aPL profile, patients have different risks for thrombosis and/or adverse obstetric events.^4,5 A recent study showed that in pregnancies with primary APS, aCL is the most common antibody present, but anti- ß2GPI is associated with most adverse events compared to single positivity for aCL or LA.⁵ In other studies both LA and anti-ß2GPI have been suggested as high-risk antibodies in single-positive patients and several studies have stated that triple positivity is a strong indicator of adverse events.^1,5–8 Moreover, novel data suggested the antibody profile might be of higher clinical value when assessing outcome than initial clinical presentation.⁸ However, there are no validated parameters for risk stratification for clinical complications according to antibody profile in primary APS.

Pregnancy is a naturally hypercoagulable state and patients with APS are at increased risk of developing thrombosis and adverse obstetric events during pregnancy as aPL induce a procoagulant and proinflammatory response. In OAPS the presence of aPL will suffice to tip the haemostatic and immunological balance at the fetal-maternal interface, unlike the aPL-associated thrombosis, which will occur only when the body is primed by the inflammation process or tissue damage despite the persistent presence of the responsible predisposing antibodies.⁹

Current guidelines suggest that pregnant women with primary APS should be treated with low-dose acetylsalicylic acid (LDA) alone or in combination with low molecular weight heparin (LMWH) during pregnancy, depending on their medical history and additional risk factors.^10,11 The frequency of administration of LMWH is under debate and it is currently administered once or twice daily, depending on the expected risk of thrombosis. The incidence of fetal loss and adverse obstetric events decreases remarkably under antithrombotic treatment.¹²

Recent studies suggest that pathogenesis and clinical manifestations could differ between patients with the two subtypes of APS.^13,14 Other investigators have identified the risk of obstetrical complications as similar between the two groups, apart from the frequency of early pregnancy loss, which seems to be higher in the OAPS group.¹⁵

This study aimed to investigate obstetric outcomes in women with primary APS and highlight the differences in obstetric outcomes between women with TAPS and OAPS as well as the correlations with the aPL profile. To our knowledge, no previous study has compared obstetric outcomes in patients with TAPS and OAPS in a cohort with only primary APS patients.

Materials and methods

Study design and population

In total, 36 women with primary APS treated at the Obstetric Department of Karolinska University Hospital in Solna, Sweden throughout their pregnancies during the years 2000–2016 were eligible for inclusion in this single-centre retrospective study. The inclusion criteria were: (a) diagnosis of primary APS and (b) at least one pregnancy after diagnosis during the timeframe 2000–2016. Exclusion criteria were: (a) secondary APS (associated with SLE or other rheumatic disorders), (b) patients diagnosed without fulfilling the Sydney criteria for APS diagnosis³ and (c) patients that delivered their infants elsewhere as we did not have access to their medical records. After reviewing the medical records, six patients were excluded because they did not fulfil the inclusion criteria of the study. In three of these cases the diagnosis of APS was not certain, two patients had no pregnancies following APS diagnosis and one was shown to have secondary APS. Therefore, the cohort of this study consisted of 30 women.

All the women included underwent measurements of weight and blood pressure and had a blood sample taken for measurements of aPL in the first trimester. According to the current recommendations from the Swedish Society of Obstetrics and Gynecology, all patients with APS should be under antithrombotic pharmacological therapy during pregnancy and all the patients in this study were treated with LDA (Trombyl® 75 mg) and LMWH according to those guidelines.¹¹

The patients were informed about the study and signed an informed consent form prior to inclusion. The study was approved by the regional ethical board, Karolinska Institute, Stockholm, Sweden.

Data collection

The data were retrieved by reviewing the medical records found in the digital medical records systems Take Care® and Obstetrix®. The data gathered included diagnosis (TAPS or OAPS), age, body mass index (BMI), blood pressure at the beginning of pregnancy, aPL profile, previous diseases, treatment, family history, previous pregnancies, heredity and previous thrombosis. Data collected on the pregnancy outcomes included preeclampsia/eclampsia, miscarriage, gestation week at delivery, complications at delivery, mode of delivery and bleeding at partus (as an indication of safety when treating with anticoagulants). Fetal outcomes that were analysed included weight, small for gestational age (SGA), intra uterine growth restriction (IUGR), APGAR score at 5 minutes after birth and health complications after birth. Some of the pregnancy outcomes in patients with APS were compared to available data on pregnancy outcomes of all women giving birth in Stockholm County during the same period of time and those data were collected from The National Board of Health and Welfare.¹⁶ Studied outcomes were: gestational week at delivery, incidence of preeclampsia, mode of delivery, APGAR score after 5 minutes, infant weight at birth and SGA/IUGR. Using this database, we collected information about all the pregnancy outcomes in all deliveries in Stockholm County during the period 2000–2016, in total 327,584 deliveries. The obstetric outcomes of the patients in our cohort were also compared by diagnosis (TAPS or OAPS), antibody profile (single, double and triple positivity, as defined by analysis during the first trimester) and frequency of LMWH administration (once or twice daily).

Statistical methods

The statistical methods that have been used are descriptive statistics and non-parametric methods for comparisons between groups. The significance level was set to a p value < 0.05. The non-comparison data were evaluated by calculating the mean with a 95% confidence interval, using the t-distribution. For the comparisons between the APS group and the control population, one sample t-test was used for continuous data, because the population variance was not known, and binomial test for dichotomous variables. Assumption of normal distribution of continuous data was proven with Shapiro-Wilk tests (when p > 0.05, then normally distributed data were assumed). If assumptions were met, an independent t-test was used for group comparisons between TAPS and OAPS in clinical outcomes; otherwise, the non-parametric Mann-Whitney U test was applied. For nominal data, Fisher's exact test was used when the expected count was <5, otherwise the Chi-squared test was used. For comparison of the three categories of antibody profile, the Kruskal-Wallis test was used for comparing continuous data. All the statistics were calculated using the program IBM SPSS Statistics® for Mac, version 24 (Armonk, NY: IBM Corp).

Results

Of the 30 included patients, 12 were diagnosed with TAPS and 18 with OAPS.

Investigation of the patients' clinical characteristics

Table 1 shows the characteristics of the APS patients. The patients' blood type was comparable to the Swedish population, with a distribution of 0 + (37%), A + (30%), B + (17%), 0- (7%), B- (7%) and AB + (3%) (17). Overall, 27 (90%) of the patients were pregnant before the diagnosis of APS. The total number of previous pregnancies for these 27 patients was 70. Of these, 14 (20%) were normal pregnancies without any adverse outcomes. Of the remaining 56, a majority (36, 51%) ended in a miscarriage before 20 weeks of gestation. In total, 10 (14%) pregnancies ended with intrauterine fetal death after 20 weeks of gestation, in eight (11%) pregnancies the woman developed preeclampsia (n = 7) or haemolysis-elevated liver enzymes low platelet count syndrome (n = 1) and 11 pregnancies (16%) ended in an acute caesarean section. Six (9%) of the pregnancies resulted in newborns that suffered from IUGR; one of these infants was born in week 25 with a birth weight of 470 g and died after a few days.

Table 1

Characteristics of APS patients

	APS patients (n = 30)	CI 95%
Age (years)	31.6	(30.1–33.1)
BMI	25.6	(23.9–27.4)
Average systolic blood pressure (mm Hg)	113	(109–117)
Average diastolic blood pressure (mm Hg)	69	(67–72)
Comorbidities^a
Autoimmune	13 (43.3%)
Hypertension	4 (13.3%)
Heredity
No heredity	13 (43.3%)
Autoimmune disease	5 (16.7%)
Thromboembolism	7 (23.3%)
Pregnancy complications	2 (6.7%)
Combination	3 (10%)
Antiphospholipid antibodies
LA	3 (10%)
aCL	3 (10%)
aCL, anti-ß2GPI	6 (20%)
LA, aCL, anti-ß2GPI	18 (60%)
Antiphospholipid antibodies categorized
Single positive	6 (20%)
Double positive	7 (23.3%)
Triple positive	17 (56.7%)
Previous thrombosis
No	15 (50%)
Yes	15 (50%)
Arterial	4 (26.6%)
Venous	10 (66.7%)
Both	1 (3.3%)
Previously pregnant
Yes	27 (90%)
No	3 (10%)
Total number of previous pregnancies^b
Normal pregnancies	70 (100%)
Adverse outcome	14 (20%)
Miscarriage	36 (51.4%)
Acute caesarean section	11 (15.7%)
Preeclampsia/HELLP	8 (11.4%)
SGA	2 (2.9%)
IUGR	6 (8.5%)
IUFD	10 (14.3%)
Thrombosis	4 (5.7%)
Number of patients with at least one miscarriage^c
Number of previous miscarriages	12 (40%)
1	3 (10%)
2–3	5 (16.7%)
≥ 4	4 (13.3%)

Autoimmune comorbidities such as hypothyroidism (n = 7), autoimmune haemolytic anaemia (n = 2), myasthenia gravis (n = 1), Addison's disease (n = 1), panniculitis (n = 1) and cardiac valve disease (n = 1), which is often correlated to APS. The second category is hypertension alone.

Total number of pregnancies represents all reported pregnancies in the cohort including miscarriages (not including the ones deliberately ended by legal abortion).

Number of patients with at least one miscarriage before diagnosis of APS. The patients have also been divided into how many miscarriages they have had.

APS: antiphospholipid syndrome; BMI: body mass index; LA: lupus anticoagulant; aCL: anti-cardiolipin antibody: anti-B2GPI: β₂-glycoprotein I antibody; HELLP: hemolysis elevated liver enzymes and low platelet count; SGA: small for gestational age; IUGR: intrauterine growth restriction; IUFD: intrauterine fetal death; CI: confidence interval.

Pregnancy outcomes in patients with APS and comparison to the control population

Table 2 shows the pregnancy outcomes of all APS patients (n = 30). Six (20%) patients developed preeclampsia. Four (13%) miscarriages occurred, of which three were in the first trimester and one in the second. The mean gestation week at delivery was 37 + 5 (P25–P75 32 + 5-39 + 1). The mean birth weight of the infants was 2808 g (95% confidence interval (CI) 2411–3205). Eight (27%) of the newborns were SGA and seven (23%) were considered IUGR. Three (10%) newborns had an APGAR score lower than 7 after 5 minutes. Overall, 10 (33%) newborns were diagnosed with different conditions at birth, namely IUGR (n = 7), ascites (n = 1), perforation of intestines (n = 1), disseminated intravascular coagulation (DIC) (n = 1), respiratory distress syndrome (n = 1) and polycythemia (n = 1).

Table 2

Pregnancy outcome for APS patients

	APS patients (n = 30)	CI (95%)
Treatment^a
LDA + LMWH one dose	18 (60%)
LDA + LMWH two dose	11 (36.7%)
Preeclampsia
Early severe	3 (10%)
Late severe	2 (6.7%)
Late moderate	1 (3.3%)
Miscarriage
First trimester	3 (10%)
Second trimester	1 (3.3%)
Gestation week at delivery	37 + 5	(32 + 5–39 + 1)^c
Bleeding at delivery (ml)	400	(250–600)^c
Weight at birth (g)	2808	(2411–3205)
SGA	8 (26.7%)
IUGR	7 (23.3%)
APGAR < 7 at 5 min	3 (10%)
Not entirely healthy infant^b	10 (33.3%)

LMWH was administered one or two times a day.

Infants that were reported not being entirely healthy at delivery suffered from IUGR, ascites, perforation of intestines, DIC, respiratory distress syndrome and polycythemia.

Median (P25–P75).

APS: antiphospholipid syndrome; CI: confidence interval; LDA: low dose acetylsalicylic acid; LMWH: low molecular weight heparin; DIC: disseminated intravascular coagulation; SGA: small gestational age; IUGR: intra uterine growth restriction.

As shown in Table 3, the patients with APS and the control group were similar in age and BMI. There was a clear difference in the occurrence of preeclampsia, where 20% of the APS patients developed preeclampsia compared to 2.9% for the controls (p value < 0.001). Concerning mode of delivery, in the APS patients group 15% (n = 4) of the deliveries were spontaneous vaginal, compared to 86.1% in the control group (p value < 0.001), whereas 50% (n = 13) of the APS patients were delivered by emergency caesarean section, compared to 8.8% of the control group (p value < 0.001). There was a difference in the gestation week at time of delivery between the two groups where the APS group had a higher incidence of preterm birth with more infants born before 32 weeks of gestation: 18.5% (n = 5) vs 1.3% (p value < 0.001), and infants born at gestation week 33–36: 18.5% (n = 5) vs 4.5% (p value 0.006). This means there was another difference in gestation week, where the APS cohort had a lower percentage of deliveries born at term, 37–41 weeks of gestation, 63% (n = 16) versus 87.5% (p value 0.002). Three infants born to a mother with APS (11%) had an APGAR score <7 after 5 minutes compared to 1% in the control group (p value < 0.001). There was a significant difference in newborn growth rate (SGA/IUGR) between the two groups (p value < 0.001) and a significant difference in the newborns' birth weight (p value 0.001), as presented in Table 3.

Table 3

APS patients' obstetric outcomes compared to the control population

	APS patients	Control group	p value
Mean age at delivery, years ( ± SD)	31.6 ( ± 4.1)	31.3	0.689
BMI	25.6 (±4.7)	23.9	0.055
Preeclampsia, % (n)	20% (n = 6)	2.9%	<0.001
Mode of delivery,^a % (n)
Spontaneous vaginal	15.4% (n = 4)	86.1%	<0.001
Induced vaginal	19.2% (n = 5)	14.0%	0.295
Assisted vaginal	7.7% (n = 2)	10.7%	0.463
Elective caesarean section	7.7% (n = 2)	9.9%	0.517
Emergency caesarean section	50.0% (n = 13)	8.8%	<0.001
Gestation week at delivery,^a % (n)
≤32 weeks	18.5% (n = 5)	1.3%	<0.001
33–36 weeks	18.5% (n = 5)	4.5%	0.006
37–41 weeks	63.0% (n = 16)	87.5%	0.002
≥42 weeks	0% (n = 0)	6.7%	0.172
APGAR < 7 at 5 min	11% (n = 3)	1%	<0.001
SGA/ IUGR	29% (n = 8)	2.4%	<0.001
Mean weight at delivery, g (CI 95%)	2808 (2411–3205)	3500	0.001

Total number of deliveries = 26.

APS: antiphospholipid syndrome; BMI: body mass index; CI: confidence interval; SGA: small for gestational age; IUGR: intrauterine growth restriction.

Obstetric outcomes in patients with TAPS compared to OAPS

There was no significant difference in age, BMI, blood pressure, comorbidities or heredity between the two groups (Table 4). Concerning the studied pregnancy, there was no significant difference in incidence of miscarriage, mode of delivery, bleeding at delivery, gestational week at delivery and APGAR score <7 at 5 minutes.

Table 4

Comparison between patients diagnosed with TAPS and OAPS

	TAPS (n = 12)	OAPS (n = 18)	p value
Age, years (CI 95%)	31.9 (29.0–34.8)	31.4 (29.5–33.3)	0.734
BMI (CI 95%)	26.3 (23.4–29.1)	25.2 (22.7–27.7)	0.563
Average systolic blood pressure (mm Hg)	112 (106–118)	114 (108–120)	0.626
Average diastolic blood pressure (mm Hg)	69 (65–74)	70 (65–74)	1.000
Comorbidities
No	7	6	0.498
Autoimmune	4	10
Hypertension	1	2
Heredity
Autoimmune disease	3	5	0.248
Thromboembolism	5	2
Pregnancy complications	1	1
Previous thrombosis	12	3	<0.001
Antibody profile
Single	2	4	0.157
Double	5	2
Triple	5	12
Treatment^b
LDA + LMWH one dose	5	14	0.063
LDA + LMWH two dose	7	4	0.063
Pregnancy outcome
Miscarriage	3	1	0.274
Live birth	9	17	0.274
Preeclampsia
No	9	11	0.063
Yes^c	0	6	0.063
Mode of delivery
Spontaneous vaginal	1	3	0.963
Induced vaginal	1	4
Assisted vaginal	1	1
Elective caesarean section	1	1
Emergency caesarean section	5	8
Bleeding at delivery, ml (CI 95%)	708 (251–1165)	521 (252–789)	0.181
Gestation week at delivery (CI 95%)	32 + 4 (25 + 0–39 + 3)	34 + 4 (30 + 6–38 + 2)	0.983
Weight at birth (CI 95%)	3324 (3095–3552)	2535 (1963–3107)	0.013
SGA	0	8	0.023
IUGR	0	7	0.058
APGAR <7 at 5 min	1	2	0.100
Not entirely healthy infant	0	10	0.004

^aAdverse outcome defined as acute caesarean section, SGA/IUGR, preeclampsia/HELLP, IUFD, child died after a few days and postpartum thrombosis.

LMWH was administered one or two times a day.

Of the six cases of preeclampsia, three were early severe, two late severe and one late moderate.

APS: antiphospholipid syndrome; CI: confidence interval; TAPS: thrombotic antiphospholipid syndrome; OAPS: obstetric antiphospholipid syndrome; BMI: body mass index; LDA: low dose acetylsalicylic acid; LMWH: low molecular weight heparin; DIC: disseminated intravascular coagulation; SGA: small gestational age; IUGR: intra uterine growth restriction; HELLP: haemolysis elevated liver enzymes and low platelet count: IUFD: intrauterine fetal death.

There was no significant difference between the two groups concerning preeclampsia even though all six cases occurred in the OAPS group with none in the TAPS group (p value 0.063). All the significant differences between TAPS and OAPS were observed in neonatal outcomes. In the TAPS group the newborns had an average birth weight of 3324 g (95% CI 3095–3552), whereas in the OAPS group the average birth weight was 2535 g (95% CI 1963–3107). Importantly, both these values are still within the range of normal birth weight, 2500–5000 g; however, the difference is statistically significant (p value 0.013). There was also a difference in the growth rate of newborns in the two groups, with eight SGA newborns in the OAPS group compared to none in the TAPS group (p value 0.023). Seven of the newborns in the OAPS group were IUGR compared to none in the TAPS group, and the difference is distinguishable but not statistically significant (p value 0.058). All 10 infants who suffered from complications at birth were born to a mother with OAPS (p value 0.004). The antibody profile did not differ significantly between the TAPS and OAPS groups (p value 0.157) but when we analysed the antibody profile within the OAPS group, we found it was the triple-positive patients that gave birth to children who were SGA (p value 0.009), IUGR (p value 0.043) and those born with complications (p value 0.043).

Relation between obstetric outcomes and antibody profile

According to the aPL profile, the patients were divided into six single-positive patients, seven double-positive patients and 17 triple-positive patients (Table 5). All double-positive patients were positive for anti-ß2GPI and aCL. The triple-positive patients had a significantly increased risk of preeclampsia (p value 0.027), giving birth to newborns that were SGA (p value 0.002) and IUGR (p value 0.012). There was a significant difference in week of gestation at delivery; the triple-positive group gave birth at week 29 + 5 (95% CI, 24 + 2 – 35 + 1) compared to the double-positive group, which gave birth at week 39 + 0 (95% CI, 36 + 5 – 41 + 1) (p value 0.011). The same applies to birth weight in infants born to mothers that were double positive (3477 g, 95% CI 3186–3768) compared to triple positive (2216 g, 95% CI 1591–2841) (p value 0.011). The mean weight at delivery for children born to mothers from the triple-positive group was therefore under the normal reference range (2500–5000 g). The triple-positive patients also had a higher incidence of newborns with complications (p value 0.012) such as IUGR, ascites, perforation of intestines, DIC, respiratory distress syndrome and polycythemia.

Table 5

Obstetric outcomes when dividing and comparing patients by antibody profile

	Triple positivity (n = 17)	Double positivity (n = 7)	Single positivity (n = 6)	p value
Pregnancy outcome
Miscarriage	4	0	0	0.365
Live birth	13	7	6	0.365
Preeclampsia
No	7	7	6	0.027
Yes^a	6	0	0	0.027
Mode of delivery
Spontaneous vaginal	1	1	2	0.088
Induced vaginal	2	2	1
Assisted vaginal	0	1	1
Elective caesarean section	0	1	1
Emergency caesarean section	10	2	1
Bleeding at delivery, ml (CI 95%)	375 (195–555)	753 (103–1403)	842 (118–1565)	0.130
Gestation week at delivery	29 + 5 (24 + 2–35 + 1)	39 + 0 (36 + 5–41 + 1)	38 + 4 (36 + 6–40 + 2)	0.011,^b 0.171,^c 1.00^d
Weight at birth, g (CI 95%)	2216 (1591–2841)	3477 (3186–3768)	3312 (2729–3894)	0.011,^b 0.966,^c 0.290^d
SGA	8	0	0	0.002
IUGR	7	0	0	0.012
APGAR < 7 at 5 min	1	0	2	0.580
Not entirely healthy child
Yes	7	0	0	0.012
No	6	7	6	0.012

Out of the six cases of preeclampsia three were early severe, two late severe and one late moderate.

Double versus triple positive.

Single versus triple positive.

Single versus double positive.

CI: confidence interval; SGA: small for gestational age; IUGR: intrauterine growth restriction.

Outcomes in patients receiving LMWH once or twice daily

No significant differences were found between the patients that received LMWH once or twice daily in any studied outcome (miscarriage, preeclampsia, mode of delivery, bleeding at partus, gestation week at delivery, weight at birth, SGA, IUGR, APGAR <7 at 5 minutes and infants born with complications).

Discussion

To the best of our knowledge, this is the first time that obstetric outcomes have been investigated and compared between TAPS and OAPS in a cohort including patients with primary APS exclusively as well as in relation to the obstetric outcomes of a control population. Our results show the APS group has a higher incidence of adverse events compared to a control group, even when on antithrombotic treatment. This confirms the outcomes of previous studies in the field.^2,18,19 We have also confirmed that triple positivity for aPL is a risk factor for adverse obstetric events.^5,8 Moreover, we found that OAPS patients had worse fetal outcomes than TAPS patients.

Compared to the control group, the APS patients had a higher incidence of preeclampsia, emergency caesarean sections, preterm birth, low APGAR score, SGA or IUGR and a lower birth weight of the infant, with a considerable part of the newborns (n = 6, 23%) weighing < 2500 g at birth and half (n = 13, 50%) of the deliveries performed by emergency caesarean sections.

Regarding the difference between TAPS and OAPS, our study demonstrates a strong association between OAPS and adverse fetal outcomes, such as SGA, low birth weight and infants born with complications. OAPS is characterized by a high rate of obstetric complications so our results are not surprising. However, this is opposite to the results by Bramham et al.,²⁰ which showed that patients with TAPS had a higher incidence of adverse obstetric outcomes such as preterm delivery and SGA. Another recent study by Mayer-Pickel et al.¹⁵ had a similar rate of pregnancy complications when comparing TAPS to OAPS. Both studies, however, included patients with secondary APS, especially in the TAPS group. The sizes of the cohorts in those studies were about double the size of ours, but as mentioned above, they also included patients with secondary APS. Therefore, the results could not be directly compared to the outcomes in our study.

Within the OAPS group, we found the triple-positive patients had a higher incidence of SGA, IUGR and children born with complications. The results were statistically significant but because the groups are so small, it is hard to analyse the association between group and antibody profile. Still, patients with OAPS and triple positivity for aPL could be considered a very high-risk group.

The comparison in outcomes when dividing the patients by antibody profile showed that mothers with triple-positive aPL had a higher incidence of preeclampsia and gave birth earlier to infants with a mean birth weight under the lower normal level and with a higher risk of complications at birth. These findings correspond to earlier research in the field.^5,7,8,21,22 There was no statistically significant difference in the mode of delivery, even though 10 of the 13 emergency caesarean sections were performed on triple-positive patients, which could indicate this group had a high incidence of potential complications, making emergency caesarean section necessary.

One can also argue that OAPS seem to be at risk of severe complications leading to emergency caesarean section. Out of the 13 acute caesarean sections, eight were performed in the OAPS group and five in the TAPS group.

Of the emergency caesarean sections in the OAPS group, six had the indication IUGR with or without preeclampsia (PE), and four of these were performed before week 34. The other two had the indications breech position and history of caesarean section. In the TAPS group, four out of the five had common obstetric indications such as threatening fetal asphyxia with cardiotocography (CTG) changes or insufficient contractions. Only one of the TAPS group, at term with the infant appropriate for gestational age, had the indication threatening PE.

The pathophysiological mechanism of APS is not yet totally understood and there might be additional, yet unknown, mechanisms that generate the adverse outcomes. Many of the clinical manifestations seem to emerge from the activation of different parts of the inflammatory response.¹³ Histopathology of the decidual tissue in mice models has shown inflammation due to the complement pathway activation and over-expression of TNFα in trophoblasts and inflammatory cells infiltrating the decidua when aPL are present.^23,24 It has also recently been discovered that aPL increases expression of microRNA in trophoblasts, which leads to increased secretion of the inflammatory mediator interleukin 8.²⁵ It has been proven that LDA and LMWH reduce the inflammatory response in APS patients, but it is uncertain to what extent.^23,26,27 Still, several studies have shown that a combination of LDA and LMWH improves the obstetric outcomes in APS patients, contributing to today's recommendation for treatment.^12,23,28,29 In our study, we showed that prior to APS diagnosis and treatment, only 14 (20%) out of 70 pregnancies were normal, without any complications, whereas the antithrombotic treatment improved this outcome to 10 (33%) out of 30 pregnancies. Hence, our results are in line with previous research and the current recommendations of treatment during pregnancy in APS patients, despite the fact that obstetric outcomes in the APS population are still worse than the outcomes in the control population.^11,12

Our results suggest that OAPS is a group associated with higher risks in pregnancy and therefore these patients could be favoured by a more offensive treatment, such receiving LMWH twice daily, or in increased dosage. Current Swedish guidelines on the treatment of OAPS do not give clear recommendations on how to prescribe LMWH.¹¹ LMWH has in mice models been shown to reduce the inflammatory response in the body by inhibiting the compliment activation induced by aPL, which could be beneficial for these patients.²³ Our investigation on the outcome depending on LMWH regime showed no significant differences in any outcome, but because the cohort was very small we suggest more research is needed on this topic.

Earlier studies have also concluded there is a need for further research on treatment for APS.^{2,5,8,10,21,30} In recent years, novel treatment strategies have been evaluated in patients with APS, including corticosteroids, rituximab and intravenous immunoglobulin. Nevertheless, there is today still no evidence of improvement in clinical manifestations by administering these drugs.^10,30 Patients with secondary APS associated with SLE are generally treated with hydroxychloroquine during pregnancy. Earlier results have shown that patients with primary APS have a higher incidence of fetal morbidity such as prematurity and IUGR than patients with secondary APS, which might be due to a lack of advantageous effects of additional treatments when given to patients with secondary APS.²

This study contributes with novel, significant observations in the field of a rare disease where much is yet unknown. Our results could be applied to identifying very high-risk groups who could benefit from enhanced antenatal controls and follow up. Another strength is the single-centre approach where all patients have been investigated and treated in the same manner. All patients had primary APS, which limits the effect that other rheumatic diseases could have on outcomes and allows for reliable and relevant conclusions. The population in our study is very well selected, including only patients with primary APS at a single healthcare centre, which gives us a small, but more homogenous, patient population. There is a large potential benefit for patients with rare disorders when their condition is investigated, and even small studies can make a significant difference for the patients.

The most apparent limitation of this study was the small size of the patient cohort. This could be considered acceptable though, since the diagnosis of APS has a low incidence. However, the cohort was comparable to the cohorts of other studies, which were similarly small due to the rarity of the disease.

To conclude, we found an increased risk of adverse obstetric events in pregnant patients with primary OAPS and triple positivity for aPL. Therefore, these patients could need even closer and more frequent monitoring during their pregnancies, to detect and treat adverse conditions early. The size of the APS population that gave birth by emergency caesarean section was remarkably large (50%). This might be an indicator that these patients need even more intensive monitoring in late pregnancy to predict the course of the pregnancy and the risk of complications with the intention to avoid emergency caesarean section. The study also shows the current protocol of antenatal antithrombotic treatment of APS patients is effective, but there is a need to further evolve the therapeutic strategies to improve obstetric outcomes.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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