Abstract
Objectives:
Ischemic placental disease (IPD), including preeclampsia, abruption, and intrauterine growth restriction, often recurs in subsequent pregnancies. Angiogenic factors of placental origin have been implicated in the pathogenesis of preeclampsia, but have not been studied as predictors of IPD in subsequent pregnancies. We hypothesized that elevated angiogenic factors in an index pregnancy would be associated with recurrence of IPD.
Study Design:
We conducted a retrospective cohort study of patients undergoing evaluation for preeclampsia who had angiogenic factors measured in an index pregnancy and experienced a subsequent pregnancy at the same institution. Patients with IPD in the index pregnancy were included. A high ratio of soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) was defined as greater than or equal to 85.
Main Outcome Measures:
The primary outcome was IPD in a subsequent pregnancy.
Results:
We included 109 patients in the analysis. The sFlt1/PlGF ratio was elevated in 30% of participants. Those with an elevated ratio were more likely to be nulliparous in the index pregnancy, and less likely to have chronic hypertension. The recurrence of IPD in the study was 27%, with a non-significant difference in risk based on a high sFlt-1/P1GF ratio RR 0.58 (95% CI 0.21 – 1.6) compared to a low ratio.
Conclusions:
A high sFlt1/P1GF ratio in an index pregnancy is not associated with a higher risk of IPD in a subsequent pregnancy. These data suggest placental angiogenic biomarkers are specific to the pregnancy and not a reflection of maternal predisposition to IPD.
Keywords: ischemic placental disease, preeclampsia, abruption, angiogenic factors, small for gestational age
Introduction
Conditions of ischemic placental disease (IPD), including preeclampsia, abruption, and intrauterine growth restriction (IUGR), often recur in subsequent pregnancies [1]. While more commonly associated with nulliparity, preeclampsia recurs in 6–65% depending on the population studied [1–4]. IUGR even without hypertension has been associated with occurrence of hypertensive disorders of pregnancy and growth restriction in subsequent pregnancies [5], and abruption has been cited as a risk factor for recurrence of preeclampsia [1]. Management of parturients with a history of preeclampsia and IUGR in subsequent pregnancies includes increased antenatal surveillance and prophylaxis with aspirin, although the clinical outcome for these parturients is highly variable [6].
The exact pathophysiology of the conditions of IPD remains unknown, but inadequate remodeling of spiral arteries in early pregnancy likely contributes to the underlying etiology [7]. While often considered placentally mediated, there is likely a maternal component to manifestation of IPD as the conditions of IPD are more likely to recur in future pregnancies [1] and be linked with future cardiovascular disease [8].
Angiogenic factors, such as soluble fms tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF), have been implicated in the pathogenesis of preeclampsia [9,10] and fetal growth restriction [11] in the same pregnancy, but the relationship between angiogenic factors and subsequent pregnancy outcomes is unknown. A significant association between angiogenic factor levels and IPD in a future pregnancy would enable more informed counseling, prevention efforts, and surveillance strategies in subsequent pregnancies.
Our objective was to evaluate the association of elevated angiogenic factors in an index pregnancy among parturients with IPD and recurrence of IPD in a subsequent pregnancy. We hypothesized that a high sFlt1/P1GF would be associated with a recurrence of IPD. In addition, we aimed to identify differences in demographics and index pregnancy delivery outcomes that may be associated with recurrence of IPD.
Methods
We conducted a retrospective cohort study of parturients who had angiogenic factors measured in an index pregnancy complicated by IPD from July 2009 to June 2012 [9,12], and experienced a subsequent pregnancy that resulted in a birth after 20 weeks of gestation at Beth Israel Deaconess Medical Center through August 2018. Patients with IPD were identified for a previous study [13]. Briefly, preeclampsia, placental abruption, and IUFD were identified with ICD-9 and ICD-10 codes and verified through a medical record review. Preeclampsia was defined using current criteria from the American College of Obstetricians and Gynecologists [14]. SGA was used as a proxy of IUGR, which has been commonly done in other studies [15–17]. We defined SGA as <10th percentile using published U.S. growth curves stratified by sex and gestational age [18]. These curves are based on all U.S. births in a given period; the racial and ethnic composition of those births was similar to that in our study cohort. To determine whether placental insufficiency led to an IUFD in the original study, autopsy, pathology, and clinician notes were reviewed for documented evidence indicating placental insufficiency as the cause. Secondary outcomes included each of the components of IPD separately, in addition to IPD with severe SGA, defined as birth weight <3rd percentile. Patients with angiogenic factors measured were identified from a prior cohort study [9]. Blood samples for angiogenic factor measurement were collected at the time of presentation to the obstetrical triage unit for evaluation of hypertension, proteinuria or symptoms associated with preeclampsia in pregnancy, such as headache, visual symptoms, right upper quadrant pain or edema [9]. Hospital administrative records were used to identify those patients with a first subsequent pregnancy and all subsequent pregnancies were confirmed via medical record review. Patients who had IPD, a measurement of angiogenic factors and a subsequent pregnancy were included in the analysis. Only singleton gestations in the index pregnancy were included. Both index and subsequent pregnancies that resulted in a birth less than 20 weeks of gestation were excluded.
The exposure was an elevated sFlt1/P1GF ratio in the index pregnancy, defined as greater than or equal to 85. We will refer to this group as “high ratio.” The reference group will be referred to as “low ratio.” We utilized this cut-off, since it was the cut-off found to be highly sensitive and specific for adverse outcomes in the index pregnancy [9]. Its measurement is described elsewhere [9], but briefly the sFlt1/PlGF ratio was performed using an automated platform with commercially available assays on Elecsys platform (Roche Diagnostics, Penzberg, Germany). Treating physicians were unaware of the test results of the sFlt1 and PlGF values, either during the index pregnancy or during the subsequent pregnancy. We abstracted demographic characteristics, obstetric history and delivery outcomes from electronic medical records, with a proportion of the demographic data provided by the Massachusetts Department of Health (DPH).
The primary outcome was IPD, defined as development of preeclampsia, abruption, or SGA, or intrauterine fetal demise due to placental insufficiency, in the subsequent pregnancy. Angiogenic factors were not measured in this subsequent pregnancy.
The primary analysis evaluated the association of a high ratio with the risk of recurrent IPD and the components of IPD, relative to a low ratio. Several sensitivity analyses were performed. We evaluated the differences in characteristics of parturients who experienced a recurrence of IPD and those that did not, to see if there were other demographic or medical factors associated with a recurrence. We also stratified the analysis by use of aspirin in the subsequent pregnancy. Since a PLGF ratio of < 100 has been associated with severe preeclampsia in a concurrent pregnancy [19], we evaluated whether recurrent IPD was associated with a PlGF ratio of < 100. This provided another lens through which to evaluate an anti-angiogenic milieu. Finally, in order to address issues related to selection bias in our population, we compared the outcomes of the index pregnancies of those that had a subsequent pregnancy with those that did not.
All data were analyzed with SAS 9.4 (SAS Institute Inc., Cary, NC, USA). All tests were two-sided and a p value < 0.05 was required to confer significance. Comparisons were made using a Chi-square or Fisher’s exact test for categorical variables and parametric or non-parametric tests for continuous variables based on data distribution. Data are presented as median (interquartile range) or proportion. Log-binomial regression was performed to calculate risk ratios and 95% confidence intervals for the risk of IPD and the individual components of IPD in subsequent pregnancies. Potential confounders were chosen a priori based on literature review. All models were adjusted for maternal age, body mass index (BMI), nulliparity, and chronic hypertension in the index pregnancy. Covariates in the subsequent pregnancy were not considered confounders, since they occurred chronologically after our exposure.
This study was approved by the institutional review boards at Beth Israel Deaconess Medical Center (BI 2019P000212) and the Massachusetts DPH.
Results
From July 2009 to June 2012, 352 participants had IPD and a measurement of angiogenic factors during their pregnancy. Of these, 109 parturients experienced at least one subsequent pregnancy from July 2010 to August 2018 and were included in our study; 33 (30%) had a high sFlt1/P1GF ratio and 76 (70%) had a low ratio in the index pregnancy. Baseline demographics from the index pregnancy are presented in Table 1, stratified by high and low ratio. Groups were similar with respect to demographics and obesity. Those with a high ratio had slightly higher rates of nulliparity and conception through in vitro fertilization (IVF). No one in the high ratio group had chronic hypertension during the index pregnancy. The proportions with preeclampsia, abruption, and preterm birth (including gestational age <34 weeks of gestation at delivery) in the index pregnancy were all higher in those parturients with a high ratio in the index pregnancy. None of the patients experienced an IUFD in the index pregnancy.
Table 1:
Baseline demographics from index pregnancy among those with IPD in the index pregnancy
| Characteristics | Overall (n=109) | sFlt-1:PlGF ≥ 85 (n=33) | sFlt-1:PlGF< 85 (n=76) |
|---|---|---|---|
| Demographics | |||
|
| |||
| Maternal age at conception (years) | 32.0 (29.2 – 33.8) | 32.4 (30.5 – 33.8) | 31.4 (28.4 – 34.0) |
|
| |||
| Caucasian | 70 (64.2) | 24 (72.7) | 46 (60.6) |
|
| |||
| Gravidity | |||
| 1 | 73 (67.0) | 25 (75.8) | 48 (63.2) |
| 2+ | 36 (33.0) | 8 (24.2) | 28 (36.8) |
|
| |||
| Parity | |||
| 0 | 88 (80.7) | 28 (84.8) | 60 (78.9) |
| 1+ | 21 (19.3) | 5 (15.2) | 16 (21.1) |
|
| |||
| Medical Factors | |||
| Chronic hypertension | 5 (4.6) | 0 (0.0) | 5 (6.6) |
| In vitro fertilization | 5 (4.6) | 2 (6.1) | 3 (3.9) |
| Pre-pregnancy BMI > 30 | 30 (27.5) | 8 (24.2) | 22 (28.9) |
|
| |||
| Gestational age at measurement of angiogenic factors (weeks) | 35.9 (33.7 – 37.7) | 34.3 (31.1 – 37.9) | 36.2 (34.7 – 37.6) |
|
| |||
| Delivery characteristics | |||
|
| |||
| Gestational age at delivery (weeks) | 37.0 (35.0 – 39.0) | 35.0 (32.0 – 38.0) | 37.0 (36.0 – 39.0) |
|
| |||
| Preterm delivery | |||
| < 34 weeks | 20 (18.3) | 12 (36.4) | 8 (10.5) |
| < 37 weeks | 41 (37.6) | 21 (63.6) | 20 (26.3) |
|
| |||
| Mode of delivery | |||
| Vaginal | 57 (52.3) | 16 (48.5) | 41 (53.9) |
| Cesarean | 52 (47.7) | 17 (51.5) | 35 (46.1) |
|
| |||
| Birth weight (grams) | 2785 (2175 – 3180) | 2140 (1575 – 3090) | 2820 (2533 – 3338) |
|
| |||
| Preeclampsia | 87 (79.8) | 30 (90.9) | 57 (75.0) |
|
| |||
| Preeclampsia delivered prior to 34 weeksa | 17 (19.5) | 11 (36.7) | 6 (10.5) |
|
| |||
| Abruption | 7 (6.4) | 3 (9.1) | 4 (5.3) |
|
| |||
| Small for gestational age | |||
| Less than 10th percentile | 33 (30.3) | 11 (33.3) | 22 (28.9) |
| Less than 3rd percentile | 7 (6.4) | 3 (9.1) | 4 (5.3) |
Data presented as median (interquartile range) or n (%)
Denominator is those with preeclampsia
Subsequent pregnancy outcomes are presented in Table 2. The groups were similar at the start of the pregnancy with respect to demographics, parity, obesity, and conception through IVF, and inter-pregnancy interval. The prevalence of chronic hypertension was lower in the high ratio group, compared to the low ratio group. Those with a high ratio in the index pregnancy utilized aspirin more commonly than those with a low ratio. Delivery outcomes for the subsequent pregnancies are also included in Table 2, and demonstrate similar gestational ages at delivery, preterm births, and multiple gestations.
Table 2:
Baseline characteristics in subsequent pregnancy
| Characteristics | Overall (n=109) | sFlt-1:PlGF ≥ 85 (n=33) | sFlt-1:PlGF< 85 (n=76) |
|---|---|---|---|
| Demographics | |||
|
| |||
| Maternal age at conception (years) | 34.8 (32.1 – 36.9) | 35.3 (32.5 – 37.8) | 34.1 (31.9 – 36.8) |
|
| |||
| Gravidity | |||
| 2 | 64 (58.7) | 22 (66.7) | 42 (55.3) |
| 3+ | 45 (41.3) | 11 (33.3) | 34 (44.7) |
|
| |||
| Parity | |||
| 1 | 88 (80.7) | 28 (84.8) | 60 (78.9) |
| 2+ | 21 (19.3) | 5 (15.2) | 16 (21.1) |
|
| |||
| Medical Factors | |||
| Chronic hypertension | 22 (20.2) | 4 (12.1) | 18 (23.7) |
| In vitro fertilization | 4 (3.7) | 1 (3.0) | 3 (3.9) |
| Pre-pregnancy BMI > 30 | 37 (33.9) | 11 (33.3) | 26 (34.2) |
|
| |||
| Inter-pregnancy interval (months) | 29.6 (20.0 – 44.1) | 34.7 (25.8 – 47.9) | 29.1 (19.6 – 40.8) |
| 0 - <12 months | 3 (2.8) | 0 (0.0) | 3 (3.9) |
| 12 - <60 months | 94 (86.2) | 30 (90.0) | 64 (84.2) |
| 60+ months | 12 (11.0) | 3 (9.1) | 9 (11.8) |
|
| |||
| Aspirin Use | 17 (15.6) | 11 (33.3) | 6 (7.9) |
|
| |||
| Delivery characteristics | |||
|
| |||
| Gestational age at delivery (weeks) | 38.4 (37.0 – 39.1) | 38.6 (37.0 – 39.4) | 38.2 (37.0 – 39.1) |
|
| |||
| Preterm delivery | |||
| < 34 weeks | 7 (6.4) | 3 (9.1) | 4 (5.3) |
| < 37 weeks | 23 (21.1) | 8 (24.2) | 15 (19.7) |
|
| |||
| Mode of delivery | |||
| Vaginal | 52 (47.7) | 14 (42.4) | 38 (50.0) |
| Cesarean | 57 (52.3) | 19 (57.6) | 38 (50.0) |
|
| |||
| Birth weight (grams) | 3200 (2895 – 3625) | 3245 (3065 – 3595) | 3140 (2872 – 3630) |
Data presented as median (interquartile range) or n (%)
The recurrence risk of IPD was 26.6%. There were no statistically significant associations between a high or low ratio with recurrence of IPD or any of the components of IPD (Table 3). Preeclampsia accounted for the majority of the IPD that recurred. The risk of abruption or SGA did not differ based on high or low ratio in the index pregnancy, although there were few cases of abruption or SGA present. Due to the finding of a higher utilization of aspirin among the high ratio group, we stratified the analysis by those who used aspirin and those who did not. We similarly found no significant association between a high or low ratio with recurrence of IPD or any of the components of IPD (Supplementary Table 1).
Table 3:
Risk of ischemic placental disease and its components in pregnancies with high and low angiogenic ratio in prior pregnancy
| sFlt-1:PlGF ≥ 85 (n=33) | sFlt-1:PlGF< 85 (n=76) | |
|---|---|---|
| Small for gestational age < 10th percentile | ||
|
| ||
| Ischemic placental disease | 6 (18.2) | 23 (30.3) |
| Crude RR (95% CI) | 0.60 (0.27 – 1.3) | Reference |
| Adjusted RR (95% CI) a | 0.58 (0.21 – 1.6) | Reference |
|
| ||
| Preeclampsia | 6 (18.2) | 17 (22.4) |
| Crude RR (95% CI) | 0.81 (0.35 – 1.9) | Reference |
| Adjusted RR (95% CI) a | 0.72 (0.26 – 2.0) | Reference |
|
| ||
| Placental abruption | 0 (0.0) | 4 (5.3) |
| Crude RR (95% CI)b | - | Reference |
| Adjusted RR (95% CI)b | - | Reference |
|
| ||
| Small for gestational age | 3 (9.1) | 5 (6.6) |
| Crude RR (95% CI) | 1.4 (0.35 – 5.4) | Reference |
| Adjusted RR (95% CI) a | 2.3 (0.45 – 11.3) | Reference |
|
| ||
| Small for gestational age < 3rd percentile | ||
|
| ||
| Ischemic placental disease | 6 (18.2) | 20 (26.3) |
| Crude RR (95% CI) | 0.69 (0.31 – 1.6) | Reference |
| Adjusted RR (95% CI) a | 0.65 (0.24 – 1.8) | Reference |
|
| ||
| Small for gestational age | 1 (3.0) | 1 (1.3) |
| Crude RR (95% CI) | 2.3 (0.15 – 35.7) | Reference |
| Adjusted RR (95% CI) b | - | Reference |
Data presented as n (%) or risk ratio (RR) and 95% confidence interval (CI)
Adjusted for maternal age, nulliparity, obesity, and chronic hypertension in the index pregnancy
Model did not converge
The demographics from the index pregnancy were stratified by those that had a recurrence of IPD and those that did not (Table 4). Those with a recurrence were less likely to be Caucasian and more likely to be obese. In addition, those with a recurrence of IPD were more likely to have had preeclampsia or an abruption and less likely to have had an infant who was SGA in the index pregnancy. The prevalence of chronic hypertension during the index pregnancy did not differ between those who had a recurrence of IPD and those who did not. Median sFlt1/PlGF ratios were not different between the groups, although the median PlGF value was slightly lower for those with a recurrence.
Table 4:
Demographics from index pregnancy, comparing those who experienced a recurrence of IPD vs. did not experience a recurrence of IPD
| Characteristics | Recurrent IPD (n=29) | No IPD (n=80) | p |
|---|---|---|---|
| Demographics | |||
|
| |||
| Maternal age at conception (years) | 32.4 (30.4 – 33.6) | 31.4 (28.3 – 34.1) | 0.44 |
|
| |||
| Caucasian | 13 (44.8) | 57 (71.3) | 0.01 |
|
| |||
| Gravidity | 0.32 | ||
| 1 | 17 (58.6) | 56 (70.0) | |
| 2 | 5 (17.2) | 14 (17.5) | |
| 3+ | 7 (24.1) | 10 (12.5) | |
|
| |||
| Parity | 0.18 | ||
| 0 | 21 (72.4) | 67 (83.8) | |
| 1+ | 8 (27.6) | 13 (16.3) | |
|
| |||
| Medical Factors | |||
| Chronic hypertension | 1 (3.4) | 4 (5.0) | 1.0 |
| In vitro fertilization | 0 (0.0) | 5 (6.3) | 0.32 |
| Pre-pregnancy BMI > 30 | 10 (34.5) | 20 (25.0) | 0.21 |
|
| |||
| Delivery characteristics | |||
|
| |||
| Gestational age at delivery (weeks) | 37.0 (36.0 – 37.0) | 37.0 (34.8 – 39.0) | 0.23 |
|
| |||
| Preterm delivery | |||
| < 34 weeks | 6 (20.7) | 14 (17.5) | 0.70 |
| < 37 weeks | 11 (37,9) | 30 (37.5) | 0.97 |
|
| |||
| Intrauterine fetal demise | 0 (0.0) | 0 (0.0) | - |
|
| |||
| Mode of delivery | 0.17 | ||
| Vaginal | 12 (41.4) | 45 (56.3) | |
| Cesarean | 17 (58.6) | 35 (43.8) | |
|
| |||
| Birth weight (grams) | 2655 (2270 – 3060) | 2795 (2153 – 3295) | 0.60 |
|
| |||
| Preeclampsia | 25 (86.2) | 62 (77.5) | 0.32 |
| Preeclampsia delivered prior to 34 weeksa | 5 (20.0) | 12 (19.4) | 1.0 |
|
| |||
| Abruption | 3 (10.3) | 4 (5.0) | 0.38 |
|
| |||
| Small for gestational age | |||
| Less than 10th percentile | 7 (24.1) | 26 (32.5) | 0.40 |
| Less than 3rd percentile | 2 (6.9) | 5 (6.3) | 1.0 |
|
| |||
| Angiogenic Factors | |||
| sFlt1/PlGF | 54.0 (11.9 – 82.8) | 55.0 (15.2 – 99.6) | 0.62 |
| sFlt1 | 5072 (2618 – 8134) | 5628 (3068 – 8924) | 0.39 |
| PlGF | 104 (73 – 223) | 114 (74 – 233) | 0.73 |
Data presented as median (interquartile range) or n (%)
Denominator is those with preeclampsia
The incidences of IPD, preeclampsia, abruption, SGA, and severe SGA were plotted and stratified by index pregnancy type of IPD, as well as high and low ratio (Figure 1). History of abruption had the strongest association with recurrence of IPD and preeclampsia, although this data is limited by small numbers of abruption. Knowledge of a high vs. low ratio did not improve upon knowledge of prior pregnancy outcome in terms of evaluating association with recurrence.
Figure 1:
Incidence of IPD and its components in a subsequent pregnancy, stratified by index pregnancy type of ischemic placental disease, as well as high and low angiogenic factor ratio.
PlGF was also evaluated with respect to subsequent pregnancy IPD. A PlGF ratio < 100, which is considered pathogenic in an index pregnancy, was associated with a higher risk of IPD in the subsequent pregnancy, but this finding was not statistically significant (RR 1.6, 95% CI 0.70 – 3.5) (Supplementary Table 2). Preeclampsia, abruption, and SGA were not statistically different in subsequent pregnancies in those with a PLGF < 100 pg/mL in the index pregnancy, compared to those with a high ratio.
Due to the possibility of selection bias by only including those who had a subsequent pregnancy, we evaluated the demographics for those who had IPD in the index pregnancy but did not have a subsequent pregnancy (Supplementary Table 3). Of those with IPD from the original cohort, 28% had at least one subsequent pregnancy. Those who had a subsequent pregnancy were more likely to be nulliparous in the index pregnancy (Supplementary Table 3). The rates of preeclampsia and abruption were similar. The rates of SGA were lower in those who had a subsequent pregnancy.
Discussion
Among patients with a history of IPD in the index pregnancy, a high anti-angiogenic profile was not associated with an increased risk of recurrence of IPD. Those with a recurrence of IPD were less likely to be Caucasian and more likely to be nulliparous and obese in the index pregnancy, but were otherwise similar demographically and with respect to index pregnancy outcome. Reassuringly, the majority of those with IPD in the index pregnancy did not have a recurrence, and gestational age at delivery was later, occurring at term in most cases.
A high sFlt1/PlGF ratio and a low PlGF have been shown to be both useful for identifying concurrent pregnancies at risk for worse outcomes [9,19,20], and in differentiating different sub-types of preeclampsia [21]. We therefore hypothesized that angiogenic biomarkers may be associated with increased risk of recurrent IPD in a subsequent pregnancy. However, we did not find a high sFlt1/PlGF or low PlGF to be associated with development of IPD, or its components such as preeclampsia, abruption or SGA in a subsequent pregnancy. To our knowledge, this is the first study evaluating association of subsequent pregnancy outcomes with prior angiogenic factor levels, although other studies have evaluated other proxies of angiogenesis. Maternal vascular malperfusion, a pathology designation used to describe lesions associated with uteroplacental insufficiency [22], has been associated with recurrent preeclampsia in at least one study [23], although another study did not find presence of maternal vascular malperfusion to improve risk prediction of IPD among a population of parturients presenting with spontaneous preterm birth in the index pregnancy [24]. Altered angiogenesis, defined by a high versus low sFlt1/PlGF ratio, has been associated with placental lesions indicative of uteroplacental insufficiency in a concurrent pregnancy [25]. Thus, our findings agree with at least one of these studies that altered angiogenesis in an index pregnancy is not associated with the risk of future pregnancy IPD.
Lack of association between prior angiogenic factors and future IPD could reflect that this marker is specific to the current pregnancy rather than a reflection of maternal predisposition to IPD. Adverse pregnancy outcomes often recur, even without recurrence of placental abnormalities [26]. Indeed, recurrence was associated with recurring risk factors in our study, such as being non-white and multiparous, but not a difference in angiogenic factors. Since nulliparity is associated with preeclampsia [27], those who had IPD without the risk factor of nulliparity in the index pregnancy may have had other unmeasured maternal risk factors for preeclampsia. Small numbers in our study limited full evaluation of all risk factors. In particular, chronic hypertension has consistently been found to be associated with higher rates of recurrence [28], but the prevalence in our cohort during the index pregnancy was low. Use of clinical risk factors to predict risk of preeclampsia is limited by poor specificity [29], further reflecting the challenge of predicting future preeclampsia and IPD.
Alternatively, our primary finding could reflect a lower rate of subsequent pregnancy at the same hospital institution among those who had severe outcomes in the index pregnancy. Those with more severe outcomes in the index pregnancy had high ratios [9], and they may have been less likely to pursue a subsequent pregnancy or to seek care at the same hospital. This would bias subsequent pregnancy risk of IPD toward the null, underestimating the risk of IPD recurrence among those with a high ratio. When we compared index pregnancy outcomes and maternal demographics of those who had a subsequent pregnancy to those who did not, we did not see a major difference in rate of preeclampsia or abruption, although there was a higher incidence of preterm birth among those who did not have a subsequent pregnancy. While factors related to severity, such as incidence of preterm birth and SGA, may have influenced whether one chose to have another pregnancy or not, it is likely that other factors contributed to one’s desire for future pregnancy. This issue was raised in another study [3], in which a fear of recurrent preeclampsia was the primary reason couples did not pursue subsequent pregnancy, rather than increased severity or medical complexity.
Furthermore, it is possible that subsequent pregnancy factors led to a difference in recurrence. There was a higher utilization of aspirin among those with a high ratio, perhaps reflecting the more severe outcomes in the index pregnancy for these parturients. However, stratification for this covariate did not demonstrate a difference in outcomes, indicating that aspirin use did not modify the association between index pregnancy angiogenic factor ratio and recurrence of IPD.
IPD conditions often recur, but not necessarily the same condition [1]. We demonstrated this overlap in our cohort. Overall, the recurrence rate of IPD was 26.6%, indicating that the majority of those who have IPD in the first pregnancy will not develop it in the second. Moreover, of those who had a recurrence of IPD, the majority did not deliver preterm. This information is consistent with other research [30,31] and helpful for counseling parents about future pregnancy.
Strengths
Strengths of this study include use of a composite outcome of IPD, which allowed for a more complete evaluation of associated clinical sequelae, and exploration of the association of angiogenic factors with future pregnancy outcomes, which has not previously been reported.
Limitations
The small sample size limited our ability to reliably evaluate individual rare outcomes, such as abruption. Moreover, this study only included participants who originally presented to the hospital with concern for preeclampsia. Thus, it likely does not capture many pregnancies afflicted with IUGR not associated with hypertension, which has been found to overlap in terms of angiogenic profile. In addition, the study would not have included those participants who solely had an abruption. This limitation likely explains the smaller numbers of participants with either SGA or abruption in our study. Furthermore, we likely lost some of the original population to follow-up, since the study hospital was a referral hospital. We may thus be overestimating the recurrence rate of IPD, but this should be non-differential based on exposure. Finally, we do not have information on angiogenic factor levels in subsequent pregnancies, which would have allowed us to better evaluate the role of angiogenic factors in the pathogenesis of IPD, relative to alternative pathways.
In conclusion, while high sFlt1/PlGF and low PlGF have been associated with adverse clinical pregnancy outcomes in the concurrent pregnancy, our study did not show a difference in the risk of recurrence of IPD in subsequent pregnancies. These data suggest placental angiogenic biomarkers are specific to the pregnancy and not a reflection of maternal predisposition to IPD. Future, larger studies should verify these findings and also include measurement of angiogenic factors in both index and subsequent pregnancies.
Supplementary Material
Highlights.
Recurrence of IPD was 27% in this cohort.
Recurrent IPD was more likely among those who were obese and not Caucasian
A high sFlt1/P1GF ratio in an index pregnancy is not associated with recurrent IPD
Data suggest placental angiogenic biomarkers are specific to the pregnancy
Acknowledgements
This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers.
Footnotes
Declarations of interest: Dr. Rana reports serving as a consultant for Roche Diagnostics and Thermofisher and has received research funding from Roche and Siemens. Dr. Karumanchi is co-listed as co-inventors on patents related to preeclampsia biomarkers that are held at Beth Israel Deaconess Medical Center. He has financial interest in Aggamin LLC and also reports serving as a consultant to Roche Diagnostics and Thermofisher. Dr. Karumanchi has received research funding from Siemens and Thermofisher. Other authors report no conflicts.
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