Abstract
This retrospective cohort study aimed to determine a better management strategy for patients with preterm preeclampsia/superimposed preeclampsia (PE/SPE). Thirty-six women with PE/SPE and their neonates managed from January 2018 to March 2019 (Period 1: P1), and 53 women with PE/SPE and their neonates managed from October 2019 to March 2021 (Period 2: P2), were enrolled. Antihypertensive therapy was initiated when blood pressure increased to ≥160/110 mmHg and ≥140/90 mmHg in P1 and P2, respectively. During P1, pregnancies beyond 34 weeks of gestation with severe features were terminated without exception. During P2, pregnancies were maintained to 37 weeks of gestation. Maternal and neonatal outcomes were compared between the two groups, with the main outcome measures being the incidences of composite adverse maternal outcomes and composite adverse neonatal outcomes. Gestational weeks of delivery were significantly prolonged in P2 than in P1. The incidence of composite adverse maternal outcomes was comparable between the two groups. The incidence of composite adverse neonatal outcomes was significantly lower, and the duration of NICU stay significantly shorter, in P2 than in P1. In conclusion, aggressive antihypertensive therapy with cautious observation can prolong pregnancy and may benefit neonates born to mothers with PE/SPE.
Introduction
Hypertensive disorders of pregnancy (HDP) are diseases that present with hypertension during pregnancy. HDP represent a major disease in obstetrics, affecting roughly 10% of pregnant women.1) HDP are classified into four subtypes according to symptoms and onset. Preeclampsia (PE) and superimposed preeclampsia (SPE) exhibit organ damage in addition to hypertension and are more serious conditions than gestational hypertension (GH) and chronic hypertension (CH). Although the prognosis of PE/SPE has improved with advancements in their management, they remain the leading causes of maternal and neonatal mortality and morbidity worldwide.2)
Since the only known therapeutic strategy for PE/SPE is delivery, there is a dilemma for management of preterm PE/SPE: to prolong pregnancy, which increases the risk of maternal complications such as cerebral hemorrhage, or to induce premature birth, which increases the risk of neonatal complications.
Previous meta-analyses have found expectant management to be preferable to early delivery in patients with severe PE before 34 weeks of gestation from the perspective of neonatal prognosis.3) Patients in late-preterm PE without severe features are also usually managed expectantly with careful monitoring, as immediate delivery increases the risk of neonatal complications, while it might reduce the already low risk of maternal complications.4) The indication for delivery in women with severe PE/SPE in the late preterm period is of great concern in terms of the trade-off between maternal and neonatal benefits.
Antihypertensive therapy is performed to prolong pregnancy and reduce maternal complications.5) Excessive antihypertensive therapy is thought to reduce placental blood flow and may adversely affect the fetal state.6) Although antihypertensive therapy targeting high normal levels has been reported to reduce severe maternal hypertension without compromising neonatal prognosis in CH and GH,7) no studies have properly addressed antihypertensive therapy in women with PE/SPE.
The optimal timing of delivery and indications for antihypertensive therapy in late-preterm PE/SPE with severe features have not been established, and clinical guidelines for the management of these patients differ by country.8,9,10) In order to improve maternal and neonatal prognoses, the most suitable strategy for the management of PE/SPE must be determined. Accordingly, the present study aimed to examine the maternal and neonatal outcomes of preterm PE/SPE managed by two different strategies at a single center.
Methods
Study population and design
This was a retrospective cohort study based on electronic case records of women diagnosed with PE/SPE before 37 weeks of gestation and their neonates. All patients were managed at Kyushu University Hospital from January 2018 to March 2019 (Period 1: P1) and from October 2019 to March 2021 (Period 2: P2). The exclusion criterion was immediate delivery after PE/SPE diagnosis. The Kyushu University Hospital Ethical Review Board approved this study, and all experiments were conducted in accordance with the Declaration of Helsinki (1964).
Main outcome measures
Primary outcomes were composite adverse maternal outcomes (maternal death, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, acute fatty liver of pregnancy, eclampsia, peripartum cardiomyopathy, placental abruption, intracranial hemorrhage, pulmonary thromboembolism, pulmonary edema, pleural effusion, and ascites) and composite adverse neonatal outcomes (fetal death, early neonatal death, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and respiratory distress syndrome (RDS)). As secondary outcomes, gestational weeks at delivery, mode of delivery, amount of blood loss during delivery, incidence of severe hypertension, neonatal body weight, incidence of light-for-date (LFD) neonate, Apgar scores, incidence of intubation, incidence of respiratory support besides intubation, and duration of neonatal intensive care unit (NICU) stay were evaluated. In addition, a blood test was performed to determine the platelet count and levels of creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT).
Patient management
All patients with PE/SPE were hospitalized. PE was defined as hypertension after 20 weeks of gestation with proteinuria, or in the absence of proteinuria with maternal acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia, or uteroplacental dysfunction. SPE was diagnosed in the following cases: 1. Hypertension present before pregnancy or before 20 weeks of gestation, and preeclampsia develops after 20 weeks of gestation; 2. Hypertension and proteinuria present before pregnancy or before 20 weeks of pregnancy, and either or both symptoms worsen after 20 weeks of pregnancy; and 3. Renal disease with proteinuria not accompanied by hypertension present before pregnancy or before 20 weeks of gestation, and hypertension occurs at or after 20 weeks of gestation accompanied by hypertension. Maternal and neonatal conditions were routinely evaluated by clinicians. Management strategies regarding antihypertensive therapy and timing of delivery differed between P1 and P2 (Figure 1): antihypertensive therapy was initiated when blood pressure increased to ≥160/110 mmHg and ≥140/90 mmHg in P1 and P2, respectively, and while pregnancies beyond 34 weeks of gestation with severe features were terminated during P1, attempts were made to maintain pregnancy to 37 weeks of gestation during P2. Delivery was considered regardless of the gestational age if there were critical situations for the mother or fetus, such as uncontrolled severe-range blood pressure; progressive deterioration in liver function, renal function, or platelet count; pulmonary edema; abnormal neurological features; stroke; HELLP syndrome; placental abruption; and non-reassuring fetal status.
Figure 1. Management strategies for PE/SPE.
Non-normally distributed data were reported as medians and ranges. The P1 and P2 groups were compared using the Mann–Whitney U-test for continuous variables and the chi-square test for categorical variables. Statistical significance was set at P<0.05. All statistical analyses were performed using JMP Pro 16.
Results
Numbers of diagnosed pregnancies with PE/SPE before 37 weeks of gestation during P1 and P2 were 38 and 57, respectively. Among these, two pregnancies were immediately terminated (non-reassuring fetal status, 1; transfer beyond 37 weeks of gestation, 1) during P1. During P2, four pregnancies were immediately terminated (non-reassuring fetal status, 2; placental abruption, 2). These pregnancies were excluded from the study (Figure 2). Maternal background and pregnancy characteristics are shown in Table 1. There were no significant differences between the two groups. In most cases, calcium channel blockers were selected as first-line antihypertensive drugs. Pregnancies in P2 were significantly prolonged than those in P1 (Table 2). The mode of delivery and amount of blood loss during delivery were comparable between P1 and P2. Regarding primary outcomes, there was no difference in composite adverse maternal outcomes. Patients in P2 who received aggressive antihypertensive therapy tended not to experience severe hypertension compared with those in P1. In contrast, the platelet count tended to be lower in P2; however, the median platelet count in P2 was 174,000/μl, and the incidence of thrombocytopenia, defined as a platelet count <15,000/ μl, was comparable between the two groups. There was no significant difference in the incidence of liver or kidney dysfunction (Table 2). Characteristics of the 38 neonates in P1 and 56 neonates in P2 are shown in Table 3. Birth weight tended to be higher in P2, probably due to prolonged pregnancy. In contrast, the incidence of LFD in P2 tended to be higher. No differences were observed in Apgar scores between P1 and P2. The incidence of composite adverse neonatal outcomes was significantly lower in P2. In particular, the incidence of RDS was significantly lower in P2 (Table 3). The duration of NICU stay was significantly shorter in P2. No differences in respiratory management were noted between the two groups.
Figure 2. Study profile.
Table 1. Maternal background
| P1 (n=36) | P2 (n=53) | P-value |
|---|
| Maternal age (y) | 35 [20–43] | 36 [24–45] | 0.90 |
| Nulliparous (%) | 26 (72.2) | 29 (54.7) | 0.10 |
| Singleton (%) | 34 (94.4) | 50 (94.3) | 0.98 |
| Assisted reproductive technology (%) | 9 (25.0) | 8 (15.1) | 0.24 |
| Smoking (%) | 1 (2.8) | 1 (1.9) | 0.78 |
| Renal disease (%) | 2 (5.6) | 5 (9.4) | 0.50 |
| Thyroid disease (%) | 5 (13.9) | 6 (11.3) | 0.72 |
| Diabetes (%) | 4 (11.1) | 5 (9.4) | 0.80 |
| Autoimmune disease (%) | 0 (0) | 2 (3.7) | 0.24 |
| Preeclampsia (%) | 24 (67.6) | 41 (77.4) | 0.26 |
| Gestational weeks at diagnosis (w.d.) | 32.3 [24.3–36.6] | 33.6 [19.1–36.6] | 0.45 |
| Antihypertensive therapy (%) | 31 (86.1) | 49 (92.5) | 0.56 |
| Use of calcium channel blockers as first-line drugs (%) | 23/31 (74.2) | 39/49 (79.6) | 0.57 |
Table 2. Maternal outcomes
| P1 (n=36) | P2 (n=53) | P-value |
|---|
| Gestational age at delivery (w.d.) | 34.0 [26.0–37.4] | 35.4 [24.6–37.6] | 0.02 |
| Transvaginal delivery (%) | 8 (22.2) | 11 (20.8) | 0.63 |
| Blood loss (g) | 569 [100–7,923] | 542 [70–1,760] | 0.97 |
| Composite adverse maternal outcomes (%) | 17 (47.2) | 18 (33.3) | 0.21 |
| Maternal death (%) | 0 (0) | 0 (0) | — |
| HELLP (%) | 0 (0) | 2 (3.8) | 0.24 |
| AFLP (%) | 0 (0) | 0 (0) | — |
| Eclampsia (%) | 1 (2.8) | 0 (0) | 0.22 |
| PPCM (%) | 0 (0) | 0 (0) | — |
| Placenta abruption (%) | 2 (5.6) | 0 (0) | 0.08 |
| ICH (%) | 0 (0) | 0 (0) | — |
| PTE (%) | 0 (0) | 0 (0) | — |
| Pulmonary edema (%) | 0 (0) | 0 (0) | — |
| Pleural effusion or ascites (%) | 14 (38.9 ) | 16 (30.1) | 0.39 |
| Severe HT (%) | 26 (72.2) | 28 (52.8) | 0.07 |
| Platelet (*10,000/μl) | 21.0 [5.7–31.9] | 17.4 [4.1–33.6] | 0.06 |
| AST (IU/L) | 24 [11–72] | 19 [12–95] | 0.08 |
| ALT (IU/L) | 15.5 [3–75] | 13 [ 4–158] | 0.38 |
| Creatinine (mg/dl) | 0.61 [0.3–1.92] | 0.56 [0.36–2.38] | 0.51 |
| Platelet <15,000 /μl (%) | 16.7 | 28.3 | 0.20 |
| AST >40 IU/L (%) | 19.4 | 15.1 | 0.59 |
| ALT >40 IU/L (%) | 5.6 | 18.9 | 0.07 |
| Creatinine >1.0 mg/dl (%) | 11.1 | 9.4 | 0.80 |
Table 3. Neonatal outcomes
| P1 (n=38) | P2(n=56) | P-value |
|---|
| Body weight (g) | 1,615 [606–3,256] | 1,959 [314–3,200] | 0.08 |
| Light-for-gestational age (%) | 18 (47.3) | 37 (66.1) | 0.07 |
| Apgar score (1 min) | 8 [1–9] | 8 [2–9] | 0.38 |
| Apgar score (5 min) | 9 [4–9] | 9 [3–10] | 0.72 |
| Male (%) | 19 (50.0) | 29 (51.8) | 0.87 |
| Composite adverse neonatal outcomes (%) | 13 (34.2) | 8 (14.3) | 0.02 |
| Fetal death (%) | 0 (0) | 0 (0) | — |
| Early neonatal death (%) | 0 (0) | 1 (1.8) | 0.41 |
| IVH (%) | 0 (0) | 2 (3.6) | 0.24 |
| PVL (%) | 0 (0) | 0 (0) | — |
| NEC (%) | 2 (5.3) | 1 (1.8) | 0.35 |
| ROP (%) | 6 (15.8) | 6 (10.7) | 0.47 |
| RDS (%) | 12 (31.6) | 7 (12.5) | 0.02 |
| Duration at NICU (d) | 30 [0–185] | 15 [0–134] | 0.001 |
| Intubation (%) | 8 (21.1 ) | 8 (14.3) | 0.78 |
| Respiratory support | | | |
| besides intubation (%) | 17 (54.7) | 20 (35.7) | 0.38 |
Discussion
Main findings
In the present study, women with PE/SPE managed by strict antihypertensive therapy were able to prolong pregnancy without increasing the incidence of maternal complications. As severe hypertension is the main risk factor for maternal complications in women with HDP,5) aggressive antihypertensive therapy might contribute to pregnancy prolongation without increasing the incidence of maternal morbidity. In P2, the incidence of neonatal complications, especially RDS, was lower, and the duration of NICU stay was shorter than that in P1. Since additional weeks of gestation have been reported to decrease the risk of neonatal morbidity,11) these outcomes may have been achieved by fetal maturation owning to prolonged pregnancy. On the other hand, the high incidence of LFD in P2 could be attributed to prolonged pregnancy under undesirable conditions, such as placental insufficiency.12) Thus, fetal well-being should be carefully monitored during pregnancy.
Strengths and limitations
The main strength of this study is that it is the first study to compare maternal and neonatal outcomes between patients who were managed by two different strategies for PE/SPE at a single center. Neonatal care was also performed at a single center following the same management guidelines throughout the two periods, suggesting that differences in neonatal outcomes are solely accounted for by differences in the management of pregnancies. This study also has some limitations. The sample size was small, and the study used a retrospective design. Data were analyzed without distinguishing between PE and SPE, which differ in pathology. However, maternal and neonatal prognoses of patients with severe SPE have been reported to be comparable with those of patients with severe PE when managed similarly.13) Thus, PE and SPE are generally managed in the same way. Furthermore, given that the proportion of PE in each group was similar in the present study (Table 1), it is likely that not distinguishing between PE and SPE had negligible effects on the present results. Randomized control trials (RCTs) with larger sample sizes will be needed to verify the impact of management policy changes on maternal and neonatal outcomes in patients with PE/SPE.
Interpretation of the results considering other evidence
Consistent with results from RCTs conducted on CH and GH,7) the present study demonstrated that strict antihypertensive therapy for PE/SPE can contribute to the prolongation of pregnancy without increasing the incidence of maternal complications. Excessive antihypertensive therapy is thought to adversely affect the fetal state by reducing placental blood flow. In the present study, neonatal birth weight tended to increase with the extension of gestational age in the strict antihypertensive treatment group. However, the incidence of LFD infants tended to be higher in this group. The possibility that aggressive antihypertensive therapy might have affected uterine circulation and resulted in fetal growth restriction cannot be ruled out. In the future, an RCT on antihypertensive therapy should be conducted to establish preferable management for PE/SPE.
The only known management approach for PE/SPE is delivery. Therefore, the severity of the disease and gestational age are used to determine the timing of delivery, which can be challenging. Meta-analysis data support the preference for expectant management in patients with PE/SPE before 34 weeks of gestation if there is no life-threatening condition in the mother or fetus3). After 37 weeks of gestation, pregnancies are usually terminated because the prematurity of the baby does not need to be considered. In late-preterm cases of non-severe PE/SPE, immediate delivery has been shown to reduce maternal complications while increasing neonatal complications associated with prematurity.4) In cases of immediate delivery, poor neurological prognosis at 2 years of age has been reported;14) however, this increased risk did not persist at 5 years of age.15) Continuation of pregnancy is often attempted in late-preterm PE/SPE without severe features. At present, no study has addressed indications for delivery in late-preterm PE/SPE with severe features. In the present study, the short-term prognosis of neonates was favorable with no increase in maternal complications in patients whose pregnancies were prolonged beyond the late preterm period, even though aggressive antihypertensive therapy was administered. However, in P2, the incidence of LFD in infants tended to increase. Since LFD has been associated with poor long-term prognosis,16) further investigation will be needed to determine the impact of pregnancy prolongation in the presence of poor placental function on long-term neonatal outcomes.
Management policies for PE/SPE differ according to national guidelines. The guidelines of the American College of Obstetricians and Gynecologists use severe hypertension (systolic blood pressure ≥160 mmHg, diastolic blood pressure ≥110 mmHg, or both) as the antihypertensive treatment threshold to prevent congestive heart failure, myocardial ischemia, renal injury or failure, and ischemic or hemorrhagic stroke. Therefore, they recommend immediate delivery in late-preterm PE with severe features.9) On the other hand, the International Society for the Study of Hypertension in Pregnancy and the National Institute for Health and Care Excellence recommend treatment for patients with blood pressure ≥140/90 mmHg. Preterm PE is delivered when the mother and baby have life-threatening conditions, such as uncontrolled hypertension, progressive organ failure, pulmonary edema, convulsion, and non-reassuring fetal status.8,10) The former management is similar to that used in P1, and the latter is similar to that used in P2 of the present study. Since the short-term prognosis of neonates was better in P2 than in P1, our findings provide a simple but solid basis on which more appropriate management guidelines could be developed for PE/SPE, as existing national guidelines vary in recommendations.
In conclusion, prolongation of pregnancy with aggressive antihypertensive therapy for women with PE/SPE might improve neonatal prognosis without increasing the risk of maternal morbidity.
Acknowledgments
The authors express their sincere appreciation to all participants of this study.
Conflict of interests
All authors declare that they have no conflicts of interest.
References
- 1. Thomsen CR, Henriksen TB, Uldbjerg N, Milidou I. Seasonal variation in the hypertensive disorders of pregnancy in Denmark. Acta Obstet Gynecol Scand. 2020; 99: 623–630.
- 2. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014; 2: e323–e333.
- 3. Churchill D, Duley L, Thornton JG, Moussa M, Ali HS, Walker KF. Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks’ gestation. Cochrane Database Syst Rev. 2018; 10: CD003106.
- 4. Chappell LC, Brocklehurst P, Green ME, et al. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019; 394: 1181–1190.
- 5. Magee LA, von Dadelszen P, Singer J, et al. The CHIPS Randomized Controlled Trial (Control of Hypertension in Pregnancy Study): Is Severe Hypertension Just an Elevated Blood Pressure? Hypertension. 2016; 68: 1153–1159.
- 6. Magee LA, Abalos E, von Dadelszen P, Sibai B, Easterling T, Walkinshaw S. How to manage hypertension in pregnancy effectively. Br J Clin Pharmacol. 2011; 72: 394–401.
- 7. Magee LA, von Dadelszen P, Rey E, et al. Less-Tight versus Tight Control of Hypertension in Pregnancy. N Engl J Med. 2015; 372: 407–417.
- 8. Hypertension in pregnancy: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2019 Jun 25.
- 9. ACOG Practice Bulletin No. 202 Summary: gestational hypertension and preeclampsia. Obstet Gynecol. 2019; 133: 211–214.
- 10. Brown MA, Magee LA, Kenny LC, et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Hypertension. 2018; 72: 24–43.
- 11. Manuck TA, Rice MM, Bailit JL, et al. Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. Am J Obstet Gynecol. 2016; 215: 103.e1–103.e14.
- 12. Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. 2018; 218: S745–S761.
- 13. Vigil-De Gracia P, Montufar-Rueda C, Ruiz J. Expectant management of severe preeclampsia and preeclampsia superimposed on chronic hypertension between 24 and 34 weeks’ gestation. Eur J Obstet Gynecol Reprod Biol. 2003; 107: 24–27.
- 14. Zwertbroek EF, Franssen MTM, Broekhuijsen K, et al. Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 2-year outcomes of the HYPITAT-II trial. Am J Obstet Gynecol. 2019; 221: 154.e1–154.e11.
- 15. Zwertbroek EF, Zwertbroek J, Broekhuijsen K, et al. Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 5-year outcomes of the HYPITAT-II trial. Eur J Obstet Gynecol Reprod Biol. 2020; 244: 172–179.
- 16. Sacchi C, Marino C, Nosarti C, Vieno A, Visentin S, Simonelli A. Association of Intrauterine Growth Restriction and Small for Gestational Age Status With Childhood Cognitive Outcomes: A Systematic Review and Meta-analysis. JAMA Pediatr. 2020; 174: 772–781.
