2023 年 11 巻 4 号 p. 63-67
A 47-year-old nulliparous woman with no significant medical history underwent a preimplantation genetic diagnosis and received a transfer of an embryo after egg donation.
At 16+1 weeks of gestation, she developed preeclampsia with hypertension and proteinuria, which gradually worsened with symptoms like hemolysis, elevated liver enzyme levels, and fetal growth restriction without anomaly. No underlying autoimmune diseases and secondary hypertension symptoms were detected. The patient underwent an emergency cesarean section at 22+3 weeks of gestation following intrauterine fetal death and a severe maternal condition. The maternal condition improved significantly post-delivery, with placental pathology revealing no molar changes. Pure preeclampsia, characterized by the absence of underlying maternal disease, fetal chromosomal abnormalities, or molar pregnancy before 20 weeks of gestation, is extremely rare. Here, we report a case of pure preeclampsia occurring at 16 weeks of gestation with an increasing trend of soluble fms-like tyrosine kinase 1/placental growth factor ratio and provide a review of relevant literature.
Preeclampsia (PE) is a pregnancy complication affecting 2–8% of pregnancies and a leading cause of maternal mortality worldwide. It is defined as the new onset of hypertension and proteinuria, or the new onset of hypertension and organ dysfunction such as central nervous system dysfunction, renal dysfunction, and elevated liver enzymes after 20 weeks of gestation. Few cases of atypical PE (occurring before 20 weeks) have been reported and are typically associated with conditions such as a history of hypertension or kidney disease, fetal triploidy, molar pregnancy, antiphospholipid syndrome, and exacerbation of maternal lupus.1) When these conditions are ruled out, it is referred to as ‘pure’ PE, which was first reported in 2003.2) Pure PE before 20 weeks of gestation is very rare. Furthermore, few reports have shown transitions in angiogenic factors, specifically soluble fms-like tyrosine kinase 1/placental growth factor (sFlt-1/PlGF) ratio, in such cases.3,4,5) Here we report a case of pure PE at 16 weeks of gestation without any underlying maternal disease, and provide details on changes observed in angiogenic factors, along with a review of relevant literature.
A 47-year-old primigravida woman, with no significant medical condition or family history of PE, underwent in vitro fertilization with oocyte donation, and the embryo was confirmed to be euploid by preimplantation genetic testing. Before pregnancy, she weighed 41 kg, measured 148 cm in height, was a non-smoker, and had a blood pressure of 123/79 mmHg during infertility treatment. At 16+1 weeks of gestation, she developed PE with high blood pressure (166/90 mmHg) and a urine protein/creatinine (Cr) ratio of 1.6 g/gCr. She was hospitalized in another facility and treated with 150 mg/day labetalol. At 17+1 weeks of gestation, her blood pressure remained elevated despite antihypertensive therapy (450 mg labetalol and 2,000 mg/day methyldopa), and she was administered nicardipine hydrochloride intravenously. Her nephrotic-range proteinuria reached 3.2 g/day.
At 19+1 weeks of gestation, she was transferred to our hospital to manage severe PE. Her blood pressure was 164/96 mmHg despite antihypertensive medication, with an increased body weight of 6 kg compared to her pre-pregnancy weight. Physical examination revealed general edema. Laboratory tests indicated hemolysis (lactate dehydrogenase 347 U/L), mildly elevated liver enzymes (aspartate aminotransferase/alanine aminotransferase 52/54 U/L), hypoalbuminemia (2.2 g/dl), and elevated serum uric acid (7.5 mg/dl) without thrombocytopenia (206×104 platelets/μl). Fetal growth restriction was confirmed (estimated fetal weight 160 g [-2.2 standard deviation]) without anomalies. We discussed the difficulty of achieving a live birth without considerable maternal complications with the patient and her family and recommended termination of pregnancy, but they declined this option.
At 20+6 weeks of gestation, a follow-up ultrasound showed an absent end-diastolic flow in the umbilical artery. No underlying autoimmune disease was found, with normal levels for all parameters (anti-nuclear antibody, lupus anticoagulant, anti-cardiolipin antibody IgG, anti-β2 glycoprotein 1 antibody IgA, IgG, IgM, anti-glomerular basement membrane antibody, MPO-ANCA, PR3-ANCA, anti-dsDNA antibody IgG, anti-mitochondrial M2 antibody, anti-RNP antibody, anti-SS-A antibody, anti-Scl-70 antibody, anti-CCP antibody, and rheumatoid factor). To exclude secondary hypertension, we measured the levels of adrenocorticotropic hormone, cortisol, aldosterone, renin activity, renin quantity, adrenaline, noradrenaline, dopamine, and brain natriuretic peptide in the patient’s blood, which were all within the normal range. Her daily urine output had decreased, and ascites effusions had gradually increased.
At 22+3 weeks of gestation, laboratory tests showed renal dysfunction (Cr 1.94 mg/dl), and urine output was only 100 ml/24 hours. She had severe general edema with an increased pre-pregnancy weight of 12 kg. Additionally, serum potassium concentration increased to 6.4 mmol/L. The patient received a calcium-gluconate injection and glucose-insulin therapy for hyperkalemia. Ultrasound confirmed intrauterine fetal death and an emergency cesarean section was performed; a male infant weighing 311 g without anomalies was delivered. The number of ascites was 3,250 ml, and intraoperative blood loss was 650 ml. The patient received a transfusion of 4 units of red blood cells, and norepinephrine was administered to treat maternal hypotension. After delivery, the patient was transferred to the intensive care unit for postoperative continuous hemodynamic monitoring. Her general condition improved rapidly after delivery, and by the sixth day postpartum, her weight had decreased by 12 kg from her weight at delivery. She was discharged on postpartum day 10 with antihypertensive medication. Finally, on postpartum day 13, her blood pressure was well controlled without antihypertensive medication, all laboratory test results were normal, and urine protein was negative.
The placenta weighed 65 g, which is less than the 5th percentile for 22 weeks of gestation. There were no hematomas or abnormalities in the attachment of the umbilical cord to the placenta. Pathological examination revealed limited evidence of maternal vascular malperfusion of the placental bed, characteristic of PE, such as decidual arteriopathy or vasculopathy, without signs of trophoblastic diseases. Only mild areas of infarction were found. The sFlt-1/PlGF ratio was examined at 19+1, 20+6, and 22+3 weeks of gestation, as well as on postoperative day 7, with values of 443, 632, 4,320, and 38 pg/ml, respectively. Three-month postpartum screening for autoimmune diseases and secondary hypertension also yielded results within the normal range.
We searched for cases of PE that occurred before 20 weeks of gestation, excluding those with a history of hypertension or kidney disease, antiphospholipid syndrome, systemic lupus erythematosus (SLE), fetal triploidy, or molar pregnancy, and identified a total of 15 cases in 12 articles, including the present case. Only two of these cases resulted in live births, while most led to intrauterine fetal death early in gestation or termination of pregnancy due to a deterioration in maternal condition (Table 1). There have been only seven cases (in four reports) of pure PE before 20 weeks of gestation, including the present case, in which trends in sFlt-1/PlGF ratio have been documented. In all of these cases, the ratio increased markedly starting early in gestation. This literature review and the course of the present case suggest two important clinical issues. First, pure PE can occur before 20 weeks of gestation and is associated with a very poor perinatal outcome. Second, even before 20 weeks of gestation, an angiogenic imbalance similar to that observed after 20 weeks of gestation can occur.
| Case | Authors | Age | GP | ART | Onset (Week) | sFlt-1/PlGF (ratio) | Maternal comorbidities | Outcome | |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Hazra et al 20032) | 41 | G4P3 | Singleton | 18 | Not measured | Hyperthyroidism | 18 weeks TOP | |
| 2 | Imasawa et al. 200613) | 35 | G1P0 | Twin | 15 | Not measured | Uterus myoma | 18 weeks TOP | |
| 3 | Stillman et al. 200714) | 30 | G1P0 | IVF | Twin | 15 | Not measured | Polycystic ovarian syndrome | TOP |
| 4 | Bornstein et al 200715) | 24 | G4P3 | Singleton | 15 | Not measured | Obesity | 17 weeks TOP | |
| 5 | Maya et al. 200816) | 17 | G1P0 | Singleton | 19 | Not measured | None | TOP | |
| 6 | Tanaka et al. 201517) | 30 | G1P0 | Singleton | 17 | Not measured | None | 22 weeks IUFD | |
| 7 | Parrott et al. 201718) | 27 | G3P0 | Singleton | 18 | Not measured | None | 18 weeks TOP | |
| 8 | Suzuki et al. 20203) | 28 | G5P1 | Singleton | 16 | 13,400/21.9 (611) | Protein S deficiency | 24 weeks CS | |
| 9 | Konstantopoulos et al. 202019) | 44 | G1P0 | Donor egg | Twin | 18 | Not measured | None | 30 weeks CS |
| 10 | Mimura et al. 20224) | 38 | G1P0 | ICSI | Singleton | 13 | 5,880/3.7 (1,589) at 15 weeks | None | 15 weeks IUFD |
| 11 | Mimura et al.4) | 42 | G1P0 | IVF | Singleton | 17 | 4,250/8.5 (500) at 17 weeks | None | 17 weeks TOP |
| 12 | Mimura et al.4) | 40 | G2P1 | Singleton | 18 | 4,380/3.0 (1,460) at 19 weeks | None | 20 weeks TOP | |
| 13 | Modzelewski et al. 20235) | G4P1 | Singleton | 15 | 3,540/9.2 (393) at 15 weeks | Diabetes mellitus, obesity | 15 weeks IUFD | ||
| 14 | Modzelewski et al.5) | G1P0 | Singleton | 17 | 10,610/20.5 (517) at 17 weeks | Idiopathic thrombocytopenia | 24 weeks IUFD | ||
| Present case | Nagao et al. | 47 | G1P0 | Donor egg | Singleton | 16 | 9,440/21.3 (443) at 19 weeks | None | 22 weeks IUFD |
TOP, Termination of pregnancy; IUFD, Intrauterine fetal death; CS, Cesarean section; sFlt-1/PlGF, soluble fms-like tyrosine kinase 1/placental growth factor
PE can occur before 20 weeks of gestation, even if not associated with conditions such as fetal triploidy, molar pregnancy, or maternal antiphospholipid syndrome. When a pregnant woman presents with symptoms of PE before 20 weeks of gestation, it is important to confirm whether the fetus has mirror syndrome or chromosomal abnormalities, such as trisomy 13 or triploidy, or whether the pregnancy is affected by molar pregnancy or gestational trophoblastic disease, by performing ultrasound examinations.1) Additional screening for maternal conditions, such as lupus nephritis, hemolytic-uremic syndrome, antiphospholipid antibody syndrome, thrombotic thrombocytopenic purpura, or secondary hypertension, should also be performed using blood tests. When the maternal disease appears to worsen and presents with PE-like symptoms, it is possible to prolong the gestational period through therapeutic interventions. If none of the aforementioned conditions are suspected, the condition should be managed as pure PE. However, perinatal outcomes for PE before 20 weeks of gestation are very poor. “Atypical” and “pure” are not official classifications. Pure PE presenting before 20 weeks of gestation falls under the category of superimposed PE according to the classification by the International Society for the Study of Hypertension in Pregnancy. Perinatal outcomes of superimposed PE have been reported, with a stillbirth rate of 1% and a preterm birth rate of 43.8% before 37 weeks of gestation and 17.3% before 34 weeks of gestation.6) Therefore, it may be necessary to consider whether the concept of “pure PE before 20 weeks of gestation” with poor perinatal outcomes should be classified in the same category as superimposed PE.
The present case suggests that an angiogenic imbalance similar to typical PE may be present before 20 weeks of gestation, as demonstrated by an increase in the sFlt-1/PlGF ratio. Biomarkers, such as sFlt-1 and PlGF, have become increasingly useful for predicting preterm PE in clinical practice, as they are significantly deranged in PE and covered by insurance in Japan. According to a previous study, sFlt-1 concentration increased after 21 weeks of gestation and more rapidly during weeks 29–32 in women who develop PE.7) However, in all seven cases of pure PE where the ratio was measured, it was markedly elevated before 20 weeks of gestation. Thus, the sFlt-1/PlGF ratio may help distinguish pure PE from the exacerbation of maternal disease. In pregnant women with SLE, an increase in the ratio has been observed in those who developed PE, but not in those who did not, even during SLE flares, suggesting its potential as an adjunct tool for differentiation.8) Rapid improvement in maternal symptoms following termination is a characteristic of pure PE, as seen in the present case. Additionally, the sFlt-1/PlGF ratio decreased rapidly after delivery, consistent with this diagnosis (Table 2).
| Variable | 16+1 weeks | 19+1 weeks | 20+6 weeks | 22+3 weeks | POD1 | POD7 | POD13 |
|---|---|---|---|---|---|---|---|
| White blood cell ( *103/μl) | 8.5 | 8.4 | 9.3 | 12.1 | 12.8 | 6.7 | 6.9 |
| Hemoglobin (g/dl) | 14.1 | 12.4 | 13.3 | 12.3 | 13.3 | 9.8 | 13.3 |
| Hematocrit (%) | 40.9 | 36.9 | 39.9 | 35.9 | 37.8 | 29.9 | 40.5 |
| Platelet (*103/μl) | 277 | 206 | 215 | 285 | 151 | 210 | 214 |
| Total protein (g/dl) | 4.0 | 4.7 | 4.8 | 5.4 | 3.9 | 3.8 | 5.8 |
| Albumin (g/dl) | 2.0 | 2.2 | 2.0 | 2.1 | 2.3 | 1.7 | 3.3 |
| Creatinine (mg/dl) | 0.71 | 0.75 | 0.73 | 1.94 | 0.98 | 0.50 | 0.59 |
| Uric acid (mg/dl) | 7.4 | 7.5 | 7.7 | 7.7 | 7.1 | 5.0 | 4.5 |
| Total bilirubin (mg/dl) | 0.3 | 0.4 | 0.4 | 0.3 | 0.7 | 0.4 | 0.4 |
| Aspartate aminotransferase (U/L) | 42 | 52 | 65 | 66 | 87 | 53 | 29 |
| Alanine aminotransferase (U/L) | 47 | 54 | 66 | 67 | 87 | 76 | 29 |
| Lactate dehydrogenase (U/L) | 274 | 347 | 405 | 443 | 340 | 324 | 271 |
| Sodium (mmol/L) | 132 | 133 | 130 | 126 | 133 | 140 | 137 |
| Potassium (mmol/L) | 4.4 | 4.9 | 4.6 | 6.4 | 4.8 | 4.4 | 4.7 |
| sFlt-1 (pg/ml) | — | 9,440 | 10,300 | 25,600 | — | 548 | — |
| PLGF (pg/ml) | — | 21.3 | 16.3 | 5.9 | — | 14.1 | — |
| sFlt-1/PLGF ratio | — | 443 | 632 | 4,320 | — | 38 | — |
| Urine protein/creatinine ratio | 1.6 | 3.4 | 2.8 | — | — | — | 0.2 |
The present case presented with a combination of well-established risk factors for PE, including advanced maternal age, primiparity, and utilization of assisted reproductive technology. In primiparous women aged ≥40 years, the relative risk was calculated to be 1.68 (95% confidence interval: 1.23–2.39), with a notable 10.7% incidence of PE specifically observed in pregnancies.9,10) In addition, an immunologic underpinning for early-onset PE has been reported.11) Conception resulting from oocyte donation may introduce a state of complete non-self, which may be associated with the early onset of PE.12)
In conclusion, PE, which is characterized by angiogenic imbalance, can occur before 20 weeks of gestation, and its prognosis is very poor, resulting in a nonviable pregnancy in most cases. The diagnosis of and optimal management for pure PE before 20 weeks of gestation remains unclear. Further research is needed to determine if the sFlt-1/PlGF ratio could be a useful adjunctive tool in this context.
We obtained written informed consent from the patient.
None.
The authors declare no conflict of interest for this article.
All authors meet the ICMJE authorship criteria.
