Objective
The purpose of this study was to evaluate the effect of maternal nifedipine on fetal survival when started 24-48 hours before selective fetoscopic laser photocoagulation (SFLP).
Study Design
We conducted a case control study of consecutive cases of twin-twin transfusion syndrome (TTTS) in which TTTS cardiomyopathy was treated with maternal nifedipine 24-48 hours before SFLP, compared with gestational age and stage-matched control cases. The primary outcome was recipient and donor survival.
Results
One hundred forty-one cases of TTTS were treated with nifedipine, and 152 gestational age- and stage-matched control cases were analyzed. There was a significant increase in overall fetal survival in nifedipine-treated cases compared with control cases (237/284 [83%] vs 232/308 [75%]; P = .015). There is an increase in survival of recipients who were treated with nifedipine in stage IIIA (100% vs 81%; P = .021) and IIIB (93% vs 71%; P = .014); however, there was no difference in donor survival.
Conclusion
Maternal nifedipine is associated with improved recipient survival in TTTS that undergoes SFLP. This is the first study to suggest a benefit of adjunctive maternal medical therapy in patients with TTTS who undergo SFLP.
Management of twin-twin transfusion syndrome (TTTS) is 1 of the most challenging clinical problems concerning multiple fetal gestations. Approximately 20% of all twin pregnancies are monochorionic, and the incidence of TTTS in monochorionic diamniotic gestation ranges from 10–20%. TTTS is a phenomenon almost exclusively of monochorionic twin pregnancies. The natural history of severe TTTS is well-established, with mortality rates approaching 100% if left untreated, especially when it occurs at <20 weeks’ gestation. This is particularly troublesome given that 2 structurally normal fetuses are affected.
Cardiovascular compromise occurs in most recipient twins and is a major cause of death for these fetuses. Because their fates are linked, cardiovascular disease in the recipient twin is a significant contributor to morbidity and death in the donor cotwin as well. Echocardiographic examination of the twins is an essential component of the initial work-up as is follow-up evaluation for the progression of TTTS.
Recipient twins in TTTS can develop a progressive cardiomyopathy. Although both ventricular dilation and myocardial hypertrophy may occur, the latter predominates, and typically only evidence of mild dilation is seen. Usually the right ventricle (RV) is compromised first and to a more significant degree than the left ventricle (LV). In one study, RV and/or LV hypertrophy was detected in 58% of recipient twins, and biventricular hypertrophy was observed in 33% of recipient twins. Biventricular diastolic dysfunction was present in two-thirds of recipient twins, whereas RV systolic dysfunction was present in 35%. Atrioventricular valve disease is also common, with moderate insufficiency reported in up to 71% of recipient twins with structurally normal hearts. Moderate-to-severe tricuspid and mitral regurgitation is more common in patients with Quintero stage III and IV. Peak velocity of tricuspid and mitral regurgitant jets suggests the presence of ventricular hypertension in echocardiographic data from 39 recipient twins. Estimates of RV systolic pressure based on tricuspid regurgitant jet velocity are elevated commonly to 60-80 mm Hg, and pressures in excess of 100 mm Hg can be seen in severe cases. Cardiovascular changes in the donor twin are usually less dramatic. Myocardial changes are rare, and ventricular function and atrioventricular valve competence usually are preserved.
The echocardiographic evidence that suggests that the recipient twin in TTTS has hypertensive cardiomyopathy led to the hypothesis that treatment of the fetal hypertension may improve recipient survival in twins who undergo laser photocoagulation. To treat the fetal hypertension in TTTS pregnancies with evidence of TTTS cardiomyopathy, we began empiric treatment with maternal nifedipine as a fetal antihypertensive agent. Nifedipine is a calcium channel blocker that is among the most commonly used medications in pregnancy; it achieves serum levels in the fetus, is not teratogenic, and has a safety profile that makes it a first-line drug for the management of maternal hypertension in pregnancy and preterm labor.
The purpose of this observational case control cohort study was to evaluate the effect of maternal nifedipine treatment on fetal survival when used as an adjunctive medical therapy that is started 24-48 hours before selective fetoscopic laser photocoagulation (SFLP).
Materials and Methods
An observational study was conducted of consecutive patients with TTTS cardiomyopathy who were treated with maternal nifedipine in patients who were evaluated and treated at the Fetal Care Center of Cincinnati between January 2008 and June 2009. Case control subjects were matched for gestational age and Cincinnati stage from May 2005 to December 2007. This study was reviewed and approved by the institutional review board of Cincinnati Children’s Hospital Medical Center (protocol #2008-0823). An amendment to institutional review board protocol #2008-0823 to cover the extended time period of observational review to June 2009 was approved by the institutional review board on June 11, 2009.
The diagnosis of TTTS was based on accepted criteria of monochorionic-diamniotic twin pregnancies (single placenta, thin dividing membrane, same gender) that was complicated by polyhydramnios in the recipient twin (deepest vertical pocket, >8 cm) and oligohydramnios in the donor (deepest vertical pocket, <2 cm), which excluded other causes of amniotic fluid and growth discordance. Exclusion criteria for the study included fetuses with congenital anomalies, chromosomal abnormalities, and discordant intrauterine growth restriction without TTTS. Discordant intrauterine growth restriction without TTTS was based on the absence of diagnostic criteria of TTTS and the presence of an estimated fetal weight <10th percentile with an elevated head circumference to abdominal circumference ratio and fetal weight discordance between twins of >20% (defined as [A – B / A] × 100, where A is estimated fetal weight of larger twin and B is the estimated fetal weight of smaller twin) measured by fetal ultrasound scanning at the time of evaluation. In addition, all growth-restricted fetuses, whether donor or recipient, had characteristic Doppler waveform abnormalities in the umbilical cord, such as complete absence of diastolic blood flow or elevated peak systolic middle cerebral artery flow. Abnormal Doppler studies characteristic of TTTS were defined as absent or reversed end-diastolic flow in the mid cord of the umbilical artery in the absence of fetal or maternal breathing, reversal of blood flow in the ductus venosus, or a pulsatile umbilical venous waveform. Patients with early stage TTTS (Quintero or Cincinnati stage I, II, III) without evidence of TTTS cardiomyopathy were excluded from the study as not having significant TTTS cardiomyopathy.
All patients who are referred to the Fetal Care Center of Cincinnati for evaluation and treatment of TTTS undergo comprehensive obstetric ultrasound scanning, fetal echocardiogram, and fetal magnetic resonance imaging. During the period under review, all patients have amniotic fluid collected at the time of SFLP for karyotype analysis, if not already done. An ultrasound scan is obtained on postoperative day 1 after SFLP to assess fetal viability, amniotic fluid status, and Doppler velocimetry of the umbilical artery, umbilical vein, ductus venosus, and middle cerebral artery. A follow-up fetal echocardiogram and ultrasound scan are obtained on all patients between postoperative days 3 and 3 before return of the patient to the care of their referring obstetrician or maternal-fetal medicine specialist.
Inclusion criteria for the study included monochorionic twin gestations, evidence of TTTS based on the criteria listed earlier, with evidence of TTTS cardiomyopathy as indicated by abnormal fetal echocardiographic findings as defined by the Cincinnati TTTS staging system stages IIIA, IIIB, IIIC, and IV. TTTS staging was assigned with the use of both the Quintero and the Cincinnati staging systems, the latter incorporates fetal echocardiographic findings to detect recipient twin cardiomyopathy and modifies staging based on the severity of recipient twin cardiovascular abnormalities ( Table 1 ). In the Cincinnati staging system, TTTS cardiomyopathy was scored as the aggregate impression of the severity of 3 parameters: (1) the presence and severity of atrioventricular valvular regurgitation (AVVR), (2) ventricular wall thickening and (3) ventricular function as assessed by myocardial performance index ( Table 1 ). The presence or absence of AVVR was assessed by color-flow Doppler interrogation. The severity of AVVR was graded semiquantitatively as mild (narrow jet, ≤0.5 atrial length), moderate (narrow jet, >0.5 atrial length), or severe (wide jet, >0.5 atrial length). The myocardial performance index (MPI) was measured in both the right and LVs. The MPI is a Doppler index that reflects both systolic and diastolic function and is defined as the sum of the isovolumic relaxation time and the isovolumic contraction time, divided by the ejection time, which are all measured from the Doppler inflow and outflow spectral profiles. The ventricular MPI is calculated for both the RVs and the LVs with pulsed Doppler evaluation of both atrioventricular inflow and ventricular outflow, as described previously. The RV MPI was measured from separate images of tricuspid inflow and pulmonary outflow Doppler tracings. RV MPI was calculated only when the heart rate difference between tricuspid inflow and pulmonary outflow Doppler tracings was ≤5 beats/minute. The mean normal RV MPI is 0.32 ± 0.08, and the mean normal LV MPI is 0.33 ± 0.05. An abnormal MPI is defined as a value >2 SDs above the mean. At our institution, this value is a RV MPI of >0.48 and a LV MPI of >0.43. The Cincinnati staging system defines mild TTTS cardiomyopathy as mild AVVR, mild ventricular hypertrophy, and RV or LV MPI >2 SDs above the mean. Moderate TTTS cardiomyopathy is defined as moderate AVVR, moderate hypertrophy, or LV or RV MPI >3 SDs above the mean. Severe TTTS cardiomyopathy is defined by severe AVVR, severe ventricular hypertrophy, or LV or RV MPI >4 SDs above the mean ( Table 1 ).
| Stage | Donor | Recipient | Recipient cardiomyopathy |
|---|---|---|---|
| Cincinnati staging system | |||
| I | Oligohydramnios (DVP <2 cm) | Polyhydramnios (DVP >8 cm) | No |
| II | Absent bladder | Bladder seen | No |
| III | Abnormal Doppler findings | Abnormal Doppler findings | None |
| IIIa | Mild | ||
| IIIb | Moderate | ||
| IIIc | Severe | ||
| IV | Hydrops | Hydrops | |
| V | Death | Death | |
| Classifications of recipient cardiomyopathy | |||
| Variables/cardiomyopathy | Mild | Moderate | Severe |
| Atrioventricular valve regurgitation | Mild | Moderate | Severe |
| Right/left ventricular hypertrophy | Mild | Moderate | Severe |
| Myocardial performance index a | >+2 Z-score | >+3 Z-score | >+4 Z-score or severe biventricular dysfunction |
| Left | >0.43 | >0.48 | >0.53 |
| Right | >0.48 | >0.56 | >0.64 |
a Standards at our institution (mean ± SD): left = 0.33 ± 0.05; right = 0.32 ± 0.08.
Clinical records that include maternal demographics, maternal history, and neonatal survival data were reviewed in all patients. Patient preoperative evaluation included comprehensive fetal anatomic survey that included Doppler evaluation of ductus venosus, middle cerebral artery umbilical artery and vein, fetal echocardiography, and magnetic resonance imaging.
Fetal echocardiography was used to “upstage” cases from Quintero stage based on presence or absence of mild (IIIA), moderate (IIIB), or severe (IIIC) recipient cardiomyopathy ( Table 1 ). All patients with Quintero and Cincinnati stage I, II, or III were excluded from the study as not having TTTS cardiomyopathy. All patients in the treatment arm had evidence of TTTS cardiomyopathy (Cincinnati stage IIIA, IIIB, IIIC, or IV) and were treated with maternal nifedipine 20 mg orally every 6 hours. Maternal intolerance of nifedipine defined as headache, hypotension, orthostasis, or palpitations were used as an indication to reduce the dosage to 10 mg orally every 6 hours or discontinue the medication entirely. All subjects in the treatment arm received nifedipine for 24-48 hours before undergoing SFLP and continued it postoperatively until all fetal echocardiographic findings of TTTS cardiomyopathy resolved or the patient delivered.
The control subjects were computer-generated from our TTTS database and were matched for gestational age and Cincinnati stage for each of the subjects in the treatment arm, with 2 control subjects for each case when possible. These control subjects were patients who were treated at the Fetal Care Center of Cincinnati by the same team of physicians who used the same management algorithm and the same SFLP technique and surgeons as were used in the nifedipine-treated subjects. The control subjects were treated before January 2008 going back to June 2005. The database from which the computer-generated control subjects were taken had fewer stage IIIC and IV subjects. As a result of this stage disparity, 37 of the 77 stage IIIC and 4 of the 9 stage IV nifedipine-treated subjects were matched with control subjects of stage IIIA or IIIB. Thus, there was an intentional bias towards more advanced TTTS cases in the nifedipine-treatment arm, compared with the matched control subjects. This had the potential effect of biasing the study against showing a benefit of nifedipine treatment.
The primary endpoint of the study was recipient and donor survival to birth. Secondary endpoints of the study included (1) acute fetal survival to postoperative fetal echocardiogram performed on days 3-5 after SFLP, (2) preoperative vs postoperative recipient fetal echocardiographic changes in Tei MPIs, (3) the percentage of cases that had a ≥10% fall in Tei MPIs in the RVs and LVs, (4) maternal tolerance of nifedipine, (5) a need to reduce the dose or discontinue nifedipine, and (6) maternal demographics. We also reviewed maternal records for complications that included maternal death, spinal headache, maternal bleeding that required transfusion, infection at the trocar insertion site or chorioamnionitis, pulmonary edema, or pulmonary embolism.
Statistical analysis
Statistical analyses were performed with the χ 2 , Fisher’s exact, or Cochran-Mantel-Haenszel (CMH) test for categoric data and with t test or analysis of variance (ANOVA) test for continuous variables, as appropriate. Stratified analyses were conducted for survival outcomes by Cochran-Mantel-Haenszel test, controlling for TTTS stage. Only a few observations were available for TTTS stage IV and were analyzed combined with stage IIIc. Data were summarized with mean ± SD or a relative frequency (percent). All tests were 2-sided, and a probability value of < .05 was considered statistically significant.
Results
During an 18-month period from January 2008 to June 2009, 141 pregnancies were identified with TTTS cardiomyopathy (Cincinnati stage IIIA, 25 pregnancies; IIIB, 30 pregnancies; IIIC, 77 pregnancies; IV, 9 pregnancies). Data on gestational age– and Cincinnati stage–matched control pregnancies (n = 152) were generated randomly by computer from a database of TTTS patients who were treated between May 2005 and December 2007. There was no significant difference in maternal age at the time of treatment between nifedipine treatment and control subjects. Survival outcome data were obtained for review in 100% of both the treated and control groups. There was no significant difference between the treatment and control groups for gestational age at time of treatment ( Table 2 ). There were no maternal deaths or complications in either group. Nifedipine was well tolerated; only 2 patients required a reduction in the nifedipine dose to 10 mg because of headache (1 patient) and orthostasis (1 patient). No patient discontinued nifedipine.
| Case | n | Gestational age at procedure, wk a | Gestational age, wk a | Survival of at least 1 twin b | Overall fetal survival c | |||
|---|---|---|---|---|---|---|---|---|
| Recipient d | Donor d | |||||||
| At birth | At death | At birth | At death | |||||
| Stage IIIa | ||||||||
| Case | 25 | 20.3 ± 2.2 | 31.2 ± 3.3 (24) | — | 30.6 ± 3.2 (17) | 21.9 ± 4.5 (6) | 25/25 (100%) | 43/50 (86%) |
| Control | 42 | 21.2 ± 2.3 | 31.2 ± 3.8 (33) | 24.0 ± 3.1 (7) | 29.9 ± 3.7 (30) | 22.7 ± 1.8 (9) | 39/42 (93%) | 64/84 (76%) |
| Stage IIIb | ||||||||
| Case | 30 | 21.2 ± 2.5 | 30.5 ± 5.2 (26) | 21.6 ± 3.1 (2) | 30.7 ± 4.9 (24) | 23.3 ± 2.4 (4) | 29/30 (97%) | 55/61 e (90%) |
| Control | 65 | 21.2 ± 2.3 | 31.6 ± 3.3 (45) | 22.0 ± 2.5 (18) | 31.9 ± 2.7 (46) | 23.0 ± 2.6 (17) | 55/65 (85%) | 95/132 f (72%) |
| Stage IIIc + IV | ||||||||
| Case | 86 | 21.0 ± 2.4 | 30.8 ± 3.3 (70) | 22.9 ± 4.2 (13) | 31.3 ± 3.2 (64) | 23.6 ± 4.2 (20) | 77/86 (90%) | 139/173 e (80%) |
| Control | 45 | 21.3 ± 3.0 | 31.0 ± 3.9 (38) | 19.3 ± 2.2 (6) | 30.5 ± 3.8 (31) | 23.2 ± 4.5 (13) | 40/45 (89%) | 73/92 f (79%) |
| T otal | ||||||||
| Case | 141 | 20.9 ± 2.4 | 30.8 g ± 3.7 (120) | 22.7 g ± 4.0 (15) | 31.1 g ± 3.7 (105) | 23.2 g ± 4.0 (30) | 131/141 (93%) | 237/284 f (83%) h |
| Control | 152 | 21.2 ± 2.5 | 31.3 g ± 3.6 (116) | 21.9 g ± 2.9 (31) | 30.9 g ± 3.4 (107) | 23.0 g ± 3.2 (39) | 134/152 (88%) | 232/308 i (75%) |
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