Surgical treatment for cervical insufficiency is cervical cerclage, widely used since McDonald and Shirodkar independently introduced their techniques 50 years ago. Another alternative is expectant management. Most of the randomised trials comparing the efficacy of cerclage versus expectant management have found no significant improvement in preterm birth and neonatal morbidity among women treated with cerclage (1–3). Therefore, justified questions are: should cerclage be used at all? and, if so, when and to whom? To answer the questions, one should be aware of the variations in the definition and diagnostic criteria of cervical insufficiency, as well as of the heterogeneity of randomised trials, and the inconsistency of their results. Cervical insufficiency is a well-recognised cause of preterm birth. The frequency of its occurrence remains unclear. Historically, cervical insufficiency or incompetence was defined as an inability of the uterine cervix to retain pregnancy to term. The diagnosis was based on the history of painless cervical dilation and pregnancy loss during the second or early third trimester of pregnancy, and on the presence of risk factors, such as past surgical trauma to the cervix or congenital anomaly. The condition was believed to re-occur in all subsequent pregnancies. Since the advent of transvaginal ultrasonography in 1990s, major attention in the diagnosis of cervical insufficiency was moved from the history to the assessment of cervical length and function by ultrasound (4). Cervical function is now viewed as a continuous variable which is affected by different factors, and expressed in different degrees in subsequent pregnancies. A short cervix with or without funnelling has been adopted as a marker of cervical insufficiency. However, there is no agreement on the thresholds for a short cervix and funnelling. So, what is the proper treatment if even the diagnostic criteria are variable? Again, the question is difficult to answer. For decades, women in whom the diagnosis of cervical insufficiency was based on history and the presence of risk factors were treated with prophylactic (elective) cerclage, placed at the end of the first trimester in subsequent pregnancies. Many observational studies lent support to this practice. In contrast, recent randomised trials on prophylactic cerclage based on historical features alone have failed to show a clear benefit in most women. This indicates that most women with a history consistent with traditional diagnosis of cervical insufficiency do not have recurrent pregnancy loss, and that more than half of prophylactic cerclage procedures have been unnecessary (5). Only a subgroup of women with a history of 3 or more mid-trimester pregnancy losses or early preterm deliveries were shown to benefit from this intervention (delivery before 33 weeks of gestation, 15% in the cerclage group versus 32% in the control group) (6). Prophylactic cerclage is recommended to be placed at 13–16 weeks’ gestation. Other women with a high risk by history should be followed by serial transvaginal cervical ultrasound, beginning between 16 and 20 weeks of gestation. If serial ultrasound measurements reveal a short cervix or progressive shortening in the cervical length, other potential causes of cervical changes (uterine contractions, fetal anomalies, decidual hemorrhage, intrauterine infections) should be ruled out before urgent/therapeutic cerclage can be considered. However, randomised trials on the effectiveness of urgent cerclage show controversial results (2), (3). Thus, even if other causes of cervical shortening have been ruled out, the decision to place an urgent cerclage should be made with caution. Expectant management is recommended in the first line if a short cervix is identified after fetal viability has been achieved. Should low-risk women be followed by transvaginal ultrasound measurements of cervical length? Should those with a short cervix be offered cerclage? This practice is not recommended at present. It is evident that a short cervical length increases the risk of spontaneous preterm birth, but only a minority of women with a short cervix have cervical insufficiency (7). This is a likely explanation why low-risk women with a short cervical length, revealed by routine transvaginal ultrasound at 22–24 weeks’ gestation, do not seem to benefit from cerclage (8). According to the guidelines of the American College of Obstetrics and Gynecology, cervical length measurements should not be performed routinely in low-risk women (9). Scientific evidence on the efficacy of emergency cerclage placed at an advanced stage of cervical dilatation in the absence of pain and contractions is limited. Older non-controlled studies are too small to draw evidence-based conclusions (10). However, the rate of complications, including premature rupture of membranes, very early preterm birth, chorioamnionitis, and placental abruption, is remarkable. The decision to perform emergency cerclage should, therefore, be made with caution considering the risks. In the first randomised trial, 23 women were randomised at 22–23 weeks’ gestation, 13 to emergency cerclage plus bed rest, and 10 to just bed rest (11). Mean interval between randomisation and delivery was significantly longer (54 days) in the cerclage group than in the bed-rest group (24 days) (p = 0.046). Cervical cerclage is an example of a surgical procedure that has been adopted to clinical use without preceding scientific evidence of its efficacy. Evidence gathered from recent randomised trials and meta-analyses is controversial and confusing. Although cerclage may provide no benefit in most women, it may still have a role in selected patients. The difficulty lies in the identification of those women. A more thorough understanding of cervical function and molecular biology may, in the future, provide help on this issue.
Cervical pregnancy accounts for approximately 0.1% of ectopic pregnancies (1). Due to its rarity, treatment is based on case reports and no randomized studies have been carried out to assess the various treatment options. A recent textbook recommends surgical management, usually hysterectomy (1). However, treatment of cervical pregnancy has improved greatly in recent years. The evolvement of non-surgical treatment modalities, such as use of methotrexate (MTX) (2), selective embolization of uterine arteries (3) or a combination of different treatments (3, 4) has made uterus-sparing treatment possible. In addition, minimally invasive treatments using currettage and prostaglandin injection, or Shirodkar cerclage of the cervix have been reported (5). Predictors of unsuccessful outcome of MTX treatment of cervical pregnancy, necessitating additional medication or surgical intervention, have included high initial serum levels of human chorionic gonadotrophin (hCG) (> 10.000 IU/l), presence of fetal heart activity, crown-rump length (CRL) measurement above 10 mm and duration of pregnancy exceeding 9 weeks (6). Among the reported cases managed successfully with MTX, the highest pre-treatment levels of serum hCG have been approximately 170.000 IU/l (7). A combination of the antiprogestin mifepristone and MTX improves the results of conservative treatment of extrauterine pregnancy (8, 9). We report a cervical pregnancy first diagnosed at the 10th week of pregnancy, with initial serum levels of hCG of approximately 100.000 IU/l, treated successfully with an initial combination of mifepristone and MTX as well as later evacuation and hemostatic measures at the cervix. The patient was a 37-year-old primigravida; her general health was good. She had used norethisterone-only contraceptive pills (Mini-Pill®, Pharmacia, Vantaa, Finland) for several years successfully. Her menstrual period was a regular 28 days. She was referred to the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, at 9 weeks and 3 days of gestational age due to uterine bleeding and suspected cervical pregnancy. Ultrasonographic examination revealed a live fetus in the cervical area and an empty uterine cavity. The fetal CRL was 24 mm and corresponded to the duration of pregnancy. After the diagnosis on day 0, intramuscular MTX was initiated at a dose of 50 mg/m2. The initial serum hCG value was 98.329 IU/l; the subsequent hCG values are shown in Fig. 1. Uterine bleeding was slight and the patient was not in pain, so she returned home and a control visit was scheduled for 5 days later. However, the patient returned to the emergency room on day 4 due to increased bleeding. The fetus was alive and the CRL had increased to 29 mm. A second dose of MTX was administered, folic acid was initiated and the patient was admitted to the ward. Serum levels of chorionic gonadotrophin (hCG), mifepristone (black bars) and progesterone (dotted bars) at different phases of the treatment are shown. The presence of fetal heart activity is indicated by the black bar. The small arrows indicate the days of methotrexate (MTX) and mifepristone (MIFE) administration; the large arrow shows the day of surgery (S). Serum levels of hCG and progesterone were analyzed using commercially available fluoroimmunoassay kits (DELFIA) from Wallac Finland Oy (Turku, Finland) and mifepristone was measured by a specific radioimmunoassay as described previously (10). Despite a slight decline in serum hCG levels, the fetus was still alive on day 6, the CRL (35 mm) corresponded to 10 weeks and 4 days of gestational age. A third dose of MTX as well as 200 mg of oral mifepristone was administered. Ultrasonography (US), repeated on day 8 – 2 days after mifepristone – revealed the absence of a fetal heartbeat. The last dose of MTX was administered on day 8. On the following day, the fetus was aborted spontaneously at the ward. Repeat US on day 10 revealed a residual mass measuring 5 × 6 × 7 cm in the cervix. Oral cephalexin and metronidazole was initiated because of a brownish discharge. The serum hCG level had declined to 36.183 IU/l, uterine bleeding continued to be slight and the patient was not in pain; thus she was discharged from the ward on day 13. A control appointment was scheduled for 2 days later. On day 17, the patient again returned to the emergency room due to uterine bleeding. The bleeding was only slight, the size of the residual mass in the cervix was unchanged and her serum hCG levels had decreased to 10.279 IU/l. The patient was again hospitalized. During observation, her hemoglobin level decreased from 101 to 95 g/l. However, on day 18, profuse uterine bleeding started at the ward, and the patient was transferred to the operating theatre. The cervix was first evacuated manually after which careful curettage of the cervix was performed. Thereafter deep hemostatic sutures were placed around the cervix. In addition, 0.5 mg of the sulprostone-prostaglandin (Nalador®, Schering Ag, Helsinki, Finland) was infiltrated at the 3 and 9 o'clock positions of the cervix. After these procedures, bleeding was only slight. A Foley catheter was placed in the uterine cavity, filled and fixed with forceps to compress the cervix. The patient received four units of packed red blood cells and epidural analgesia was started after the surgical procedures. The Foley and epridural catheters were removed the following morning. The patient recovered rapidly and returned home 3 days after the surgery, on day 21. Antibiotic treatment was continued for an additional week. Control appointments were scheduled at 1, 2 and 6 months after the treatment. Slight uterine bleeding continued for approximately a month, after which she resumed her normal menstrual period. The results of US of the cervix were normal at the 6-month follow-up. Despite the decline in the levels of hCG, fetal heart activity persisted for at least 6 days after initiation of the MTX therapy. On the basis of recent reports of improved efficacy of the combination of mifepristone and MTX in the treatment of tubal pregnancy (8, 9), 200 mg mifepristone was added to the treatment. Albeit possibly coincidentally, at 2 days after mifepristone the fetal heartbeat was absent. The initial level of serum hCG declined from approximately 100.000–10.000 IU/l after four injections of MTX and a single 200 mg dose of mifepristone. On day 18 of the treatment, a profuse bleeding ensued. The bleeding was controlled by evacuation of the cervix, locally administered suplrostone prostaglandin and surgical compressive measures. Thus, as in the majority of cases of cervical pregnancy presenting with a fetal heartbeat (6), surgical treatment was eventually needed. It may well be argued that surgical procedures to remove the large residual tissue in the cervix were unavoidable; the optimal timing for evacuation remains a matter of speculation. The mechanisms of action by which mifepristone accelerates the resolution of ectopic pregnancy is uncertain. Serum levels of mifepristone and progesterone were measured in samples collected at approximately 12 h and at 2 days after mifepristone administration (Fig. 1). Both mifepristone and progesterone levels were still high on day 2; thus mifepristone appeared not to induce rapid luteolysis. It may be speculated that a combination of the antitrophoblastic effect of MTX with the suspected antidecidual-like action of mifepristone in the cervix might enhance the resolution of trophoblastic tissue. In conclusion, a combination of MTX, mifepristone, and hemostatic measures at the cervix in the treatment of a case of advanced cervical pregnancy is presented. We propose that a combination of MTX with mifepristone in the treatment of cervical pregnancy might be of benefit and should be considered when treating this rare form of ectopic pregnancy. We wish to thank Ms. Ketty Gunnerholm of Exelgyn Nordisk (Stockholm, Sweden) for supplying us with mifepristone for this patient in 1999. Oskari Heikinheimo Department of Obstetrics and Gynecology Helsinki University Central Hospital PO Box 140 SF-00029 HUCH Helsinki Finland e-mail: oskari.heikinheimo@helsinki.fi
Impaired postnatal growth in very low birth weight (VLBW, <1500 g) infants is per se a major clinical challenge and may also serve as a model in studying the mechanisms of growth retardation in general. This study was undertaken to characterize the role of IGFs and their binding proteins (IGFBPs), key regulators of fetal and infant growth, during the postnatal period in VLBW infants. Forty-eight VLBW infants (gestational age 27.6 +/- 2.2 wk, birth weight 923 +/- 257 g) were studied. Blood samples were drawn at 1, 2, 4, and 8 wk of age for measurements of IGF-I, IGFBP-1 (lesser phosphorylated, lpIGFBP-1, and highly phosphorylated, hpIGFBP-1), IGFBP-3, and insulin, simultaneous growth velocities being assessed by a rigorous protocol of repeated, frequent lower leg length and body weight measurements. All regression analyses were adjusted for postnatal age and repeated measurements. Lower leg growth velocity showed a positive correlation with IGF-I (P = 0.01) and IGFBP-3 (P = 0.03), and weight growth velocity with IGFBP-3 (P = 0.057) and with lpIGFBP-1/hpIGFBP-1 ratio (P = 0.01). Moreover, concurrent glucocorticoid dose showed a negative correlation with both IGFBP-1 isoforms, observable, however, only in samples with high (>10 U/liter) insulin (lpIGFBP-1, P = 0.02; hpIGFBP-1, P = 0.007). In backward multiple regression analysis, the factor remaining significantly associated with lower leg growth velocity (R(2) = 0.63) was IGF-I, and factors associated with weight growth velocity (R(2) = 0.81) were IGFBP-3 and the lpIGFBP-1/hpIGFBP-1 ratio. In conclusion, circulating IGF-I and IGFBP-3, and the lpIGFBP-1/hpIGFBP-1 ratio, reflect short-term growth velocity in VLBW infants. lpIGFBP-1 isoforms, abundant in the circulation of these infants, may thus also have properties that are at least less inhibitory, if not promoting, on the growth-stimulating action of IGF-I. Finally, the regulation of IGFBP-1 by glucocorticoids may be divergent in situations with a high or low insulin concentration.
In Brief Objective To determine whether serum concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1), a major decidual protein, at 16 weeks' gestation differ between women who later develop pregnancy-related hypertension and normotensive women. Methods Concentrations of IGFBP-1 were measured using immunoenzymometric assay in serum samples collected for alpha-fetoprotein (AFP) and free β subunit of hCG (free β-hCG) determinations in a Down syndrome screening program at 16 weeks' gestation in a population-based cohort of 1049 nulliparous women. After exclusion of subjects with multiple pregnancies, insulin-dependent diabetes, major fetal malformations, and incomplete data, 917 subjects remained eligible. Results The mean levels (± standard deviation) of IGFBP-1 were significantly lower in 34 women who later developed preeclampsia (73 ± 43 μg/L, P < .01) and in 80 women with White A diabetes (84.7 ± 53 μg/L, P < .01) compared with controls (103 ± 58 μg/L). In seven women with White A diabetes and subsequent preeclampsia IGFBP-1 levels were especially low (41 ± 34 μg/L). The concentrations of AFP and free β-hCG in the subgroups with hypertensive disorders were not significantly different from those of normotensive women. Conclusion Decreased IGFBP-1 levels at 16 weeks' gestation in women who develop preeclampsia might indicate impaired decidual function. Hyperinsulinemia, a known risk factor for preeclampsia, might contribute to decreased concentrations of serum IGFBP-1. However, due to low sensitivity, assay of serum IGFBP-1 was not clinically valuable for predicting preeclampsia. Women who develop preeclampsia have decreased levels of circulating insulin-like growth factor binding protein-1 at 16 weeks' gestation.
Specific receptors for insulin-like growth factor I (IGF-I) on cultured human choriocarcinoma cells (JEG-3 and BeWo) were characterized. The binding of 125I-labeled recombinant (Thr59)IGF-I to the cells was reversible and time, temperature, and pH dependent. Steady state of binding occurred after 16 h at 4 C, pH 7.4. Natural human IGF-I (hlGF-I), hIGF-II, recombinant (N-Met)IGF-I, rat multiplication-stimulating activity, and insulin were 200%, 37%, 37%, 1.6%, and 0.1% as potent as (Thr89)IGF-I in inhibiting the binding of [125I]iodo- (Thr69)IGF-I to JEG-3 cells, respectively. Epidermal growth factor was ineffective. The half-maximal displacement of [125I] iodo-(Thr59)IGF-I by unlabeled (Thr89)IGF-I occurred at 11 ± 2 ng/ml (mean ± SEM) in both JEG-3 and BeWo cells. Scatchard analysis of the competitive binding data revealed linear plots indicating a single species of binding sites with an association constant of 0.8 x 109 M-1 for the binding of [125I]iodo-(Thr69)IGFI to both cell lines. The binding capacity was 30,000 and 20,000 sites/cell for JEG-3 and BeWo cells, respectively. Chemical cross-linking of [125I]iodo-(Thr59)IGF-I to JEG-3 cells revealed two receptor complexes of 130K and 260K. Their formation was completely inhibited by an excess of unlabeled (Thr59)IGF-I or hIGF-II. Increasing amounts of insulin affected both labeled bands equally, suggesting that the 130K and 260K bands represent the monomer and dimer forms, respectively, of the ligandbinding α-subunit of type I IGF receptor. (Thr59)IGF-I, in a dose-dependent manner, stimulated uptake of nonmetabolizable α-[3H]aminoisobutyric acid by JEG-3 cells, showing that the receptor is biologically active. Our results demonstrate that choriocarcinoma cells possess functional high affinity type I IGF receptors and suggest that IGF-I is involved in the growth-regulating processes of JEG-3 and BeWo cells. These cells may provide a useful model to study the role of IGFs in trophoblast physiology. (Endocrinology122: 395–401, 1988)
Objective: To study the isoforms of insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretion and to evaluate whether their assessment could serve in prediction of cervical ripeness at term. Methods: We measured the concentrations of IGFBP-1 in cervical swab samples of 64 women scheduled for labor induction by amniotomy or cervical ripening with prostaglandin E2 gel. Two immunoenzymometric assays were used: a previously described assay 1, which detects the nonphosphorylated and lesser phosphorylated isoforms, and a novel assay 2, which detects the lesser and highly phosphorylated isoforms of IGFBP-1. A set of 39 amniotic fluid (AF) samples also was analyzed to compare the phosphorylation status of IGFBP-1 in cervical secretion with that in AF. Results: In all cervical samples, IGFBP-1 concentration was higher by assay 2 than by assay 1, whereas in all AF samples, the results were the opposite. Initially, the median IGFBP-1 concentration in the ripe cervices (Bishop scores 6 or greater; n = 29) was approximately four times as high as that in the unripe cervices (Bishop scores 5 or less; n = 35). The cervical IGFBP-1 concentrations increased eight-fold in 6 hours after the first application of PGE2. Conclusion: Phosphorylated isoforms of IGFBP-1, different from those in AF, are present in the cervical secretion of women with intact fetal membranes and reflect cervical ripeness. A bedside test for those IGFBP-1 isoforms might help in predicting amenability for labor induction.
