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[Uteroplacental haemodynamics and uterine artery Doppler practice at 12 weeks gestation].

Last years, feasibility and possible interest of uterine artery Doppler during the third month of gestation were confirmed. Doppler flow velocity waveforms can be obtained and assessed in both uterine arteries using abdominal ultrasonography at 12-14 weeks' gestation. The no notch group (one third of women) has a low risk for hypertension, intra-uterine growth restriction, abruptio placentae. The "protecting" effect of the absence of uterine artery notch is as high as this physiological change occurs earlier.

Arteries↗

Obstetric and prenatal outcome in menopausal women: a 12-year clinical study.

The obstetric and prenatal outcome in post-menopausal women of advanced age in an oocyte donation programme is described in this paper, the oldest being aged 63 years. A total of 2729 candidates were visited up to November 2000. Only 1150 (42%) were accepted, with 1579 being rejected during a rigorous selection procedure. Several excluding clinical conditions were noted, including hypertension of varying severity, cardiovascular disease, smoking, dysfunctions of the hepatic, thyroid and renal systems and diabetes. Overall, 489 (38%) clinical pregnancies were established in 1288 recipient cycles, with 390 healthy babies delivered out of 363 pregnancies (28%), while 126 (25.7%) were lost. In all, 327 (90%) of the pregnancies reached full term, with 36 involving premature deliveries, 24 involving multiple gestation, 21 sets of twins, three sets of triplets (0.9%) and no quadruplets. Antenatal complications arising in 86 patients (23.6% of deliveries) included 33 preterm deliveries, 43 cases of gestational hypertension, four cases of pre-eclampsia, three cases of gestational diabetes and three of abruptio placentae. A total of 272 (75%) of all deliveries were by Caesarean section. Neonatal complications included two cases of growth retardation. There were no neonatal or maternal deaths. The 63-year-old woman reached full term pregnancy in July 1994, with delivery by Caesarean section of a boy in good health. Proper screening for risks has enabled this treatment to be given to a preselected group of patients.

Abortion, Spontaneous↗

Thrombophilia and its treatment in pregnancy.

Pulmonary embolism is the most common cause of maternal death during pregnancy and the puerperium in the industrialized world. The risk of venous thromboembolism (VTE) in pregnancy is 0.05%-1.8%, 6 times greater than in the non-pregnant state. The risk is increased in women over 35 years and those with obesity, previous VTE, operative delivery, or underlying thrombophilia. Women presenting with recurrent miscarriages, preeclampsia, intrauterine growth restriction, abruptio placentae, or stillbirth (all associated with microvascular thrombosis in placental blood vessels) have high incidence (65%) of thrombophilia. About 70% of the women who present with VTE during pregnancy are carriers of hereditary or acquired thrombophilia. Treatment of women with VTE during pregnancy, and especially those with thrombophilia, requires individualized dosing and duration of antithrombotic therapy and the formulation of thromboprophylactic strategies for future pregnancies. Warfarin is contraindicated during the first trimester due to fetotoxicity; unfractionated heparin (UFH) is associated with practical disadvantages and the risk of heparin-induced thrombocytopenia (HIT) and osteoporosis with long-term use. Low molecular weight heparins (LMWHs) are convenient to use, do not cross the placenta, carry a lower risk of HIT and osteoporosis, and are safe and effective. LMWHs are replacing UFH as the anticoagulant of choice during pregnancy and improve pregnancy outcome in women with a history of obstetric complications and confirmed thrombophilia.

Anticoagulants↗

The effects of intrauterine cocaine exposure on the respiratory status of the very low birth weight infant.

OBJECTIVES: This study examined the effects of intrauterine cocaine exposure on very low birth weight infants with respect to their surfactant requirement and need for ventilatory support. STUDY DESIGN: A retrospective cohort study was conducted on infants with birth weight between 750 and 1500 g admitted to the neonatal intensive care unit between January 1992 and January 1995. RESULTS: Of the 149 infants studied, 48 infants were exposed only to cocaine and 101 infants had no drug exposure. There were no significant differences between the two groups for gestational age, sex, abruptio placenta, prolonged rupture of membranes, and antenatal steroid usage. The cocaine-exposed group had a significantly greater birth weight (1190 vs. 1109, p<0.02), less prenatal care (48% vs. 14%, p<0.00007), older maternal age (30 vs. 24, p<0.00002), more black race (79% vs. 57%, p<0.01), and more rapid plasma reagin (RPR) positivity (25% vs. 2%, p<0.00006). There were no significant differences in median APGAR scores, or incidence of necrotizing enterocolitis, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), and bronchopulmonary dysplasia (BPD) between the two groups. Cocaine-exposed infants received surfactant treatment less often (73% vs. 48%, p<0.0035), received fewer mean doses of surfactant (0.4 vs. 10.0, p<0.0014), and were intubated less frequently (44% vs. 65%, p<0.012). There was no significant difference between groups for intubation at 24 and 48 hours and for the development of bronchopulmonary dysplasia. CONCLUSION: Perinatal cocaine exposure appears to have some significant short-term effects on the need for surfactant replacement therapy and need for initial intubation in respiratory distress syndrome (RDS) but no overall effect on the development of BPD.

Bronchopulmonary Dysplasia↗

Sudden infant death syndrome among extremely preterm infants: United States 1997-1999.

BACKGROUND: Preterm infants have been reported to be at higher risk than term infants for sudden infant death syndrome (SIDS). Reasons for this higher risk are not clear. OBJECTIVE: The objective of this study was to analyze medical and demographic characteristics among infants 24 to 32 weeks gestation to identify characteristics more prevalent among infants dying of SIDS in the postneonatal period than among infants of similar gestation who survived or who died of other causes in the postneonatal period. DESIGN/METHODS: United States linked birth and death certificate period data for 1997 to 1999 were used for this analysis. The population used was limited to infants 24 to 32 weeks gestation weighing 500 to 2500 g. SIDS deaths were limited to the postneonatal period and compared to survivors and infants dying in the postneonatal period of other causes. RESULTS: There were 469 postneonatal SIDS deaths with complete data (rate=2.2/1000 live births surviving > or =28 days); 3950 other postneonatal deaths (rate=18.7/1000) and 206,640 survivors. Compared with survivors, infants dying of SIDS were more likely to be born to mothers with <12 years of education (odds ratio=2.5, 95% confidence interval (95% CI=1.8, 3.3); be born to mothers < or =17 years of age (OR=2.0, 95% CI=1.4, 2.8); and be born to mothers with >3 previous pregnancies (OR=2.6, 95% CI=1.9, 3.5). Compared with infants dying in the postneonatal period of other causes, these same demographic factors continued to be significant risk factors for SIDS. There were no medical risk factors such as breech presentation, abruptio placenta, Apgar score <4 at 5 minutes, or mechanical ventilation for >30 minutes after birth, for which infants dying of SIDS were at greater risk than survivors or infants dying of other causes. CONCLUSIONS: Risk factors for SIDS among infants 24 to 32 weeks gestation appear to be more associated with sociodemographic characteristics than medical characteristics. This suggests that for the immediate future, the risk for SIDS among very preterm infants will be best addressed through further modification of the environment and parent behavior.

Educational Status↗

CD36 autoantibodies and thrombotic diathesis, thrombocytopenia and repeated early fetal losses.

BACKGROUND AND OBJECTIVES: Autoantibodies to CD36, a platelet glycoprotein, have been found in patients with thrombotic thrombocytopenic purpura, and in those with lupus-like anticoagulant with thrombotic complications. MATERIALS AND METHODS: Conventional hematologic and laboratory methods were used. The patient was a pregnant woman, who had had two early fetal losses separated by a normal offspring. Despite severe thrombocytopenia, she was asymptomatic. RESULTS: Serological investigations were strongly suggestive of CD36 autoantibodies. Neither clinical nor laboratory data were typical of those usually associated with cd36 autoantibodies, namely thrombotic thrombocytopenic purpura (TTP), systemic lupus erythematosis (SLE), or prothrombotic compliance. Prophylaxis with salicylates and prednisone was started at the 8th week of gestation, and an offspring with mild thrombocytopenia was delivered by cesarean section at the 32nd week of gestation because of abruptio placentae. CONCLUSIONS: There may be a cause-and-effect relationship between early fetal losses and CD36 autoantibodies.

Abortion, Habitual↗

Ultrasound findings in gestations destined for unanticipated fetal demise.

There are few reports of ultrasound findings in the second and third trimesters preceding intrauterine fetal demise. To describe these findings, the ultrasound assessments of 36 structurally normal singleton fetuses with subsequent intrauterine fetal demise were compared to gestational age-matched controls. Compared to controls, it was found that biparietal diameter, head circumference, femur length and estimated fetal weight were all decreased, abnormalities of amniotic fluid volume were more frequent, but the cephalic index was not different. Upon delivery, the group with subsequent intrauterine fetal demise was not found to have any major anomalies, but had a high incidence of abnormal umbilical cord position, abruptio placentae, chorioamnionitis and meconium aspiration.

Journal Article↗

Inherited thrombophilias and adverse pregnancy outcome: screening and management.

Inherited thrombophilias are a heterogenous group of conditions which have been implicated in a variety of pregnancy complications. Evidence is mounting that implicates these inherited disorders in a range of pregnancy outcomes, including recurrent miscarriage, late fetal loss, preeclampsia, abruptio placentae, and intrauterine growth restriction. The most commonly identified inherited thrombophilias consist of Factor V Leiden and the prothrombin gene mutation G20210A. Rarer inherited thrombophilic conditions include deficiencies of protein S, C and antithrombin. More recently, deficiency of protein Z has been linked to pregnancy complications, including preterm delivery. Clinical manifestations often are associated with the presence of more than one inherited thrombophilia, consistent with their multigenic nature. Some, but not all, studies investigating the use of heparin to prevent adverse pregnancy outcome have demonstrated a benefit. However, an adequate randomized trial is required to definitively determine whether heparin anticoagulation is the best prevention option in patients who harbor one or more inherited thrombophilias and are at risk for adverse pregnancy outcome. This review will summarize the association of thrombophilic conditions and obstetrical complications.

Anticoagulants↗

The 4G/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an independent risk factor for serious pregnancy complications.

The specific aim of the current study of 133 women with at least 1 pregnancy and measures of hypofibrinolytic and thrombophilic gene mutations was to determine retrospectively whether the mutations were associated with adverse pregnancy outcomes including prematurity, miscarriage, stillbirth, intrauterine growth retardation (IUGR), eclampsia, and abruptio placentae. Four gene mutations (factor V Leiden, methylenetetrahydrofolate reductase [MTHFR], prothrombin, and 4G/5G polymorphism of the plasminogen activator inhibitor type 1 [PAI-1] gene) were assessed by polymerase chain reaction (PCR). One hundred twenty-two women were genotyped for all 4 genes and divided into gene mutation (n = 68) and non-gene (n = 54) groups. The gene mutation group included those with at least 1 thrombophilic mutation (heterozygous for factor V Leiden, heterozygous for prothrombin, and homozygous for MTHFR), or hypofibrinolysis with homozygosity for the 4G polymorphism of the PAI-1 gene. The non-gene mutation group included those with no mutation for all 4 genes (wild-type normal) or who were wild-type normal for the prothrombin and factor V Leiden mutations and heterozygous for MTHFR and/or 4G/5G for the PAI-1 gene, neither heterozygosity associated with coagulation abnormalities. The 68 women with gene mutations, versus 54 in the non-gene mutation group, has more prematurity (10% v 4%, chi2 = 5.4, P = .021), more IUGR (3% v 0%, P = .035), and more total complications of pregnancy (37% v 21%, chi2 = 11.6, P = .001). The number of pregnancies (P = .0001) and 4G/4G polymorphism of the PAI-1 gene (P = .029) were positively associated with complications of pregnancy by stepwise logistic regression when the age, number of pregnancies, and all 4 gene mutations were the explanatory variables. Heritable hypofibrinolysis, mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent significant, potentially reversible risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency.

Antibodies, Anticardiolipin↗

The tissue factor pathway in disseminated intravascular coagulation.

In most instances, tissue factor (TF) exposed to the circulation is the sole culprit underlying the initiation of disseminated intravascular coagulation (DIC), although notable exceptions because of a more direct activation of the coagulation system, by snake venoms, for example, do occur. Peripheral monocytes and subendothelial structures are the potential sources of such TF; in the former, TF emerges on the cell surface on synthesis induction and in the latter it becomes available subsequent to permeability changes or damage to the endothelium. Subendothelial TF is constitutively present in fibroblasts, pericytes, and macrophages and at a higher than normal level in tumor-associated macrophages. This scenario of coagulation activation probably describes the principal events underlying emerging acute DIC states under pathophysiological conditions such as abruptio placentae, septic abortion, amniotic fluid embolization, and pregnancy toxemia. Under disease conditions associated with DIC, the continuous exposure to excess TF typically exhausts the available tissue factor pathway inhibitor (TFPI), leading to rampant thrombin generation, persistent feedback activation of factor XI (FXI) by the generated thrombin, and hence virtually uncheckable ongoing fibrin generation (DIC). Recently, it was shown that patients subject to meningococcal sepsis had comparatively large amounts of mainly monocyte-derived circulating TF-containing microparticles. Because phosphatidylserine (PS) is exposed on such particles, in addition to TF, they probably contribute crucially to DIC during meningococcal sepsis. Although endothelial cells (EC) have been shown to express large amounts of TF in vitro, this observation hardly relates to the situation in vivo, where, in contrast, synthesis and exposure of EC TF is very limited and not likely to be of any significance in emerging and ongoing DIC.

Animals↗

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications.

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.

Blood Coagulation Factors↗

Inherited thrombophilia and gestational vascular complications.

Severe obstetric complications, including preeclampsia, intrauterine growth retardation, abruptio placentae, and stillbirth, constitute a major cause of maternal and perinatal morbidity and death. The etiology of these severe obstetric complications is still unknown. However, the frequent finding of structural and thrombotic changes in placental capillaries, which lead to inadequate fetomaternal circulation and decreased placental perfusion, and the high prevalence of heritable or acquired risk factors for thrombosis found in women with these complications strongly suggest a cause-and-effect relationship. This review describes the recent findings on the association between these obstetric complications and the various thrombophilias, and recent therapeutic approaches. Aspirin, which was regarded as the drug of choice for the prevention of such obstetric complications, has proved to be ineffective in a large clinical trial. The encouraging observations on the efficacy of low-molecular-weight heparins, which are also included in the recently published guidelines of The American College of Chest Physicians, are summarized in this review. However, controlled clinical trials are still necessary to allow the development of better clinical standards.

Aspirin↗

[Cerebral hemorrhage and periventricular leucomalacia in preterm neonates after intravenous tocolysis with fenoterol: results of postnatal ultrasound examination].

BACKGROUND: This study tested whether tocolysis with beta-adrenergic agonists (Fenoterol) had an effect on the frequency of cerebral lesions in preterm neonates. PATIENTS AND METHODS: Head ultrasound scans of preterm neonates who were born after long-term (> 24 h) tocolysis were compared with scans of preterm neonates without preceding tocolysis. The gestational and neonatal data were analyzed retrospectively. RESULTS: Preterm neonates after (n = 102) and without (n = 101) tocolysis were subdivided into three groups according to their gestational age (23 - 28 wk: n = 41; 29 - 33 wk: n = 66; 34 - 36 wk: n = 96). Within these groups, no significant differences were found with respect to birth weight, rate of cesarean section, or pulmonary morbidity. Preterm babies < 28 weeks of gestation from the control group had lower Apgar scores (after 1 and 5 minutes, respectively) and arterial umbilical cord pH values. Intravenous tocolysis did not lead to an increase in pseudocystic periventricular leucomalacia (PVL) or intracerebral hemorrhage (ICH) in any of the subgroups studies. However, cerebral lesions were found in preterm neonates after tocolysis who exhibited signs of infection (29 - 33 wk: PVL n = 2; 23 - 28 wk: ICH n = 1) and in preterm neonates without tocolysis who had undergone fetal hypoxia or abruptio placentae (29 - 33 wk: PVL n = 4; antenatal terminal vein bleeding n = 1; 23 - 28 wk: PVL n = 2; terminal vein bleeding n = 5; posterior cerebral artery bleeding n = 1). When compared to preterm neonates of 34 - 36 weeks of gestation, the risk of infection was increased 4-fold in neonates of 29 - 33 weeks of gestation (odds ratio 5.43, 1.10 - 26.83) and 10-fold in neonates of 23 - 28 weeks of gestation (odds ratio 20.50, 3.65 - 115.03). Chorioamnionitis also was a more common finding in preterm neonates < 28 weeks of gestation. CONCLUSION: Preterm neonates who were born after intravenous long-term (> 24 h) tocolysis with Fenoterol do not exhibit an increase in periventricular leucomalacia or intracranial hemorrhage. The occurrence of cerebral lesions in these patients merely depends on their degree of immaturity and on the presence or absence of perinatal infection. In preterm neonates without tocolysis, brain lesions are mainly associated with hypoxic events.

Cerebral Hemorrhage↗

Comparative study between isolated intestinal perforation and necrotizing enterocolitis.

INTRODUCTION: Intestinal perforations in the neonatal period are usually related to necrotizing enterocolitis (NEC) or intestinal occlusion. Intestinal perforation in the absence of these conditions is called isolated perforation (IP). Several risk factors and pathogenic mechanisms have been suggested, and most of them are common to those classically attributed to NEC. AIM: To identify and compare the clinical and pathological features of IP and NEC. MATERIAL AND METHODS: We reviewed all cases of neonatal intestinal perforation and NEC in the last five years. Thirty-three patients were retrospectively classified into Group NEC: 24 cases, and Group IP: 9 cases. We collected multiple data as study variables: 1) General features; 2) Obstetric history; 3) Neonatal treatment; 4) Comorbidity; 5) Perforation features; 6) Treatment and outcome. RESULTS: Comparing the groups, we found statistical significant differences in isolated perforation cases with these risk factors: extreme prematurity, very low birth weight, abruptio placenta, intubation and neonatal mechanical ventilation, umbilical catheterization, precocious sepsis, and indomethacin therapy. A more precocious operation and a good prognosis also reached statistical significance. In the other hand, we found statistically significant differences in NEC with congenital cardiopathy (excluding isolated patent ductus arteriosus), with intestinal pneumatosis, with diffuse bowel involvement and a worse prognosis. Risk factors and pathologic findings seem to support an ischaemic pathogenesis in both diseases.

Enterocolitis, Necrotizing↗

[Pregnancy and labor in idiopathic thrombocytopenic purpura].

Clinical data from eight pregnant women with idiopathic thrombocytopenic purpura (ITP) were retrospectively analyses. The mean age of the women was 28.2 years. Five women underwent splenectomy during childhood. The lowest maternal platelet count observed ranged from 8000 to 88000/mm3. Genital bleeding occurred in only one case. Treatment was based on administration of corticosteroids with or without human-pooled immunoglobulins. Caesarian section was performed in all cases. Six newborns were healthy and had a successful subsequent course. Two infants died, one in utero because of abruptio placentae and the other one 1 month post partum because of a cerebral haematoma. After a mean follow-up of eighteen months, thrombocytopenia is still present in two women, despite the continuous treatment. In conclusion, ITP rather rarely coincides with pregnancy. Treatment is usually successful for the mother but the risk for the fetus remains considerably high.

Adult↗

[Oligohydramnios--perinatal complications and diseases in mother and child].

In our study, complications of oligohydramnios were examined. In medical records of all 5,210 deliveries of our department between 1987 and 1990 181 cases of oligohydramnios were identified. The diagnosis was confirmed by ultrasound and based on the method described by Mannings and Platt: amniotic fluid depots of less than 1 cm were defined as oligohydramnios. All 181 cases met the above definition, which results in an incidence of 3.5% pregnancies with reduced amniotic fluid. We examined the records of mother and foetus, the delivery and perinatal complications and follow-up of the newborn. In more than 60%, foetal asphyxia, breech position and other anomalies during delivery were followed by Cesarean section or vaginal operative delivery by forceps or vacuum extraction. In 30 cases, oligohydramnios was caused by premature rupture of membranes. In the other cases, the diagnosis based on maternal or foetal complications such as gestosis (n = 7), abruptio placentae (n = 10), foetal growth retardation (n = 47) and malformations or chromosomal anomalies. 89 newborn were transferred to a paediatric hospital immediately after delivery. Potter's syndrome was the main anticipated diagnosed malformation (n = 20). The lack of amniotic fluid was furthermore followed by a higher rate of pulmonary complications such as RDS and hypoplasia of the neonatal lung (n = 21). In conclusion, our study underlines the fact, that oligohydramnios must be regarded as an important reason of high risk pregnancy followed by many complications for foetus and newborn. The incidence of perinatal mortality in our examination was 7.2%. This rate is 10 fold higher than in the total number of deliveries of our department.

Adolescent↗

Do uterine leiomyomas influence pregnancy outcome?

To evaluate the clinical significance of the presence, location, size, and number of uterine leiomyomas in pregnancy, a retrospective cohort study in which pregnancy complications and outcome of pregnant women with uterine myomas was undertaken by routine second trimester ultrasound examination. The case group consisted of 183 consecutive women with uterine myomas detected and followed during the years 1983-1989; the control group was made up of all pregnancies diagnosed and followed at the obstetric clinic during the period 1985-1987. The incidences of preterm delivery (less than 37 weeks), preterm premature rupture of membranes, in utero growth retardation (less than 5th percentile), placental abruptio, placenta previa, postpartum hemorrhage (more than 500 cc), and retained placenta were not significantly increased in the group of women with myomas compared with the general population. However, cesarean sections were more common in women with myomas (23 vs 12%; P < 0.001). Within the group of women with myomas, the incidence of cesarean section was not different in cases with multiple rather than solitary myomas, but it was significantly higher in cases of lower uterine segment compared with fundal myomas (39 vs 18%; P < 0.01) and when the mean diameter of the myoma was greater than 5 cm (35 vs 17%; P = 0.01). Stepwise logistic regression analysis showed that both myoma location and size were independent predictors of the odds of cesarean section.

Adult↗

Hypercoagulability and DIC in high-risk infants.

Asphyxiated newborns have evidence of disseminated intravascular coagulation (DIC). Several hemostatic parameters were assayed in venous umbilical cord blood of 93 infants, 58 of which suffered from asphyxia due to abruptio placentae, breech delivery, preeclampsia, dead twin, and amniotic fluid embolism. Levels of factor XIII were markedly lower in the high-risk infants; the lowest values coincided with lowest Apgar scores. Plasma levels of thrombin-antithrombin (TAT) complexes, D-dimer, fibrin(ogen) degradation products (FDP), and soluble fibrin monomer complexes (SFMC) were markedly higher in the asphyxiated newborns with good correlations to DIC scores. DIC scores for infants were explained. A significant negative correlation was found between plasma levels of SFMC and Apgar scores. Also primary hemostasis measurements by a Thrombostat 4000 revealed defects in the asphyxiated infants. The data strongly suggest the presence of DIC in the high-risk group of infants.

Antithrombin III↗