Pregnancy Outcomes Complicated with Cavernous Angioma: a Systematic Review-Juniper publishers

Open Access Journal of Neurology & Neurosurgery

Purpose of the study: The aim of this study was to analyze whether the risk of intracranial hemorrhage, focal neurological deficits and seizure from a cerebral Cavernous Malformations (CCM) changes significantly during pregnancy, delivery and post-partum, and based on the data from this study a recommendation or to give advice for clinical practice regarding maternal and fetal outcomes from the risk of haemorrhagic CCM during pregnancy. Yet there is a paucity of information relating to this in the medical literature. Basic procedures: We searched for publications on cavernous malformation in pregnancy in the MEDLINE database through PubMed. All publications till January 2019 were included in the search, and 16 related articles and 32 case reports were found. Main findings the studies reported that most patients (40%) presented with clinical symptoms of focal neurological deficits such as changes in the motor or sensory function, visual field deficits, ataxia, and hemiparesis. In most patients, the onset of symptoms was during the antepartum period, whereas some patients showed delayed symptoms at 2 weeks to 10 years postpartum. During pregnancy and the peripartum period, conservative management (no surgical intervention) may be used in cases with asymptomatic or minimally symptomatic lesions; however, in cases of severe symptoms occurring early in the course of pregnancy and endangering maternal and fetal life, neurosurgical intervention may be warranted before delivery. Principal conclusion: Most studies have suggested that pregnant women with CCMs can be managed safely even when symptomatic without a significant risk of adverse perinatal outcomes.

Keywords: Cerebral cavernous malformations; Epileptic seizures; Maternal and fetal outcomes

Abbrevations: ICH: Intracranial Hemorrhage; FNDs: Focal Neurological Deficits; MRI: Magnetic Resonance Imaging; GA: gestational age; H: Hemorrhage; S: Seizures; D: Diplopia; FNS: Focal Neurological Deficit; HE: Hemiparesis; CS: Cesarean Section; VD: Vaginal Delivery; TOP: Termination of Pregnancy; CCMs: Cavernous Malformation; N/R: Not Reporting; Term: Term gestation more than 37 weeks

Introduction

Cerebral Cavernous Malformations (CCMs) are focal proliferative hemorrhagic lesions comprising dilated sinusoidal vessels enclosed in a single endothelial layer and embedded in variably thin fibrous adventitia with little or no intervening functional neural parenchyma. These vessels account for 8% to 15% of all cerebrovascular malformations and exhibit distinct features of angioarchitecture and biological mechanisms of genesis and progression; however, they do not exhibit high pressure-flow profile that is characteristic of other intracranial vascular malformations, such as arteriovenous malformations [1]. These lesions can occur throughout the central venous system in the following approximate proportions to the tissue volume 80% supratentorial, 15% posterior fossa, and 5% spinal cord. Further, the lesions can occur in either of the following two forms: the sporadic form characterized by a single lesion and the familial form involving inheritance of multiple lesions in an autosomal dominant pattern with variable penetrance [2]. CMs, with a prevalence of 0.4%-0.5%, have a highly variable presentation ranging from incidentally discovered lesions during evaluation for nonspecific symptoms, such as headache, to symptomatic Intracranial Hemorrhage (ICH) presenting with acute new Focal Neurological Deficits (FNDs) and epileptic seizures [3]. Because of the increasing availability of brain Magnetic Resonance Imaging (MRI), the rate of CCM diagnosis is increasing without the need of pathological confirmation. This, in turn, has revealed that CCMs were historically more benign than previously thought, particularly compared with their arteriovenous counterparts [4].

In cases of CCM diagnosis in women of childbearing age or in pregnant women, the risk of ICH during pregnancy is substantial and consideration of the delivery mode is crucial because of a high risk of morbidity and/or mortality due to severe hemorrhagic events and progressive neurological deterioration [5]. As the magnitude of the risk of ICH and its rupture rate and outcome events during pregnancy were long uncertain, a few studies attempted to calculate the overall risk of ICH or ICH with intractable seizures in a diverse female population with CCM during pregnancy and delivery or during the 6-week postpartum period; however, the conclusions were not very definitive. The knowledge of these risks is useful for decision making regarding the treatment course to be selected for pregnant women, i.e., conservative management or neurosurgical excision; however, neither of these treatment options has been assessed in a randomized trial, and the use of neurosurgical excision remains controversial and challenging [6]. Therefore, we sought to address these uncertainties by conducting a systematic review of the literature on CCM patients with risks of first ICH or FND during pregnancy. In particular, we aimed to examine the efficacy and safety of management approaches for these lesions during gestation and the implications of the timing of labor and mode of delivery on the maternal and fetal outcomes.

Methods

In this systematic review, we searched of the electronic databases Medline (1946 onwards), Central, Embase (1980 onwards) for all articles on this topic published in English. Articles published till January 2019 were considered, using search strategy outlined in Supplement 1, and the following keywords were used for the search pregnancy with cerebral cavernous malformation or cerebral cavernomas in pregnancy or cavernous malformation during pregnancy or puerperium. Inclusion criteria were articles published in English with the primary topic being CCMs complicated with pregnancy and clear descriptions of the clinical presentation, management, and outcomes. Reference lists of the eligible articles were examined to identify other relevant articles. Articles that did not clearly describe the clinical presentation, management, and outcomes were excluded. Initial decisions to include or exclude studies were made based on the study title. Subsequent decisions were made based on the abstract and full-body text.

Results and Discussion

The systemic search revealed 60 related publications. After primary screening based on the inclusion criteria, 22 articles based on title/abstract assessment and 18based on full-text assessment were found eligible. Of these articles, 18 were selected, resulting in the inclusion of 16 articles and 32 single case reports published until January 2019. Of the 16 articles, 14 included only one to three cases, one article included five cases, and another included six cases [7,8]. The gestational age at presentations, clinical presentations, and site of CCMs and obstetric outcomes of all the patients reported in the literature are listed in Table 1. The results and discussion may be presented separately, or in one combined section, and may optionally be divided into headed subsections.

clinical presentations of CCMs

According to symptomatic CCMs, during pregnancy or puerperium, assuming an average of 40 weeks of pregnancy and the 6-week postpartum period (puerperium). Out of the 32 patients reported in single case reports, the gestational age at the time of presentation of symptomatic CCMs has been documented for 22 (79%) patients. Of these 22 patients, 16 presented with symptomatic CCM antepartum (second or third trimesters). However, four patients (18%) showed early onset of CCM symptoms in the first trimester (6 weeks of gestation), and two showed delayed onset in the postpartum period.

The 32 patients showed clinical presentations of symptomatic CCMs ranging from acute ICH and onset or worsening of neurological symptoms, including seizures, FNDs, diplopia, and hemiparesis. Notably, 19 of these 32 patients (59%) had ICH. New onset or exacerbation of seizures occurred in 10 patients (31%), and other 10 patients (31%) showed progressive symptoms of hemiparesis. Further, 13 of the 32 patients (40%) exhibited symptoms of FNDs, and other nine patients (28%) had a history of worsening symptomatic hemiparesis with diplopia.

Anatomically, CMs can occur throughout the central nervous system. Of these 32 patients, 15 (47%) had a high propensity of having symptomatic CCMs in the infratentorial area (2 patients had in the brainstem, 10 had in the pons, 1had in the medulla oblongata, and 2 had in the mesencephalic nucleus). Further, the anatomical site of the CCMs in 13 patients (40%) with symptomatic events was the supratentorial area; 7 of these 13 patients had CCMs in the predominant frontal lobe, 3 had in the temporal lobe, 2 had in the supratentorial deep area, and 1had in the insular cortex. One patient (3%) had an intramedullary symptomatic lesion.

Obstetric outcomes of CMMs during pregnancy or puerperium

Information on the obstetrical mode of delivery and/or gestational age at delivery was available only for 24 of the 32 patients (75%). Two of these 24 patients underwent abortion on each 20 weeks of gestation who showed worsening of neurological symptoms due to bulbar CCMs and required therapeutic termination, and the other at 10 weeks of pregnancy for obstetric indication due to severe preeclampsia. Of the 24 patients, nine pregnant women (31%) with symptomatic CCMs had uncomplicated vaginal delivery. The gestational age at the time of delivery was not reported for five of these nine patients, whereas three patients delivered successfully at term gestation and one patient required preterm delivery at 33 weeks because of severe preeclampsia symptoms. Of these nine patients, two underwent neurosurgical intervention after uncomplicated pregnancy and delivery one at 7 weeks postpartum and another at 10 years after her last pregnancy [7]. The first patient had focal seizure episodes involving the right face and arm and underwent successful resection of left insular CCMs after pregnancy at 7 weeks. The second patient underwent surgery for CCMs in the cervical medullary junction because of progressive right-sided weakness 10 years after her last pregnancy [9,10].

Thirteen of the 24 patients (45%) underwent cesarean delivery: six at term gestation, four at preterm gestation, and the gestational age at delivery was unreported for the remaining three cases. Of these 13 patients, eight underwent cesarean delivery because of concerns over CCMs and to reduce the risks of bleeding, one underwent cesarean delivery because of dystocia at 40 weeks, and the indication for cesarean delivery was unreported in the remaining three cases. Of the former eight patients, three underwent cesarean delivery at 36 weeks of gestation because of symptomatic hemorrhages, and one underwent cesarean delivery at 30 weeks of gestation because of severe neurological deficits, with the most common symptom being acute hemorrhage with diplopia.

Neurosurgical resection of CCMs was performed in 4 of the 13 patients who underwent cesarean delivery. Two of these patients had symptomatic CMMs in the pons, one of whom underwent surgery at 27 weeks of gestation and another at 29 weeks of gestation [11-22]. Of the other two patients, one patient with intramedullary CCMs underwent laminectomy 2 weeks after her uneventful cesarean delivery [6], and the other patient with a CCM in the pons underwent neurosurgical resection 6 years postpartum during the fourth haemorrhage [8]. One of these 13 patients had a symptomatic lesion with refractory seizure and was recommended to undergo neurosurgical resection after cesarean delivery at 36 weeks of gestation, but the surgery was not performed as the patient was diagnosed with thyroid cancer. Burkhardt et al. [19]. reported three patients who underwent neurosurgical interventional during and after pregnancy One patient underwent Ponto-mesencephalic CCM resection during 12 weeks of gestation, but 2 weeks after the uncomplicated delivery of her second child, this patient underwent complete resection of this lesion with favorable outcomes [19]. The other two patients underwent CCM resection postpartum: one patient at 1week postpartum and the other at 3 months postpartum. Note that one more patient was reported to have undergone neurosurgical resection postpartum, but her obstetrical data were missing [10].

To the best of our knowledge, this is the first systemic review to highlight whether pregnancy, delivery, and puerperium are associated with an increased risk of symptomatic CCMs and to provide useful information for clinical practice. The incidence of CCMs is extremely rare and only 16 articles and 32 case reports on CCMs are present in the literature. Despite the increasing diagnosis of the de novo formation of CCMs in both sporadic and familial cases, to date, little information is available about their pathogenesis, clinical presentation, imaging characteristics, and related complications, and their pathogenesis and management during pregnancy remain uncertain. Notably, previous studies have emphasized that the increased production of steroid hormones and vascular proliferation during pregnancy are associated with an increased risk of hemorrhage from CCMs Kaya A et al. [23]. demonstrated that progesterone and estrogen receptors are absent in the cerebral vasculature. Therefore, several researchers have speculated that a different pathway mediates the vascular activity of cerebral cavernomas during pregnancy. The development of advanced neuroimaging modalities and techniques for evaluating the expression of immunobiological markers has allowed researchers to implicate the expression of cerebral angiogenic growth factors, such as vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor, which are normally dormant in the adult brain tissue, in promoting angiogenesis and proliferation of vascular lesions in CCMs; these same physiological mechanisms are involved in the preparation for and promotion of pregnancy-related vasculogenesis [23] (Figure1).

In clinical practice, the definitive diagnosis for cavernous angiomas involves histopathological confirmation. However, the advancements in neuroimaging modalities has allowed the visualization of the entire cranio-spinal axis using MRI and the consequent diagnosis of CCMs with accuracy, without the need of pathological examination; this technique is especially useful when neurosurgical intervention during pregnancy or puerperium may not be recommended.4 This recommendation was supported by Safavi-Abbasi et al. [6] who reported a 21-year-old woman in whom an intramedullary hemorrhage from a spinal CCM occurred during the peripartum period and therefore spinal cord decompression was performed. The histopathology report of this patient confirmed the diagnostic features of CCMs on T2-weighted images obtained using MRI. Most patients showed clinically symptomatic presentations due to hemorrhagic CCMs during pregnancy, with the onset of symptoms during the antepartum or intrapartum period. Some patients developed delayed symptoms at 2 weeks to 10 years postpartum. Witiw et al. [20] reviewed the pregnancy history data of 186 patients: Of the 49 hemorrhagic events that occurred during childbearing years in pregnant or nonpregnant women, only three hemorrhages occurred during a total of 349 pregnancies (one in the first trimester and two in the third trimester). No hemorrhage occurred during labor or 6 weeks postpartum. Safavi-Abbasi et al. [6] reported a case of hemorrhage that occurred during the peripartum period in a patient with symptomatic spinal intramedullary CCMs; the event occurred 2 weeks postpartum, and she subsequently underwent T9-12 laminectomy for completely resection of the lesion.

Although seizure has been widely reported as the most common neurological manifestation of symptomatic CCMs during pregnancy, Kalani et al. [7] retrospectively reviewed 168 pregnancies among 64 patients and reported only five symptomatic hemorrhages in four patients. The most common symptom was found to be the new onset or exacerbation of seizures, which accounted for 31% of all the symptoms, whereas FNDs accounted for 40% of the symptoms. As expected, the risk of hemorrhage was somewhat higher in patients with brain stem lesions (47%) than in those with supratentorial lesions (40%). Simonazzi et al. [8] reported a case series of six patients, three of whom had a hemorrhagic CCM in the pons and only one of these three underwent neurosurgical resection 6 years postpartum during the fourth hemorrhage. No clear evidence is present in the literature to support or refute prophylactic neurosurgical resection of CCMs for women planning pregnancy or the avoidance of pregnancy on the grounds that it will increase the risk of hemorrhage from CCMs; Kalani et al.[7] reported one patient with a family history of CCMs who had undergone resection of a CCM in the right temporal lobe to control seizure at 8 years of age. At 19 years of age, she had uncomplicated pregnancy and delivered her second child. Although all cases of CCMs should be assessed on individual bases, the occurrence of symptoms in the first trimester does not justify the need for a therapeutic abortion as there is no reported evidence to support such recommendations to reduce the risk of hemorrhage.

Our review revealed that only one patient who had severe symptomatic lesions underwent abortion because of the worsening of neurological symptoms at 20 weeks of gestation. However, the practice of choosing an elective cesarean delivery, with the knowledge that vaginal delivery increases the risk of ICH, to reduce the risks of hemorrhage has been revised. Although limited number of cases of CCMs occurring during pregnancy have been reported, it appears that the risk of hemorrhage from CCMs remains similar antepartum, during delivery or postpartum. In addition, no strong evidence is available showing that the mode of delivery influences the risk of hemorrhage from CCMs; hence, we believe that the decisions regarding the management of labor and mode of delivery should be based on obstetric indications. Witiw et al. [20] reported three cases of symptomatic hemorrhages that occurred during pregnancy. All three women delivered healthy newborns; one via vaginal delivery and the other two via cesarean delivery because of neurological indication (hemifacial weakness, mild hemisensory symptoms, and diplopia) and the risks from vaginal delivery perceived by their obstetricians. Notably, all of these patients recovered well from their hemorrhagic events.

As with any rare condition for which guidelines are lacking, surgical management of pregnant women with asymptomatic or minimally symptomatic lesions will likely increase the risk of developing new symptoms or of aggravating the existing ones, which even if transient, may have devastating consequences (worsening of symptoms). Nevertheless, most reported patients eventually improved with retention of only little disability. Regardless, management must be tailored on a case-by-case basis, based on the neurological or obstetric indications. Neurosurgical resection can be performed postpartum. Burkhardt et al. described three patients with symptomatic lesion of CCMs in the supratentorial deep area during pregnancy [19]. Two of these patients were treated neurosurgically postpartum and one during 6 weeks of gestation. Initially, one of former two patients showed minor clinical symptoms and a stable lesion (left-thalamo-mesencephalic CCM) on MRI, and she underwent surgical resection 1 week after term delivery. The other of the two patients who became symptomatic in her last trimester was treated surgically 3 month after uncomplicated delivery and showed favorable surgical outcomes. In some cases, however, if the symptoms are severe and occur early in the course of pregnancy, an emergency neurosurgical intervention may be required before term for completely removing the symptomatic lesions and avoiding recurrence and rebleeding. Burkhardt et al. reported a similar case of a brainstem (rightponto- mesencephalic) CCM in a patient at 11 weeks of gestation who underwent resection at 12 weeks of gestation, followed by a compete surgical removal of this lesion at 2 weeks postpartum.

There are several limitations to our systematic review should be acknowledged. Only studies that were published in English were included in our study, and thus it may not be representative of all the relevant literature published to date. Second, there are also limitations pertaining to a retrospective study included in our review as some data may not have been validated as well as in planned prospective study. However, it may be hard to define a prospective study considering of the pathological condition is rare and available literature is poor. These are important limitations that must be considered to draw conclusion in this particular subject.

Conclusion

Certainly, it may be difficult to validate or recommend the management of pregnancy in women with symptomatic CCMs mainly because of the lack of obstetrical evidence in the literature due to the rarity of this disease. Regardless, decision making regarding conservative management or neurosurgical intervention of CCMs during pregnancy or postpartum should be based on the time of symptom onset during the course of pregnancy and the lesion location. Most neurosurgeons consider that the risk of hemorrhage remains similar during pregnancy or postpartum and that the need for emergency neurosurgical intervention during pregnancy is rare. No quantitative data are available to support cesarean delivery as the delivery mode of choice in patients with CCMs, and taken together, the results of the previous studies suggest that the mode of delivery should be decided based on obstetric indications. Studies have suggested that the risk of ICH does not particularly increase during pregnancy or postpartum. We generally suggested, based on retrieved data and shared decision between the clinician and patient, that women with CCMs can be managed safely during trial of labor without a significant risk of adverse perinatal outcomes, and consideration needs to be given to planned cesarean section in patients with symptomatic CCMs or when prolonged labor anticipated.

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The Effectiveness of Ferric Carboxymaltose in Childbearing Age with Iron Deficiency Anemia-Juniper Publishers

Journal of Gynecology and Women’s Health

Iron deficiency is the most common minerals deficiency worldwide. Iron has a major role in producing hemoglobin in red blood cells, which is responsible for carrying oxygen to the body’s tissues. Treatment for an iron inadequacy depends on the cause and severity of the condition. Intravenous iron preparations are highly recommended when anemic pregnant women unable to tolerate, respond accordingly with better adherence to the regimen.

Aim of the research: This study is conducted to evaluate the possibility of using ferric carboxymaltose (FCM) as a first line treatment in pregnant women with IDA; and the effect of other contributor factors such as age, education, occupation, number of pregnancies and most importantly is the time of receiving FCM in term of first, second and third trimesters.

Methodology: Participants were gone through out personal interview answering some questions about their gestational situation and habits to achieve the study outcomes. All participants were pregnant women with abnormal hemoglobin whose either already received their first dose of FCM or those who are scheduled to take their first dose.

Result: Eighty-eight (88) pregnant women were participated in this study and their ages were divided into groups. The average of post FCM hemoglobin (10.99) after injection was significantly higher compared to the baseline hemoglobin (9.06). A shift to healthy and better response was shown after the FCM were shown in all participants.

Conclusion: A single intravenous injection of FCM improves the hemoglobin level in a significant consideration in anemic pregnant women. It showed also that the respond of sever anemic cases were more positive in improving the level of hemoglobin than mild and/or moderate cases. Blood transfusion could be avoided by using FCM injection to optimize the iron stores rapidly and effectively. Intravenous injection of FCM could be used as trend in the first and second trimester during pregnancy with or without IDA if the hemoglobin level is low.

Keywords: Ferric carboxymaltose; Iron deficiency; Iron deficiency; Hemoglobin

Introduction

Anemia is a blood disorder in which hemoglobin (Hgb) concentration is less than the normal Hgb level. It is affected by age, sex, physiological condition(s) and altitude above the sea level of that person [1]. It is a global public health problem with major consequences affecting both developing and developed countries [2]. The most common type of anemia is Iron deficiency anemia (IDA), which is defined as anemia because of insufficient iron [3]. Iron deficiency is the most common minerals deficiency worldwide. Women are at higher risk compared with men [4,5]. Iron has a major role in producing hemoglobin in red blood cells which is responsible for carrying oxygen to the body’s tissues [6]. Iron is a mineral naturally found in food and supplements, and it is available in two dietary forms: heme like in (meat, poultry, and seafood) and non-heme in (iron-fortified foods, plants- beans, nuts and vegetables). Essentially, meat and seafood are the richest sources of iron. However, some vegetables such as spinach, broccoli, and beetroot are considered as a good source for iron too. Although this disagrees with previous review concludes that “Vegetarians have a higher risk for developing low iron stores, iron depletion, and associated iron deficiency anemia, compared to non-vegetarians” [7].

According to world health organization (WHO) data, the prevalence of IDA in Saudi Arabia is 32.0% of pregnant women and 32.3% of women of reproductive age with anemia, which presents a moderate public health risk. Hemoglobin estimation is the most common and classical hematological screening test used for iron deficiency. According to (WHO), anemia is defined as low hemoglobin status; the cut off value for the pregnant women is Hgb<12g/dl, mild anemia (10.0-11.9g/dl), moderate (8.0-9.9g/dl) and severe (≤ 7.9g/dl). However, bone marrow aspiration is the definitive test to assess iron stores and diagnose its deficiency. Serum ferritin is an alternative to the bone marrow aspiration, and it is the best test to distinguishing those with IDA from those who are not iron deficient [2,8,9].

The level of serum ferritin, hemoglobin and hematocrit, and transferrin or total iron-binding capacity could evaluate iron inadequacy. The symptoms of iron deficiency vary, depending on its severity. Iron deficiency anemia can cause chronic fatigue, hair loss, cold hands and feet, shortness of breath and many other symptoms in addition to several physical signs. One of the characteristics symptoms is pagophagia, which is known by a craving to eat substance without nutritional value such as ice, dust or paint due to iron deficiency [10,11].

The reasons behind iron deficiency anemia during pregnancy can be classified into three causes. First, it can be as a result of the decrease in the hemoglobin level due to an increase in the maternal plasma volume. Second, begin the pregnancy with inadequate iron storage, which can lead to an inability to meet the requirements throughout the pregnancy. Last, an increase in the maternal demand for iron [12]. The body requirements for iron in pregnant woman nearly increases to 1000mg, which can be divided by, 350mg for placental and fetal growth, 250mg for blood loss at the delivery and the biggest part will be for the dilation in the red blood cell mass that will consume approximately 500mg iron [13]. Iron deficiency anemia lead to health problems such as rapid or irregular heartbeat, premature births and low birth weight babies and delayed growth and development [14].

Treatment for an iron inadequacy depends on the cause and severity of the condition. Iron deficiency anemia could be treated either orally or by intravenous (IV) injection. In spite of the fact that oral iron supplementations are considered as the first line option for the majority of pregnant women with IDA due to their effectiveness, safety, and lower cost; yet an intolerable side effects (gastrointestinal side effects), non-compliance and/or predisposing pathology such as malabsorption (celiac disease) may limit the use of oral ferrous supplements [15].

On the other hand, intravenous iron preparations are highly recommended when anemic pregnant women unable to tolerate, respond accordingly with better adherence to the regimen. Ferric carboxymaltose (FCM) is a new type of iron III complex, dextran free, which makes it possible to be administered without a test dose for hypersensitivity, has a neutral PH (5.0-7.0) and physiological osmolality. Therefore, up to 1000 mg as single dose can be infused over 15-30 minutes, with lower side effects than oral iron supplement thus the patients are more compliant with injectable dosage form. If the patient did not respond adequately after a single dose of FCM, another dose can be administered one week later [10,16-18].

Ferrous as an element is a trend use for all pregnant women in most if not all gynecological clinics, usually the practitioners start with ferrous sulfate (FS) 325mg orally or ferrous gluconate (FG) 300mg orally. However, the starting point to prescribe ferrous is crucial to decide whether if the first, second or third trimester; moreover, what is the most appropriate and effective way to initiate FCM injection during pregnancy; and what is the most cost-effective treatment specifically if the pregnant women with IDA [19].

Methodology

Study Design

This is a cross-sectional, prospective study conducted to monitor symptoms improvement and normalization of hemoglobin level of the recruited participants.

Subjects

This study was conducted with a sample of eighty-eight (88) pregnant women aged between (20) and (44) years old; whom participated through out personal interview answering some questions about their gestational situation and habits to achieve the study outcomes. All participants were pregnant women with abnormal hemoglobin whose either already received their first dose of ferric carboxymaltose or those who are scheduled to take their first dose. Women who are post-delivery or pregnant women with normal hemoglobin are excluded from the study

Data Analysis

Data were analyzed using SPSS 21.0 version statistical software. Descriptive statistics (mean, standard deviation, frequencies and percentages) were used to describe the quantitative and categorical variables. Student’s paired t test was used to compare the mean values of quantitative variables (Hgb) between the baseline and post ferric carboxymaltose (FCM). One-way analysis of variance was used to compare the mean difference of Hgb values in relation to the categorical variables, which has more than two categories. A p-value of ≤0.05 was used to report the statistical significance of findings to report the precision of results.

Setting

Research data were obtained from the King Abdullah University Hospital at the Princess Noura bint Abdulrahman University.

Ethical Consideration

All the participants involved in this study provided written informed consent acknowledging the investigation’s purpose and were assured of the confidentiality of the results. Institutional review board approval for the research was obtained from Health Sciences Research Center at Princess Noura bint Abdulrahman University, with IRB Log Number: 18-1098.

Result

Eighty-eight (88) pregnant women were participated in this study and their ages were divided into groups, from 20-25 years were 13 participants (14.8%), from 26-30 years 28(31.8%), from 31 to 35 years 27 (30.7%), and for 36 years and older were 20(22.7%). Their educational level was distributed as following: under high school 2(2.3%), high school 32(36.4%), bachelor’s degree 41 (46.6%), and master’s degree or above 13(14.8%). Their occupational status was assigned as employed 48 (54.5%) and un-employed 40(45.5%). More detail for the timing of FCM injection during the gestational trimester whether if it is first, second or third trimester, were shown in (Table 1), together with information related to the number of deliveries. The average of post ferric carboxymaltose hemoglobin (10.99) after injection was significantly higher compared to the baseline hemoglobin (9.06) (P<0.0001; 95% CI: 1.65-2.21).

In regard to age groups and its efficient in absorbing Hgb before FCM injection as a baseline and after FCM injection, compared to the whole group as shown in (Figure1). The range of hemoglobin level between baseline and after FCM injection was (9.06-10.99), showing the response of the participants after FCM injection with a difference of 1.93 for the whole group, where the maximum difference was 2.16 found with the group of 25 years and lower with no significant difference (p>0.05) compared with any of other age group including the minimal difference for the age group of 30-35 years with 1.7.

Another comparison for level of hemoglobin was found when FCM was injected within the gestational trimester, first, second and third trimester. It was found that although the third trimester with the highest hemoglobin level compare to the others, yet the first trimester showed the best response with a difference between the baseline and post FCM injection with 2.15. None of these differences were calculated as significantly different. Figure 2 showed relative differences between gestational trimesters first, second and third trimester compared with the total group before and after receiving one full dose of FCM.

Participants (at the baseline) were classified in accordance with WHO classification to mild, moderate and sever anemia. A shift to healthy and better response was shown after the FCM with 14 participants were shown within healthy hemoglobin level, compared with none at the baseline. Then a big shift 8, 70 and 10 out of the total participants as baseline before FCM injection for severe, moderate and mild anemia correspondingly. The improvement had shown after the FCM injection with only one participant with severe anemia or low hemoglobin level, 15 participants for moderate, and 58 participants become with mild anemia. It is also shown that 14 participants were getting full improvement and considered as health or non-anemic women. Table 2 showed full detail for all the data of this study mainly the shift of hemoglobin level during sever, moderate and mild to moderate, mild and healthy hemoglobin level before and after receiving FCM.

Discussion

This is the first prospective study for ferric carboxymaltose in Saudi Arabia among pregnant women presenting with IDA. An intravenous ferric carboxymaltose was remarkably increased hemoglobin levels without serious side effects were recorded. Only one case in this study had experienced dizziness, which were reported at the emergency department after FCM injection. FCM shown to be effective in childbearing age women with IDA, this phenomenon had been shown noticeable with those who aged with 25 or younger, where they have remarkably better response compared with other groups of age due to the ability to quickly absorb of iron as shown in (Figure 1). This difference is numerically deferent but not statistically deferent. Age as a factor in pregnant women with IDA had not been studied elsewhere; whereas in this study, age was divided into 4 age groups to study the associated differences of Hgb levels post FCM injection.

Results from this FCM analysis of pregnant women with IDA during first, second and third trimester of pregnancy showed that Hgb levels increased after FCM treatment with full safety parameters; therefore, intravenous FCM could be considered as a first line treatment for IDA pregnant women in case of severe cases. This is in contrast to CDC [20], WHO [21] and Society of Obstetricians and Gynecologists of Canada [22], where all these authorities recommended oral iron supplementation in pregnant women as first line therapy. Intravenous iron is recommended when oral iron is poorly tolerated, absorption is likely to be impaired, the response to oral iron is inadequate, or when rapid restoration of Hgb and iron stores is required [23].

Oral iron supplementation could increase hemoglobin and ferritin levels in pregnancy, with or without IDA. This study demonstrated safe and effective use of FCM infusion in pregnant women during the first, second, and third trimesters of pregnancy. Safety profile for intravenous FCM had been shown, having the practical advantage of allowing a higher iron dose in one time of administration (minimizing repeated administration times and increasing patient comfort) [24]. Another study showed Hgb levels significantly increased above baseline levels with 66% of women reported an improvement of their wellbeing with mostly minor and self-limiting side effects [25]. The cases described in this study was also in line with the retrospective case-control study from the Netherlands reporting similar significant increases in maternal Hgb levels above baseline and low rates of adverse outcomes [24]. Third trimester cases in this study had improvement with 21.3% with a single dose of intravenous injection of FCM (Figure 2).

It was noticed from this study that Ferric Carboxymaltose (FCM) was significantly increased hemoglobin levels, this increment in Hgb had been noticed started at 3 to 4 weeks interval post FCM dose; this achievement also had been previously studied [26]. The responses of severe anemic cases are more positive in improving the level of hemoglobin than mild and/or moderate cases after a single dose (1000mg) FCM. All cases related to severity of IDA had been shifted from sever, moderate, mild to moderate, mild, healthy respectively. Only one case with severe IDA remained severe after using FCM, therefore another dose maybe warranted.

Treatment of IDA will never lead to iron toxicity, however, incase of injection of higher dose above the requirements, it needs further monitoring although teratogenicity is with limited possibility, specifically if the treatment within the first trimester. If iron accumulation has been noticed, intravenous deferoxamine should be administered as chelation therapy [27]. Excessive Hgb levels were not observed in this study, all participants on FCM injection had elevated levels that fell within normal ranges.

Traditionally, blood transfusion is considered as an option in severe anemic cases; especially when oral replacement is not effectively and rapidly replenished the iron stores. The newly developed iron formulation such as FCM is offering the benefit of administrating a single higher dose with rapid, effective and safe repletion of iron, which can employ to avoid the risk of blood transfusion in severe anemia. This study could not find any correlation between Hgb levels and education, job, number of pregnancies, the consumed iron from food (vegetarian or not), and pagophagia.

A side issue related to the cost of treatment in comparison between FCM and oral ferrous treatment considering that the cost of FCM is 200$ per injection of 1000mg single dose with almost absolute treatment for more than 6 months and only one visit comparing with multiple visits, cost more than 200$ USD per each visit, and irregular treatment subjecting premature births and low birth weight babies and delayed growth and development.

Conclusion

This study approved that one intravenous injection of FCM improves the hemoglobin level in a significant consideration in anemic pregnant women. Also, it showed that the respond of sever anemic cases were more positive in improving the level of hemoglobin than mild and/or moderate cases. Only one case remained severe despite receiving one dose of FCM. Dizziness was experienced and reported by only one pregnant woman at the emergency department post FCM injection, which indicated its effectiveness and safety. Blood transfusion could be avoided by using FCM injection to optimize the iron stores rapidly and effectively. The proposed recommendation is that intravenous injection of FCM could be used as trend in the first and second trimester during pregnancy with or without IDA if the hemoglobin level is low. Moreover, Intravenous iron can be given late in pregnancy in the third trimester when rapid restoration of the iron stores and hemoglobin is required to avoid blood transfusion at delivery, it is also often needed after delivery when there is excessive bleeding in labor.

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