Editorial
Acromegaly and pregnancy
Acromegalia y gestación
Elena Valassi
Departamento de Medicina/Endocrinología, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau y Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Universitat Autònoma de Barcelona, Barcelona, Spain
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A marked increase is seen in consultations for diabetes.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Xavier Oliva, Teresa Micaló, Sonia Pérez, Beatriz Jugo, Silvia Solana, Carlos Bernades, Marta Sanavia, Caridad Delgado" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Xavier" "apellidos" => "Oliva" ] 1 => array:2 [ "nombre" => "Teresa" "apellidos" => "Micaló" ] 2 => array:2 [ "nombre" => "Sonia" "apellidos" => "Pérez" ] 3 => array:2 [ "nombre" => "Beatriz" "apellidos" => "Jugo" ] 4 => array:2 [ "nombre" => "Silvia" "apellidos" => "Solana" ] 5 => array:2 [ "nombre" => "Carlos" "apellidos" => "Bernades" ] 6 => array:2 [ "nombre" => "Marta" "apellidos" => "Sanavia" ] 7 => array:2 [ "nombre" => "Caridad" "apellidos" => "Delgado" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1575092212002768" "doi" => "10.1016/j.endonu.2012.09.004" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1575092212002768?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173509313000111?idApp=UINPBA00004N" "url" => "/21735093/0000006000000001/v1_201305081711/S2173509313000111/v1_201305081711/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Acromegaly and pregnancy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "3" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Elena Valassi" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Elena" "apellidos" => "Valassi" "email" => array:1 [ 0 => "EValassi@santpau.cat" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Departamento de Medicina/Endocrinología, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau y Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Universitat Autònoma de Barcelona, Barcelona, Spain" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Acromegalia y gestación" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Pregnancy in acromegaly is a complex subject, and few data are available in the literature to answer three main questions:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1.</span><p id="par0010" class="elsevierStylePara elsevierViewall">Does pregnancy worsen acromegaly?</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2.</span><p id="par0015" class="elsevierStylePara elsevierViewall">How does acromegaly influence pregnancy?</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3.</span><p id="par0020" class="elsevierStylePara elsevierViewall">What are the consequences of medical treatment for the fetus?</p></li></ul></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Does pregnancy worsen acromegaly?</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Hormone levels</span><p id="par0025" class="elsevierStylePara elsevierViewall">Placental GH (GH-V) becomes the main component of circulating GH from the second term of pregnancy. GH-V is continuously secreted and induces production in maternal liver of IGF-I, which inhibits pituitary GH secretion in healthy women. In pregnant women with acromegaly, adenomatous somatotroph cells are resistant to IGF-I inhibitory feedback, and circulating levels of pituitary GH therefore remain elevated throughout pregnancy.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Since RIA or IRMA used in routine clinical practice do not detect GH-V, specific tests able to differentiate GH of pituitary origin from GH-V should be used to diagnose acromegaly during pregnancy. Serum IGF-I levels during pregnancy vary, depending on the term. A decrease in IGF-I levels has been reported in healthy women during the first term, and also in women with hypopituitarism treated with GH and with type 1 diabetes.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However, serum IGF-I levels increase in most women during the second half of pregnancy through a mechanism independent of the pituitary gland.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> A recent multicenter study conducted in France retrospectively analyzed 59 pregnancies in 46 acromegalic women, and IGF-I levels significantly decreased during the first and second term as compared to levels measured before conception.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In a subgroup of 12 women with acromegaly who had been treated with dopamine agonists (DAs) (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) or somatostatin analogs (SAs) (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7) before conception, IGF-I levels significantly decreased during the first term, maintaining stable GH production.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In a recent systematic review of 47 pregnancies in patients with acromegaly reported in the previous 10 years, stable or decreased IGF-I levels were reported in most of them.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Specifically, women with a macroadenoma or receiving medical treatment before pregnancy were more prone to have stable or reduced (by more than 30%) IGF-I levels at some time during pregnancy as compared to those with a microadenoma and those with no prior treatment, respectively.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">It should be noted that stable or reduced IGF-I levels in the third term were more frequently found in women who had received continuous treatment with somatostatin analogs during pregnancy than in those not given drugs.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Thus, significant IGF-I reduction associated with subjective symptom improvement may be seen in pregnant women with acromegaly, particularly in the first term. This could be the consequence of a carryover affect of prior treatment but is, more probably, due to the inhibition of IGF-I production by hyperestrogenism.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Tumor size</span><p id="par0035" class="elsevierStylePara elsevierViewall">During normal pregnancy, the pituitary gland enlarges, and its volume may increase by up to 45% during the first term, mainly due to hyperplasia of mature lactotroph cells and the subsequent reduction in the number of gonadotroph cells.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Theoretically, the stimulating effect of peripheral hormones during pregnancy may cause enlargement of the GH-secreting adenoma, either by growth, hemorrhage, or tumor infarction. In addition, the normal increase in size of the pituitary gland during pregnancy also contributes to the mass effect on the optic nerve. In the French multicenter study, only four women experienced visual field defects during pregnancy, which led to a diagnosis of acromegaly in three of them. The remaining patient, who had a macroadenoma secreting GH and PRL and was being treated with bromocriptine, experienced intratumoral hemorrhage in the 34th week.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Of the 27 patients for whom MRI was available within six months of delivery, 22 (20 with macroadenoma) had a stable adenoma size. Tumor size only increased in three patients (11%) with macroadenoma. One of these had previously been treated with surgery and bromocriptine, and the other two had visual defects.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Seven patients reported headache, and one of them developed diplopia three months after delivery despite a stable MRI at 22 weeks of pregnancy.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> A review of cases reported to date shows that pregnancy aggravated acromegaly in four out of 24 patients (17%). In one patient, therapeutic abortion was decided upon in the 10th week due to severe symptom exacerbation.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The recurrence of GH hypersecretion and the return of clinical signs of acromegaly were documented in a single patient with macroadenoma in whom treatment with bromocriptine was discontinued at pregnancy onset.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Another patient showed signs of increased intracranial pressure due to adenoma re-expansion in week 39 of pregnancy.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Lactation was not associated with tumor growth in any of the 20 women with acromegaly reported in the French study. Therefore, it is usually not contraindicated, particularly in patients with minimal or no obvious residual tumor.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Overall, it may be stated that pregnancy does not cause the growth of a GH-secreting tumor in most patients, particularly in those who have a microadenoma or macroadenoma previously treated by surgery and/or radiotherapy. However, close clinical monitoring, including evaluation of vision changes, should be performed in all pregnant acromegalic women with an adenoma greater than 1.2<span class="elsevierStyleHsp" style=""></span>cm in size, because of the potential risk of vision loss.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">How does acromegaly influence pregnancy?</span><p id="par0040" class="elsevierStylePara elsevierViewall">Pregnant women with active acromegaly are potentially at risk because of their increased risk of glucose intolerance, diabetes mellitus, high blood pressure, and preeclampsia. Particularly, gestational diabetes may be more prevalent in acromegaly due to an insulin resistance state resulting from the anti-insulin effect of GH. However, only some cases of mild gestational diabetes, most of them controlled with dietary measures,<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–11</span></a> are reported in the literature, while most patients with acromegaly do not experience clinically relevant metabolic or cardiovascular complications during pregnancy. However, Caron et al. noted a trend to an increased prevalence of gestational diabetes and high blood pressure in acromegalic women as compared to the overall French population. No differences were seen between patients with and without preconception control of GH/IGF-I.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Interestingly, the occurrence of these complications was not associated with the type of medical treatment, as only one woman who developed gestational diabetes had been treated with a somatostatin analog during the first half of pregnancy.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> As regards newborns from women with acromegaly, no malformation has been documented, and birth weight was normal in 83 of the 95 babies reported in the Cheng review,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> in agreement with the premise of placental impermeability to GH and IGF-I.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In conclusion, although acromegaly itself does not appear to significantly affect the course of pregnancy, prospective studies of larger populations should be conducted to conclusively assess the metabolic and cardiovascular consequences of GH/IGF-I excess during pregnancy for both the mother and fetus.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">What are the consequences of medical treatment for the fetus?</span><p id="par0045" class="elsevierStylePara elsevierViewall">Dopamine analogs (DAs), particularly bromocriptine, have been shown to be safe during pregnancy.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However, in the recent systematic review conducted by Cheng et al., a greater prevalence of macrosomic fetuses was seen in women treated with DAs as compared to untreated women, and the difference was borderline significant.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However, this result needs to be confirmed in larger prospective studies. There are currently few conclusive data about SAs. All five subtypes of somatostatin receptors are expressed in the placenta, including SST4 (which shows little affinity for octreotide).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Maffei et al. detected a very low number of somatostatin receptors in placental cell membrane and umbilical cord tissues, which suggests that the maternal–fetal barrier is able to exert a weak functional response to SAs.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Although the fetus may be exposed to the drug in the first few weeks following conception, pregnancy is likely to continue without complications if treatment is discontinued after pregnancy is confirmed. In the few cases reported of women with acromegaly in whom treatment with SAs was continued during pregnancy, no maternal complication of fetal malformation was reported.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,13</span></a> However, delayed uterine growth was documented in the fetus of a woman treated with octreotide LAR throughout pregnancy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In fact, in the systematic review by Cheng, women treated with SAs during pregnancy were more likely to have low birth weight newborns as compared to untreated women.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Maffei et al. documented transient reductions in uterine artery flow and systolic velocity after injections of short-acting octreotide in a pregnant woman with acromegaly.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This may explain, at least partly, the association between delayed growth/microsomia and the previously mentioned use of SAs. The use of pegvisomant during pregnancy has been reported as being safe and effective in two cases.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15,16</span></a> Fetal drug levels were minimal, suggesting low or no transplacental passage, while GH-V levels in maternal and cord blood were within the normal range.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In conclusion, although the medical treatment of pregnant women with acromegaly is not associated with major side effects in the mother or fetus, drug discontinuation is recommended during pregnancy. If drugs are used, strict monitoring of fetal development is recommended.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0050" class="elsevierStylePara elsevierViewall">To sum up, although no adequate scientific evidence is available about the management of acromegalic women during pregnancy, the following suggestions may be made: (a) it is important to control GH/IGF-I hypersecretion before pregnancy is planned; (b) medical treatment should be discontinued at least two months before a planned pregnancy or upon pregnancy diagnosis, because pregnancy does not aggravate acromegaly in most cases, and may even lead to a reduction in IGF-I levels and an improvement in associated symptoms, particularly in the first half of pregnancy; (c) in women with microadenoma, clinical signs suggesting a potential tumor growth (such as headache and/or vision disturbances) should be monitored every term; (d) in women with macroadenoma, strict clinical control and visual field examination are recommended every six weeks, because symptomatic macroadenoma growth may occur during pregnancy, particularly if previously untreated or if given drug treatment only; (e) in patients with evidence of tumor enlargement, in addition to ophthalmological monitoring, a control MRI may be considered in the second term. In these patients, a cesarean section to minimize the risk of pituitary apoplexy should be considered. If vision impairment is documented, urgent transsphenoidal resection is recommended; (f) all pregnant women with acromegaly should be monitored because of the risk of the occurrence of diabetes and gestational hypertension; (g) the available evidence does not support the maintenance or restart of medical treatment for acromegaly during pregnancy, because of the potential increase in the risk of impaired fetal development; and (h) lactation may be permitted in pregnant women with acromegaly, particularly in those with minimal or no residual tumor.</p><p id="par0055" class="elsevierStylePara elsevierViewall">However, little experience is available, and prospective multicenter studies will be needed to clarify whether or not acromegalic mothers and their fetuses have an increased risk during and after pregnancy as compared to normal pregnant women.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Does pregnancy worsen acromegaly?" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Hormone levels" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Tumor size" ] ] ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "How does acromegaly influence pregnancy?" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "What are the consequences of medical treatment for the fetus?" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Valassi E. Acromegalia y gestación. Endocrinol Nutr. 2013;60:1–3.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pregnancy in acromegaly: successful therapeutic outcome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "V. Herman-Bonert" 1 => "M. Seliverstov" 2 => "S. Melmed" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.83.3.4635" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1998" "volumen" => "83" "paginaInicial" => "727" "paginaFinal" => "731" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9506716" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Longitudinal study of the maternal insulin-like growth factor system before, during and after pregnancy in relation to fetal and infant weight" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Olausson" 1 => "M. Lof" 2 => "K. Brismar" 3 => "M. Lewitt" 4 => "E. Forsum" 5 => "A. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 11 | 6 | 17 |
| 2024 October | 41 | 2 | 43 |
| 2024 September | 38 | 5 | 43 |
| 2024 August | 33 | 3 | 36 |
| 2024 July | 41 | 6 | 47 |
| 2024 June | 44 | 4 | 48 |
| 2024 May | 26 | 5 | 31 |
| 2024 April | 16 | 2 | 18 |
| 2024 March | 25 | 10 | 35 |
| 2024 February | 19 | 4 | 23 |
| 2024 January | 11 | 4 | 15 |
| 2023 December | 21 | 3 | 24 |
| 2023 November | 13 | 11 | 24 |
| 2023 October | 22 | 7 | 29 |
| 2023 September | 17 | 5 | 22 |
| 2023 August | 12 | 2 | 14 |
| 2023 July | 14 | 9 | 23 |
| 2023 June | 14 | 3 | 17 |
| 2023 May | 20 | 7 | 27 |
| 2023 April | 24 | 1 | 25 |
| 2023 March | 22 | 3 | 25 |
| 2023 February | 18 | 8 | 26 |
| 2023 January | 14 | 8 | 22 |
| 2022 December | 17 | 5 | 22 |
| 2022 November | 26 | 18 | 44 |
| 2022 October | 21 | 8 | 29 |
| 2022 September | 15 | 5 | 20 |
| 2022 August | 14 | 10 | 24 |
| 2022 July | 16 | 12 | 28 |
| 2022 June | 14 | 6 | 20 |
| 2022 May | 28 | 20 | 48 |
| 2022 April | 45 | 9 | 54 |
| 2022 March | 15 | 10 | 25 |
| 2022 February | 36 | 6 | 42 |
| 2022 January | 37 | 11 | 48 |
| 2021 December | 21 | 7 | 28 |
| 2021 November | 14 | 6 | 20 |
| 2021 October | 25 | 8 | 33 |
| 2021 September | 21 | 13 | 34 |
| 2021 August | 21 | 5 | 26 |
| 2021 July | 14 | 5 | 19 |
| 2021 June | 10 | 11 | 21 |
| 2021 May | 17 | 9 | 26 |
| 2021 April | 21 | 11 | 32 |
| 2021 March | 13 | 14 | 27 |
| 2021 February | 13 | 10 | 23 |
| 2021 January | 9 | 8 | 17 |
| 2020 December | 14 | 11 | 25 |
| 2020 November | 12 | 8 | 20 |
| 2020 October | 17 | 6 | 23 |
| 2020 September | 25 | 9 | 34 |
| 2020 August | 5 | 10 | 15 |
| 2020 July | 10 | 9 | 19 |
| 2020 June | 12 | 11 | 23 |
| 2020 May | 9 | 7 | 16 |
| 2020 April | 8 | 1 | 9 |
| 2020 March | 23 | 7 | 30 |
| 2020 February | 14 | 4 | 18 |
| 2020 January | 17 | 6 | 23 |
| 2019 December | 19 | 4 | 23 |
| 2019 November | 11 | 4 | 15 |
| 2019 October | 9 | 7 | 16 |
| 2019 September | 15 | 2 | 17 |
| 2019 August | 14 | 0 | 14 |
| 2019 July | 7 | 10 | 17 |
| 2019 June | 24 | 16 | 40 |
| 2019 May | 66 | 6 | 72 |
| 2019 April | 26 | 5 | 31 |
| 2019 March | 12 | 6 | 18 |
| 2019 February | 17 | 6 | 23 |
| 2019 January | 6 | 6 | 12 |
| 2018 December | 16 | 6 | 22 |
| 2018 November | 13 | 1 | 14 |
| 2018 October | 11 | 3 | 14 |
| 2018 September | 12 | 3 | 15 |
| 2018 August | 17 | 1 | 18 |
| 2018 July | 8 | 1 | 9 |
| 2018 June | 3 | 0 | 3 |
| 2018 May | 4 | 4 | 8 |
| 2018 April | 4 | 0 | 4 |
| 2018 March | 4 | 0 | 4 |
| 2018 February | 8 | 1 | 9 |
| 2018 January | 16 | 1 | 17 |
| 2017 December | 13 | 2 | 15 |
| 2017 November | 15 | 0 | 15 |
| 2017 October | 12 | 1 | 13 |
| 2017 September | 17 | 4 | 21 |
| 2017 August | 20 | 4 | 24 |
| 2017 July | 16 | 3 | 19 |
| 2017 June | 24 | 5 | 29 |
| 2017 May | 32 | 11 | 43 |
| 2017 April | 20 | 4 | 24 |
| 2017 March | 33 | 8 | 41 |
| 2017 February | 32 | 2 | 34 |
| 2017 January | 11 | 0 | 11 |
| 2016 December | 10 | 6 | 16 |
| 2016 November | 18 | 2 | 20 |
| 2016 October | 26 | 8 | 34 |
| 2016 September | 27 | 2 | 29 |
| 2016 August | 19 | 9 | 28 |
| 2016 July | 15 | 2 | 17 |
| 2016 June | 12 | 5 | 17 |
| 2016 May | 13 | 11 | 24 |
| 2016 April | 12 | 13 | 25 |
| 2016 March | 18 | 16 | 34 |
| 2016 February | 22 | 14 | 36 |
| 2016 January | 10 | 14 | 24 |
| 2015 December | 15 | 11 | 26 |
| 2015 November | 15 | 19 | 34 |
| 2015 October | 17 | 18 | 35 |
| 2015 September | 27 | 5 | 32 |
| 2015 August | 35 | 4 | 39 |
| 2015 July | 22 | 3 | 25 |
| 2015 June | 8 | 1 | 9 |
| 2015 May | 15 | 2 | 17 |
| 2015 April | 23 | 17 | 40 |
| 2015 March | 11 | 10 | 21 |
| 2015 February | 16 | 5 | 21 |
| 2015 January | 38 | 10 | 48 |
| 2014 August | 2 | 0 | 2 |
| 2014 June | 2 | 0 | 2 |
| 2014 May | 2 | 0 | 2 |
| 2013 July | 3 | 1 | 4 |
| 2013 June | 1 | 1 | 2 |
| 2013 April | 4 | 0 | 4 |
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