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الرعاية أثناء الولادة

المخاض المبكر عند النساء المصابات بالسكري

لا يعد مرض السكري مانعا لمضادات المخاض أو الستيرويدات السابقة للولادة لتحفيز نضج رئة الجنين.

بالنسبة للنساء المصابات بداء السكري المعالج بالأنسولين واللوات يتناولن الستيرويدات لتحفيز نضوج رئة الجنين، يعطى أنسولين إضافي وفقًا لبروتوكول متفق عليه

توقيت وطريقة الولادة

يجب مناقشة توقيت وطريقة الولادة مع النساء الحوامل المصابات بالسكري قبل الولادة وخصوصا خلال الأشهر الثلاثة الأخيرة من الحمل.

يمكن تقديم المشورة للنساء الحوامل المصابات بالسكري من النوع 1 أو النوع 2 وليس لديهن أي مضاعفات أخرى للولادة بين 37 أسبوعًا و 38 أسبوعًا و6 أيام من الحمل، وذلك من خلال تحفيز الولادة أو الولادة القيصرية.

يمكن تقديم الولادة الاختيارية قبل 37 أسبوعًا للنساء المصابات بالسكري من النوع 1 أو النوع 2 المصابات ببعض مضاعفات الأم أو الجنين

تنصح النساء المصابات بسكري الحمل بالولادة في موعد لا يتجاوز 40 أسبوعًا و6 أيام. ويوضع في الاعتبار  الولادة الاختيارية قبل ذلك الموعد للنساء المصابات بسكري الحمل اللواتي يعانين من مضاعفات الأم أو الجنين

لا يعتبر مرض السكري مانعا للولادة الطبيعية بعد ولادة قيصرية سابقة.

بالنسبة للنساء الحوامل المصابات بالسكري اللواتي اكتشفت الموجات فوق الصوتية (السونار) أن لديهن جنين كبير الحجم، يجب على الطبيب شرح مخاطر وفوائد الولادة الطبيعية والقيصرية

التخدير

للنساء المصابات بالسكري والأمراض المصاحبة مثل السمنة أو الاعتلال العصبي اللاإرادي، يجب تقييم جميع جوانب التخدير في الأشهر الثلاثة الأخيرة من الحمل

إذا تم استخدام التخدير العام في الولادة، يجب مراقبة نسبة الجلوكوز في الدم كل 30 دقيقة من بداية التخدير العام حتى بعد ولادة الطفل وعودة المرأة إلى وعيها الكامل

السيطرة على نسبة السكر في الدم أثناء المخاض والولادة

يجب مراقبة نسبة الجلوكوز في الدم كل ساعة أثناء الولادة للنساء المصابات بالسكري، والحفاظ عليه بين 4 مليمول / لتر و 7 مليمول / لتر.

يمكن استخدام حقن الدكستروز (سكر الجلوكوز النقي) في الوريد وحقن الأنسولين أثناء الولادة للنساء المصابات بداء السكري اللواتي يصعب في حالتهن الحفاظ على معدل الجلوكوز في الدم بين 4 مليمول / لتر و 7 مليمول / لتر.

الرعاية بعد الولادة

ضبط جلوكوز الدم والأدوية والرضاعة الطبيعية

يجب على النساء المصابات بالسكري (منذ ما قبل الحمل) المعالج بالأنسولين تقليل جرعة الأنسولين فور الولادة ومراقبة مستويات الجلوكوز في الدم للوصول إلى الجرعة المناسبة.

يجب أن تعلم النساء المصابات بالسكري (منذ ما قبل الحمل) المعالج بالأنسولين أنهن معرضات بشكل متزايد للإصابة بنقص سكر الدم في فترة ما بعد الولادة (خاصة عند الرضاعة الطبيعية)، وينصحن بتناول وجبة خفيفة قبل أو أثناء الرضاعة.

يجب على النساء المصابات بسكري الحمل التوقف عن العلاج الخافض للسكر في الدم فور الولادة

يمكن للنساء المصابات بالسكري من النوع 2 (الموجود مسبقًا قبل الحمل) والمرضعات استئناف استخدام الميتفورمين (جلوكوفاج) بعد الولادة مباشرة، ولكن يجب تجنب أي علاج خافض للجلوكوز في الدم آخر يؤخذ بالفم أثناء الرضاعة الطبيعية.

يجب على النساء المصابات بالسكري المرضعات الاستمرار في تجنب أي أدوية لمضاعفات مرض السكري والتي كان قد تم إيقافها لأسباب تتعلق بالسلامة عندما بدأن التخطيط للحمل

المتابعة بعد الولادة

النساء المصابات بالسكري الموجود مسبقًا (منذ قبل الحمل)

ينصح بإحالة النساء المصابات بالسكري الموجود مسبقًا إلى رعايتهن الروتينية لمرض السكري

ينصح بتذكير النساء المصابات بالسكري بأهمية وسائل منع الحمل والحاجة إلى رعاية ما قبل الحمل عند التخطيط للحمل مرة أخرى في المستقبل

النساء المصابات بسكري الحمل

قبل نقل النساء المصابات بسكري الحمل إلى الرعاية المجتمعية (وحدات الرعاية الأولية)، يجب أن نختبر مستوى السكر في الدم لاستبعاد استمرار ارتفاع السكر في الدم بعد الحمل، وينصح بتذكير النساء المصابات بسكري الحمل بأعراض ارتفاع السكر في الدم.

يجب توعية النساء المصابات بسكري الحمل بمخاطر تكرار الحمل في المستقبل، ويعرض عليهن اختبار السكري عند التخطيط للحمل في المستقبل.

بالنسبة للنساء المصابات بسكري الحمل، إذا عادت مستويات السكر في الدم إلى وضعها الطبيعي بعد الولادة::

يجب تقديم نصائح حول نمط الحياة (بما في ذلك الحفاظ على الوزن والنظام الغذائي المناسبين والتمارين الرياضية)

كما يجب تقديم اختبار الجلوكوز الصومي في الدم بعد 6 إلى 13 أسبوعًا من الولادة لاستبعاد مرض السكري (لأسباب عملية قد يحدث هذا في فحص ما بعد الولادة بـ 6 أسابيع)



يجب توعيتهن بأن لديهن احتمالية منخفضة للإصابة بمرض السكري في الوقت الحالي ويجب أن يستمروا في اتباع نصائح تحسين نمط الحياة (بما في ذلك التحكم في الوزن والنظام الغذائي والتمارين الرياضية) المقدمة بعد الولادة وسيحتجن إلى اختبار سنوي للتحقق من أن مستويات الجلوكوز في الدم لديهن طبيعية. يجب توعيتهن بأن لديهن خطر  قليل للإصابة بمرض السكري من النوع 2، وتفدم لهن المشورة والتوجيه بشأن الوقاية من مرض السكري من النوع 2

على الجانب الآخر، يجب تقديم المشورة للنساء اللواتي لديهن مستوى جلوكوز صومي في الدم بين 6.0 مليمول / لتر و 6.9 مليمول / لتر بأنهن معرضات بشكل كبير للإصابة بمرض السكري من النوع 2، وتقدم لهن المشورة والتوجيه والتدخلات بشأن الوقاية من مرض السكري من النوع 2

كما يجب توعية النساء اللواتي لديهن مستوى جلوكوز صومي في الدم يبلغ 7.0 مليمول / لتر أو أعلى بأن إصابتهن بمرض السكري من النوع 2 مرجحة، ويعرض عليهن اختبارًا لتأكيد ذلك.

Alpha-1 antitrypsin (AAT) is the most abundant serine proteinase inhibitor in human plasma. When Laurell and Erikson (Laurell C.B., and Erickson S.: The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15: pp. 132-140) first noted the association between a deficiency of the protein (AAT deficiency [AATD]) and emphysema in 1963, they probably didn't know that interest in the mechanisms of chronic obstructive pulmonary disease (COPD) pathogenesis associated with AATD would continue for the next half century. Genetic deficiency of AAT is associated with emphysema, particularly in individuals who smoke cigarettes or are exposed to other inhaled particulates and/or fumes. (Piitulainen E., Tornling G., and Eriksson S.: Environmental correlates of impaired lung function in non-smokers with severe alpha 1-antitrypsin deficiency (PiZZ). Thorax 1998; 53: pp. 939-943) Features of this unique endotype of COPD continue to inform aspects of smoking-related COPD and suggest the pathway forward if cigarette cessation is ever eliminated as a public health risk. In AATD, COPD continues to progress with aging in the absence of smoking. For that reason, this disease helps answer questions on genetic risks, protease/antiprotease biology, and translation of these findings to the AATD patients in the clinic.(https://0710fsntj-1106-y-https-www-clinicalkey-com.mplbci.ekb.eg/#!/content/playContent/1-s2.0-S0272523120300290?scrollTo=%23hl0000338)

Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine-protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein-misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms. Lack of its antiprotease activity is associated with premature development of pulmonary emphysema and loss-of-function due to accumulation of resultant aggregates in chronic obstructive pulmonary disease (COPD). This’ in turn’ markedly reduces the amount of AAT that is available to protect lungs against proteolytic attack by the enzyme neutrophil elastase. The coalescence of AAT deficiency, its reduced efficacy, and cigarette smoking or poor ventilation conditions have devastating effect on lung function. (https://www.sciencedirect.com/science/article/pii/S1383574216300771?casa_token=P7-lgf7zzYYAAAAA:hwS0imIV1TU5hMDszcwqohqoZCfWhIALuT9YC0UU3Y8Wpb43X-Bs9zTLkIrTFseWpoqMdaKTL1jn)

Severe α1-antitrypsin (AAT) deficiency is a rare autosomal codominant genetic condition caused by mutations of the SERPINA1 gene, which mainly affects Caucasian individuals of European heritage. (Αlpha1-antitrypsin in Europe: geographical distribution of Pi types S and Z DCS Hutchison Respir Med, 92: 367-377, 1998) In clinical practice, 96% of severe AAT deficiency index cases are homozygous for the SERPINA1 Z mutation (Glu342Lys) expressing a protease inhibitor ZZ (PiZZ) genotype.

The percentage of α1-antitrypsin protease inhibitor ZZ (PiZZ) genotypes in patients with COPD is controversial, with large differences among various studies. A recent study (https://err.ersjournals.com/lens/errev/29/157/200014) aimed to estimate the prevalence of PiZZ in COPD patients from 20 European countries with available data, according to the number of PiZZ and COPD individuals in each country. The authors found 36 298 PiZZ individuals at high risk and 30 849 709 COPD patients, with a PiZZ/COPD ratio of 0.12% (range 0.08–0.24%), and a prevalence of 1 out of 408 in Northern, 1 out of 944 in Western, 1 out of 1051 in Central, 1 out of 711 in Southern, and 1 out of 1274 in Eastern Europe. These data may be useful to plan strategies for future research and diagnosis, and to rationalise the available therapeutic resources.

Severe alpha-1 antitrypsin (AAT) deficiency, a well-established genetic risk factor for chronic obstructive pulmonary disease (COPD), is relatively common in populations of European ancestry, occurring in about 1 in 3,000 individuals. (Silverman EK, Sandhaus RA. Alpha1-antitrypsin deficiency. N Engl J Med 2009;360:2749–2757.)

Worldwide, there are estimated to be 181,894 and 1,269,054 individuals with the PI*ZZ and PI*SZ genotypes, respectively.(Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. de Serres FJ, Blanco I Ther Adv Respir Dis. 2012 Oct; 6(5):277-95.)

However, only a small fraction of these individuals have been identified and most patients are identified long after symptoms begin (Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Stoller JK, Sandhaus RA, Turino G, Dickson R, Rodgers K, Strange C Chest. 2005 Oct; 128(4):1989-94.)

Despite the status of AATD as a rare disease, it is one of the most common fatal genetic disorders, and respiratory failure accounts for as much as 45% of deaths in never smoking AATD patients (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373587/)

SERPINA1 Z mutation results in the synthesis of a structurally malformed Z-AAT glycoprotein, which polymerises and is retained in hepatocytes, predisposing PiZ homozygotes to neonatal hepatitis, liver cirrhosis and hepatocellular carcinoma, while the subsequent secretory defect results in a marked reduction of about 80% of both its inhibitory capacity against neutrophil elastase and the circulating levels of the protein, which may be insufficient to ensure a lifetime of protection of the lungs from the proteolytic damage of proteinases, thus favouring the development of COPD in adults (https://err.ersjournals.com/lens/errev/29/157/200014#content/citation_reference_1) (The mechanism of Z α1 antitrypsin accumulation in the liver DA Lomas, DL Evans, JT Finch Nature, 357: 605-607, 1992.)

In clinical practice, lung emphysema and chronic bronchitis are the most common clinical phenotypes of COPD associated with PiZZ deficiency.(Characteristics of Italian and Spanish patients with alpha-1-antitrypsin deficiency: Identifying clinical phenotypes B Piras, I Ferrarotti, B Lara Eur Respir J, 42: 54-64, 2013) Environmental factors, particularly cigarette smoke, greatly increase the risk of COPD development (American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency American Thoracic Society, European Respiratory Society Am J Respir Crit Care Med, 168: 818-900, 2003), and while the onset of respiratory disease in smokers occurs in the third or fourth decades of life, in nonsmokers the onset can be delayed to the fifth or sixth decades, and even some nonsmokers may have a normal life span without developing COPD or other diseases associated with AAT deficiency. (Survival in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison to a general population with known smoking habits HA Tanash, M Ekström, E Rönmark Eur Respir J, 50: 2017) (Ongoing research in Europe: Alpha One International Registry (AIR) objectives and development

RA Stockley, M Luisetti, M Miravitlles

Eur Respir J, 29: 582-586, 2007) (Long-term evolution of lung function in individuals with alpha-1 antitrypsin deficiency from the Spanish Registry

C Esquinas, S Serreri, M Barrecheguren) (Serum levels of alpha1-antitrypsin and their relationship with COPD in the general Spanish population

S Janciauskiene, DS DeLuca, M Barrecheguren

Arch Bronconeumol, 56: 76-83, 2020)

This striking variability of clinical expression suggests that in a number of cases AAT deficiency alone is not enough to cause COPD, and that, in addition to smoking and other environmental pollutants, genetic modifiers not yet definitively identified likely influence this clinical variability (Exome sequencing reveals immune genes as susceptibility modifiers in individuals with α1-antitrypsin deficiency

C Rigobello, S Baraldo, M Tinè

Sci Rep, 9: 2019) (European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency

M Miravitlles, A Dirksen, I Ferrarotti

Eur Respir J, 50: 2017). In fact, according to the data provided by registries of patients with AAT deficiency, the genetic penetrance of the SERPINA1 Z homozygotes (i.e. number of individuals with the PiZZ genotype who develop COPD) reaches at most 60%. This is an important fact to consider, as severe AAT deficiency is the only subtype of COPD with a specific augmentative therapy with infusions of purified plasma-derived AAT (Augmentation therapy for emphysema due to alpha-1 antitrypsin deficiency: Pro M Barrecheguren, M Miravitlles Arch Bronconeumol, 54: 363-364, 2018); so it's of high importance to know the number of patients with PiZZ at high risk of developing COPD in each country, in order to enhance awareness of this association among healthcare providers and the general public, for planning health policies and financial medical resources and their utilisation by the scientific community, governments and pharmaceutical industry.(https://err.ersjournals.com/lens/errev/29/157/200014#content/citation_reference_9)

A study from the 1980s found that 1.87% of 965 patients with COPD had PiZZ-AAT deficiency. However, subsequent screening studies provided much lower rates of prevalence, while case-finding programmes that focused on individuals with low serum levels of AAT and clinical or radiological data indicative of AAT deficiency provided higher detection rates.(Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis

T Greulich, CF Vogelmeier

Ther Adv Respir Dis, 10: 72-84, 2016)

The genetics of AATD

AAT is coded by the serine-protease inhibitor (SERPINA1) gene which encodes a 52 kDa AAT protein whose locus is located on chromosome 14q32.1 close to immunoglobulin heavy chain cluster (Bashir A, Shah NN, Hazari YM, et al. Novel variants of SERPIN1A gene: interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease. Respir Med 2016; 117: 139–149).

Mature AAT protein is secreted in the blood after cleaving the first 24 amino acids of the N-terminal region which codes for signal peptide in the rough endoplasmic reticulum. However, AAT is a polymorphic protein with >100 genetic variants coded for by two alleles in a co-dominant manner [Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Respir J 2017; 50: 1700610.].

Many of these reflect point mutations in the gene sequence leading to amino acid substitutions, which may affect the electrophoretic mobility of the resulting AAT protein. In effect, a large body of evidence has shown that SERPINA1 is highly polymorphic, and mutations in this gene cause a hereditary co-dominant autosomal disorder [Greene CM, Marciniak SJ, Teckman J, et al. α1-Antitrypsin deficiency. Nat Rev Dis Primers 2016; 2: 16051.].

Pathological SERPINA1 variants are classified as either deficient or null. Deficient variants occur as a result of a point mutation that causes retention of the AAT in the cytoplasm. Null mutations generally occur owing to the presence of a premature stop codon and patients with these mutations have no detectable AAT in serum. Isoelectric focusing detects these variants, which are labelled A–Z depending on their mobility, i.e. faster or slower, compared to the most common (normal variant) labelled M, branded with earlier or later letters, respectively.

Other common variants are S and Z, with MM, MS, MZ, SS, SZ and ZZ protein phenotypes accounting for >99% of all variants in most of population surveys. Dysfunctional variants lead to abnormal function of AAT, with reduced binding to neutrophil elastase (as in the F variant) or, as with Pittsburgh, structural abnormality that causes the protein to serve as a thrombin inhibitor rather than as an anti-elastolytic protein, causing a bleeding diathesis [Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 2005; 365: 2225–2236.].

Common M alleles account for ∼95% of those observed in the Caucasian population, and are characterised by normal levels of serum AAT [Bashir A, Shah NN, Hazari YM, et al. Novel variants of SERPIN1A gene: interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease. Respir Med 2016; 117: 139–149.], with serum AAT levels ranging between 102 and 254 mg·dL−1 [Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA, University of Washington, Seattle; 1993–2020. www.ncbi.nlm.nih.gov/ books/NBK1519/ Date last accessed: August 16, 2019. Date last updated: Jan 19, 2017].

AAT alleles that confer high risk for the pathogenesis of pulmonary emphysema are those in which deficiency or null alleles are combined in homozygous, heterozygous or compound heterozygous states that result in serum AAT levels below a defensive threshold (57 mg·dL−1 ). The MS variant of AAT is associated with minor reductions in serum AAT levels (86–218 mg·dL−1 ) [7]. Z variant of AAT, characterised by one amino acid substitution of lysine for glutamic acid at position 342 is the commonest deficient variant [6]. It has reduced capacity to inhibit neutrophil elastase. Serum AAT levels in subjects with the MZ phenotype are 62–151 mg·dL−1 [Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle, WA, University of Washington, Seattle; 1993–2020. www.ncbi.nlm.nih.gov/ books/NBK1519/ Date last accessed: August 16, 2019. Date last updated: Jan 19, 2017]. Presence of two copies of mutant Z allele is associated with severe AATD with serum levels ranging between ⩽29 and 52 mg·dL−1.

Controversial results have been published revealing chronic obstructive pulmonary disease (COPD) risk among protease inhibitor (Pi)MZ heterozygotes. A normal protease/antiprotease balance exists in healthy (MM) individuals, in which high levels of MAAT surround the resting neutrophil [Carroll TP, O’Brien ME, Fee LT, et al. Alpha-1 antitrypsin deficiency – a missed opportunity in COPD? In: Panos R, ed. COPD Clinical Perspectives. London, IntechOpen, 2014]. During exposure to increasing levels of interleukin (IL)-8 the cell moves down a concentration gradient of AAT and up a gradient of IL-8, thus leading to neutrophil migration to the area of inflammation [2].

Nonsmoking MZ individuals have intermediate levels of AAT and increased sputum IL-8 levels and neutrophil counts. In AATD individuals homozygous for the Z allele, low levels of circulating ZAAT surround the neutrophil and the described AAT gradient is grossly disrupted, resulting in increased chemotactic responsiveness of neutrophils with an overwhelmed anti-protease defence that contributes to the development of COPD. In smoking MZ individuals, reactive oxygen species in cigarette smoke inactivate AAT, resulting in a protease/antiprotease imbalance with increased amounts of neutrophil elastase. Polymerisation of ZAAT protein and increased amounts of IL-8 intensify neutrophil influx into the MZ lung, which could facilitate the development of COPD [Bergin DA, Hurley K, McElvaney NG, et al. Alpha-1 antitrypsin: a potent anti-inflammatory and potential novel therapeutic agent. Arch Immunol Ther Exp 2012; 60: 81–97.].

In fact, ZAAT polymers found within lungs can also fuel inflammation in the AAT deficiency [3]. Since ZAAT polymers are chemotactic for neutrophils, co-localisation can trigger the release of myeloperoxidase and upregulation of neutrophil adhesion molecules [3]. It has been found that ZAAT polymers co-localise with neutrophils in the alveoli of patients with AAT deficiency [3]. Accumulation of ZAAT in the rough endoplasmic reticulum of hepatocytes leads to reduced availability of AAT in the circulation, and thus AAT is insufficient to neutralise the excessive amount of protease synthesised, especially in the lungs during the course of inflammation [3]. Presence of Z-polymer in the circulation and in bronchoalveolar lavage fluid of patients with severe AATD generates a substantial concentration dependent influx of neutrophils that is not driven by chemokines. Furthermore, ZAAT creates endoplasmic reticulum stress in the hepatocytes, which may have severe consequences in the liver ranging from liver cirrhosis to hepatocellular carcinoma directly [3].