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備孕、反覆流產、妊娠糖尿病、妊娠高血壓與孕期不適，常常不只是單一器官問題。青璞中醫從中醫體質、睡眠、腸胃、循環、壓力與免疫發炎狀態出發，協助備孕與孕期女性進行安全、個別化的體質調理。
關鍵字：
青埔中醫、青埔中醫推薦、桃園中醫、備孕中醫調理、懷孕中醫調理、反覆流產中醫、妊娠糖尿病中醫、孕期體質調理、青璞中醫
為什麼備孕與懷孕期間，不能只想著「補」？
為什麼備孕與懷孕期間，不能只想著「補」？
很多人在準備懷孕、懷孕初期，或曾經有流產、著床不穩、妊娠糖尿病、妊娠高血壓等經驗時，第一個想到的常常是：「是不是身體太虛？是不是要補一下？」
但在臨床上，身體的狀態往往比「虛不虛」複雜得多。
有些人確實是氣血不足，容易疲倦、頭暈、手腳冷、月經量少，這類人可能需要補養。但也有些人是壓力大、睡不好、肝氣鬱結、胃腸濕熱、痰濕偏重，甚至本來就容易口乾、便秘、長痘、胸悶、煩躁。這時如果一味進補，反而可能讓身體更悶、更熱、更不舒服。
從現代醫學研究來看，懷孕並不是單純「營養夠不夠」的問題，而是母體、胚胎、胎盤、免疫系統、血管循環與代謝狀態之間非常細緻的平衡。孕期需要足夠的免疫防禦，卻不能過度發炎；需要良好的血液供應，卻不能讓血管與凝血系統過度緊張；需要能量與營養，卻也要避免血糖、胰島素與脂肪代謝失衡。
這也是為什麼在青璞中醫，我們看備孕與孕期調理時，不會只問「要不要補」，而會回到一個更重要的問題：
你的身體現在是需要補？需要清？需要疏？需要安？還是需要先把睡眠、腸胃與壓力穩下來？
現代研究提醒我們：孕期健康與「免疫發炎平衡」有關
現代研究提醒我們：孕期健康與「免疫發炎平衡」有關
近年免疫醫學研究越來越重視一種現象，稱為 NETs，中文可稱為「嗜中性球胞外網」。簡單說，嗜中性球是人體免疫系統中很重要的白血球，當身體遇到感染或刺激時，它可以釋放出像網子一樣的結構，把病原體困住，協助身體防禦。
這本來是身體保護自己的機制。
但問題在於，如果這種免疫反應太強、太久，或清除不順，就可能從保護變成負擔。過多的免疫發炎反應，可能影響血管內皮、胎盤環境、凝血狀態與母胎介面的穩定。現代研究已經發現，NETs 失衡與子癲前症、妊娠糖尿病、早產、反覆流產、紅斑性狼瘡相關妊娠問題、抗磷脂症候群相關妊娠問題等有關。
這不代表每一位孕婦都需要檢測 NETs，也不代表所有孕期問題都能用單一免疫機制解釋。更不代表中醫治療可以取代婦產科追蹤。
但這些研究提供了一個很重要的提醒：
備孕與懷孕期間，身體不是越補越好，而是要維持一個適當、穩定、可調節的狀態。
中醫所說的「調體質」，其實也可以從這個角度來理解：不是把身體推向某一個極端，而是讓氣血、寒熱、濕燥、升降、睡眠、腸胃、月經與情緒壓力慢慢回到比較穩定的節奏。
從中醫看備孕：不是只有卵子和子宮，也要看整個人
從中醫看備孕：不是只有卵子和子宮，也要看整個人
備孕調理常常會被簡化成「調卵」、「補腎」、「補子宮」。這些說法雖然容易理解，但臨床上不能只看局部。
中醫在看備孕時，會觀察的是整個身體環境。月經週期是否穩定？經血顏色是否過深或過淡？有沒有血塊？排卵期分泌物如何？經前會不會胸脹、煩躁、頭痛、失眠？平常腸胃好不好？容易腹瀉或便秘？睡眠品質如何？壓力大時身體會出現什麼反應？
這些看似分散的症狀，其實都可能反映身體的調節能力。
例如，有些人是「氣血不足」型，常見表現包括容易疲倦、臉色偏白、月經量少、頭暈、心悸、睡眠淺。這類人備孕時，重點可能是補氣養血、穩定脾胃吸收。
有些人是「肝鬱氣滯」型，常見表現包括壓力大、胸悶、經前乳房脹痛、情緒起伏、睡不好、排卵期或月經前特別不舒服。這類人不能只補，還要疏肝理氣，讓身體不要長期處在緊繃狀態。
有些人是「痰濕偏重」型，常見表現包括容易水腫、身體沉重、胃脹、痰多、白帶多、體重上升、代謝變慢。這類人體質若只是一直補，可能越補越悶，反而更不舒服。
也有些人是「陰虛火旺」或「內熱偏盛」型，可能容易口乾、便秘、煩躁、睡眠差、冒痘、夜間盜汗。這時如果自行吃溫補藥膳、人參、鹿茸、薑母鴨、麻油雞等，未必適合。
所以備孕中醫調理的重點，不是所有人都使用同一套補藥，而是辨證後確認：現在身體最需要被調整的是哪一個環節。
反覆流產、著床不穩：中醫會注意哪些身體訊號？
反覆流產、著床不穩：中醫會注意哪些身體訊號？
曾經歷流產、胚胎萎縮、著床不穩，或人工受孕、試管療程反覆失敗的人，常常承受很大的心理壓力。這類狀況一定要先配合婦產科與生殖醫學檢查，包括染色體、子宮結構、荷爾蒙、免疫、凝血、感染、甲狀腺、血糖與其他相關因素。
中醫不能取代這些檢查，也不能保證改善懷孕結果。
但中醫可以做的是，在西醫追蹤之外，從體質角度協助身體進入比較穩定的狀態。尤其在反覆流產或著床不穩的患者身上，我們會特別留意幾個面向：
第一，月經狀態。月經太少、週期不穩、經血有血塊、經前症狀明顯，都可能提示氣血、肝鬱、瘀滯或寒熱失衡。
第二，睡眠與壓力。長期失眠、半夜醒、早醒、睡醒仍疲倦，會影響身體修復與內分泌節律。很多備孕女性不是不努力，而是身體長期處於高壓狀態，沒有真正休息下來。
第三，腸胃吸收。中醫很重視脾胃，因為營養吸收、氣血生成與身體穩定度都與腸胃有關。若經常胃脹、腹瀉、便秘、食慾不穩，就不能只談補腎補血。
第四，發炎與體質熱象。有些人容易長痘、口乾、喉嚨乾、便秘、皮膚癢、睡不好，這類身體訊號可能代表不適合盲目溫補。
第五，循環與瘀滯。手腳冰冷、經痛明顯、血塊多、下腹冷痛，可能需要從溫通、活血、調經方向思考，但懷孕後用藥更需謹慎，必須由醫師面診評估。
妊娠糖尿病與孕期代謝：中醫看的是「脾胃、痰濕與身體負擔」
妊娠糖尿病與孕期代謝：中醫看的是「脾胃、痰濕與身體負擔」
妊娠糖尿病不是單純「吃太甜」造成的，也不是孕婦做錯了什麼。懷孕本身會改變胰島素敏感性，胎盤荷爾蒙也會影響血糖調節。如果本來就有代謝壓力、體重增加、睡眠不足、壓力大、活動量不足，孕期血糖就更容易失衡。
從中醫角度來看，妊娠糖尿病相關體質常常不只是一個「血糖數字」，而是身體整體代謝負擔的表現。臨床可能看到痰濕、脾虛、胃熱、陰虛、肝鬱等不同型態。
有些人懷孕後特別疲倦、胃脹、飯後昏沉、身體沉重，這可能偏向脾虛痰濕。有些人食慾很旺、容易口渴、便秘、口乾，可能偏向胃熱或陰虛內熱。有些人壓力一大就想吃甜食，睡眠變差，血糖也跟著波動，則要把肝鬱、壓力與睡眠一起納入考量。
青璞中醫在面對妊娠糖尿病相關調理時，會提醒患者：飲食控制與婦產科、新陳代謝科追蹤是基礎，中醫調理不能取代血糖監測。中醫能協助的是依照體質，調整睡眠、腸胃、痰濕、壓力與孕期不適，讓身體比較容易回到穩定節奏。
妊娠高血壓、子癲前症風險：一定要以婦產科監測為主
妊娠高血壓、子癲前症風險：一定要以婦產科監測為主
妊娠高血壓與子癲前症是孕期需要高度重視的狀況，可能與血管內皮、胎盤功能、免疫發炎、凝血與多系統壓力有關。若出現血壓升高、蛋白尿、頭痛、視覺模糊、上腹痛、突然水腫、胎動變少等情形，務必立即回婦產科或急診評估。
這類問題不是靠自行吃中藥、食補或保健食品可以處理的。
中醫在這裡的角色，應該是輔助性的體質照護，而不是急症處理。若婦產科評估穩定，且患者有睡眠差、焦慮、胃脹、水腫、疲倦、頭暈等伴隨症狀，可以由合格中醫師在了解孕週、產檢狀況、用藥與風險後，謹慎評估是否適合調理。
尤其懷孕期間用藥需要更保守，不能因為是天然藥材就自行服用。很多活血、攻下、過度溫燥或過度寒涼的藥物，都不適合在孕期自行使用。
懷孕期間可以看中醫嗎？
懷孕期間可以看中醫嗎？
可以，但前提是要安全、保守、清楚知道目的。
懷孕期間看中醫，常見需求包括孕吐、胃脹、便秘、睡眠不佳、疲倦、水腫、感冒後咳嗽、鼻過敏、皮膚癢、情緒緊繃、腰痠等。這些狀況若經婦產科確認沒有急性危險，中醫可以依照體質進行輔助調理。
但有幾件事很重要：
第一，不建議孕期自行購買中藥粉、藥膳包或網路偏方。
第二，就診時一定要告知目前孕週、產檢狀況、是否有出血、宮縮、胎盤位置、妊娠糖尿病、妊娠高血壓或其他高風險狀況。
第三，若正在使用阿斯匹靈、肝素、黃體素、降血糖藥、免疫相關藥物或其他婦產科處方，一定要主動告知中醫師。
第四，中醫調理應與婦產科照護配合，而不是互相取代。
青璞中醫如何看備孕與孕期體質？
青璞中醫如何看備孕與孕期體質？
在青璞中醫，我們比較重視「把身體狀態講清楚」。
很多患者來看診時，會說：「我是不是太虛？」但實際詢問後，可能發現她同時有睡不好、胃脹、壓力大、經前煩躁、便秘、手腳冰冷、容易冒痘。這時如果只用一句「太虛」來概括，反而容易忽略真正需要調整的順序。
我們會從幾個方向評估：
月經與排卵節律：週期、經量、經色、血塊、經痛、經前症狀。
睡眠與壓力狀態：入睡困難、半夜醒、早醒、多夢、醒來疲倦。
腸胃與代謝：胃脹、腹瀉、便秘、食慾、飯後疲倦、痰濕、水腫。
寒熱與發炎傾向：怕冷、怕熱、口乾、皮膚癢、痘痘、喉嚨乾、便秘。
循環與氣血：頭暈、心悸、手腳冰冷、疲倦、臉色、經血狀態。
孕期安全性：孕週、產檢結果、目前用藥、是否高風險妊娠。
這樣做的目的，是避免把所有備孕與孕期問題都套進同一個公式。每個人的身體狀態不同，中醫處方、針灸、飲食建議與生活調整，也應該因人而異。
常見問題
常見問題
Q1：備孕一定要補腎嗎？
Q1：備孕一定要補腎嗎？
不一定。補腎是中醫備孕調理中的一個常見方向，但不是唯一方向。有些人確實需要補腎、補氣血；但有些人更需要疏肝、健脾、化痰濕、清內熱、改善睡眠與壓力。如果本身火氣大、便秘、痘痘多、睡不好，盲目溫補可能不適合。
Q2：懷孕後還可以吃中藥嗎？
Q2：懷孕後還可以吃中藥嗎？
懷孕後是否適合中藥，需要由合格中醫師面診判斷，並且要清楚告知孕週、產檢狀況與目前用藥。孕期中藥應以安全、必要、保守為原則，不建議自行購買藥粉或偏方。
Q3：反覆流產可以靠中醫治好嗎？
Q3：反覆流產可以靠中醫治好嗎？
反覆流產一定要先做婦產科與必要的生殖醫學檢查，確認是否有染色體、子宮結構、荷爾蒙、免疫、凝血、感染或代謝問題。中醫可以作為輔助調理，協助改善體質、睡眠、腸胃、壓力與月經狀態，但不能保證懷孕結果，也不能取代西醫檢查與治療。
Q4：妊娠糖尿病可以看中醫嗎？
Q4：妊娠糖尿病可以看中醫嗎？
可以作為輔助調理，但血糖監測、飲食控制與婦產科追蹤仍是核心。中醫會依體質評估脾胃、痰濕、胃熱、陰虛、睡眠與壓力狀態，協助身體穩定，但不能取代血糖控制。
Q5：青埔附近想找備孕中醫，可以怎麼準備第一次看診？
Q5：青埔附近想找備孕中醫，可以怎麼準備第一次看診？
建議帶上近期抽血報告、婦產科檢查結果、月經紀錄、基礎體溫或排卵紀錄、目前使用的藥物與保健品。若已懷孕，請務必告知孕週、產檢狀況與是否有高風險妊娠。
結語：真正的備孕與孕期調理，是讓身體回到穩定
結語：真正的備孕與孕期調理，是讓身體回到穩定
備孕與懷孕不是一場單純靠補品完成的任務。它牽涉到睡眠、腸胃、情緒、壓力、代謝、免疫、循環與荷爾蒙之間的協調。
現代研究讓我們看到，孕期健康與免疫發炎平衡、胎盤環境、血管循環和代謝狀態密切相關。中醫則提供另一種觀察身體的方式：從氣血、陰陽、寒熱、痰濕、瘀滯與臟腑功能，理解為什麼有些人明明很努力備孕，身體卻一直沒有真正穩下來。
青璞中醫位於桃園青埔，提供備孕、孕期不適與女性體質調理的中醫評估。若你正在準備懷孕，或曾經歷反覆流產、著床不穩、妊娠糖尿病、妊娠高血壓風險，建議先完成必要的婦產科檢查，再由中醫師依照你的體質、檢查結果與生活狀態，規劃安全、個別化的調理方向。
青埔中醫推薦｜青璞中醫
我們重視的不只是症狀本身，而是症狀背後的身體狀態。備孕與孕期調理，請讓醫師先了解你，再決定該不該補、怎麼調、什麼時候該保守。
懷孕不是只要「補」就好：從免疫發炎、胎盤循環到中醫體質調理
懷孕不是只要「補」就好：從免疫發炎、胎盤循環到中醫體質調理
一、為什麼備孕與懷孕調理，不能只問「要不要補」？
一、為什麼備孕與懷孕調理，不能只問「要不要補」？
很多女性在備孕、懷孕初期，或曾經歷著床不穩、胚胎萎縮、反覆流產、妊娠糖尿病、妊娠高血壓時，第一個想到的常常是：
「是不是身體太虛？」
「是不是子宮太寒？」
「是不是要補氣血、補腎、補黃體？」
這些想法並不是完全錯。中醫確實很重視氣血、腎氣、脾胃與子宮環境。但如果把所有備孕與孕期問題都簡化成「身體太虛，所以要補」，反而可能忽略更重要的問題。
懷孕不是單純把營養補進去就好。現代免疫醫學研究顯示，懷孕是一個非常精密的母胎互動過程，牽涉到免疫防禦、胎盤發育、血管內皮、凝血狀態、代謝調節與發炎反應。母體需要有足夠免疫力來防禦感染，但免疫反應又不能過度；胎盤需要良好血流，但血管與凝血系統不能過度緊張；身體需要供應胎兒營養，但血糖與代謝也不能失衡 [1]。
因此，從青璞中醫的角度來看，備孕與懷孕調理的重點不只是「補」，而是要先問：
現在身體是需要補？需要清？需要疏？需要化濕？需要安神？還是需要先讓睡眠、腸胃、壓力與循環穩下來？
二、什麼是 NETs？為什麼和懷孕有關？
二、什麼是 NETs？為什麼和懷孕有關？
近年研究越來越重視一種免疫現象，稱為 neutrophil extracellular traps，簡稱 NETs，中文可稱為「嗜中性球胞外網」。
嗜中性球是人體血液中很重要的一種白血球，也是先天免疫系統的第一線防禦細胞。當身體遇到細菌、病毒、黴菌、寄生蟲，或某些發炎刺激時，嗜中性球可以釋放出由 DNA、組蛋白與顆粒蛋白組成的網狀結構，把病原體困住、限制擴散，協助身體清除感染 [1,2]。
所以 NETs 本來是保護機制。
但問題在於，NETs 是一把雙面刃。適度形成時，它有助於防禦感染；如果形成過多、持續存在，或清除不良，就可能造成發炎放大、血管內皮受損、凝血活化與組織傷害 [1,3]。
在懷孕期間，這件事特別重要。因為母胎介面本來就需要一種很精細的免疫平衡：母體不能完全排斥胎兒，也不能讓感染輕易入侵。文獻指出，正常懷孕時，NETs 在母胎介面可能扮演抗感染防禦角色；但若 NETs 調控失衡，則與多種妊娠併發症有關，包括子癲前症、妊娠糖尿病、早產、反覆流產、紅斑性狼瘡相關妊娠不良結果，以及抗磷脂症候群相關妊娠問題 [1]。
三、正常懷孕：免疫不是變弱，而是重新調節
三、正常懷孕：免疫不是變弱，而是重新調節
很多人以為懷孕就是免疫力下降，但更精確地說，懷孕期間的免疫系統不是單純變弱，而是重新調節。
文獻提到，在正常懷孕過程中，嗜中性球會受到懷孕相關荷爾蒙與細胞激素影響。例如 G-CSF、人類絨毛膜促性腺激素 hCG、雌二醇 E2 等因素，可能促進 NETs 生成；而黃體素 P4 與滋養層細胞分泌的 vasoactive intestinal peptide，則可能抑制過度的嗜中性球活化與 NETs 形成 [1,4,5]。
這個平衡很有意思。
一方面，適度的 NETs 有助於母胎介面抵禦感染。另一方面，黃體素與胎盤相關訊號又會避免 NETs 過度形成，以免傷害血管內皮與胎盤組織 [1]。
用中醫的語言來轉譯，這其實很接近「懷孕不是單純大補，而是要維持陰陽、氣血、寒熱、升降的穩定」。如果身體太虛，確實可能不穩；但如果發炎太旺、熱象太重、痰濕太盛、氣機太鬱、睡眠太差，也一樣會讓身體難以維持穩定。
所以備孕與孕期調理不能只用「補不補」來判斷，而要回到整體體質。
四、子癲前症與妊娠高血壓：血管、胎盤與發炎失衡
四、子癲前症與妊娠高血壓：血管、胎盤與發炎失衡
子癲前症是懷孕 20 週後可能出現的重要妊娠併發症，核心表現包括新發生的高血壓、蛋白尿，或在沒有蛋白尿的情況下出現其他器官受損。這是需要婦產科嚴密監測的狀況，不能用中醫調理取代產檢與必要治療 [6,7]。
文獻指出，子癲前症患者常見嗜中性球增加，而且與疾病嚴重度有關；相較於正常懷孕，子癲前症患者的 NETs 形成增加，母體循環與胎盤組織中也可見嗜中性球過度活化與 NETs 增加 [1,8,9]。
其可能機制包括胎盤來源的 syncytiotrophoblast microparticles、IL-8、sFlt-1 等因素活化嗜中性球，促進 NETs 釋放。過多 NETs 可能造成氧化壓力、滋養層細胞功能受損、血管內皮損傷、補體活化與局部發炎，進一步影響螺旋動脈重塑與胎盤血管發育 [1,10,11]。
從中醫臨床角度來看，這類患者不能被簡化成「孕婦水腫，所以利水」或「懷孕虛，所以補」。如果已經出現血壓升高、蛋白尿、頭痛、視覺模糊、上腹痛、突然水腫、胎動異常，必須優先回婦產科或急診評估。
中醫可以做的是在安全前提下，針對睡眠、壓力、腸胃、體質寒熱與水腫不適做輔助調整，但不能宣稱治療子癲前症，也不能延誤產科處置。
五、妊娠糖尿病：不只是血糖，也是代謝與免疫發炎問題
五、妊娠糖尿病：不只是血糖，也是代謝與免疫發炎問題
妊娠糖尿病是懷孕期間出現或首次發現的葡萄糖耐受異常。它不只是「吃太甜」造成，也不代表孕婦做錯了什麼。懷孕本身會改變胰島素敏感性，胎盤荷爾蒙也會影響血糖調控 [12,13]。
文獻整理指出，妊娠糖尿病患者可能出現嗜中性球活化增加、NETs 形成傾向上升。研究也提到，妊娠糖尿病患者血中 TNF-α 增加、adiponectin 降低、高血糖誘發 PAD4 活化等因素，都可能促進 NETs 過度形成 [1,14,15]。
此外，NETs 不只是出現在血液中，也可在妊娠糖尿病患者的胎盤組織中增加。過多 NETs 可能影響滋養層細胞的增殖、侵入、遷移與血管新生能力，並可能透過 ROS 相關路徑促進滋養層細胞凋亡 [1,15]。
用中醫的語言來說，妊娠糖尿病相關體質往往不只是一個「血糖數字」，而可能牽涉到脾胃運化、痰濕、內熱、陰虛、肝鬱與睡眠壓力。
有些人是飯後昏沉、胃脹、身體沉重、水腫，偏向脾虛痰濕。
有些人是口乾、便秘、容易餓、煩躁，偏向胃熱或陰虛內熱。
有些人是壓力大、睡不好、情緒波動後血糖更不穩，則需要把肝鬱與自律神經壓力納入考量。
但不論是哪一型，妊娠糖尿病都必須以婦產科與營養衛教追蹤為基礎。中醫調理只能作為輔助，協助穩定睡眠、腸胃、壓力與體質狀態，不能取代血糖監測、飲食控制與醫囑用藥。
六、早產風險：感染、發炎與胎膜穩定
六、早產風險：感染、發炎與胎膜穩定
早產是指懷孕未滿 37 週即分娩。文獻指出，子宮內感染是 spontaneous preterm birth 的重要誘發因素之一，而絨毛膜羊膜炎常伴隨大量嗜中性球浸潤與母胎介面發炎反應 [1,16]。
研究顯示，在早產與急性絨毛膜羊膜炎相關情境中，羊水、胎膜與羊膜組織可觀察到 NETs 形成增加。細菌刺激、LPS、B 群鏈球菌、TNF-α 與 MAPK/ROS 相關路徑，都可能促進 NETs 形成 [1,17,18]。
NETs 可能進一步促進 ROS 生成，誘導羊膜上皮細胞凋亡，影響胎膜完整性。由於 NETs 含有 neutrophil elastase 等水解酶，文獻也推測其可能影響膠原纖維與胎膜機械強度，但這部分仍需要更多研究確認 [1]。
這對臨床的提醒是：懷孕期間如果有規則宮縮、出血、破水感、異常分泌物、發燒、下腹痛或胎動改變，不能先想著「吃中藥安胎」，而是要立即回婦產科評估是否有感染、早產徵象或其他急性問題。
中醫在孕期可以協助處理某些體質性不適，例如睡眠差、胃脹、便秘、疲倦、咳嗽、鼻過敏等，但凡涉及早產風險，都必須以婦產科處置優先。
七、反覆流產：免疫、凝血與母胎介面不能被忽略
七、反覆流產：免疫、凝血與母胎介面不能被忽略
反覆流產通常指連續兩次或以上的妊娠喪失。原因可能非常複雜，包括胚胎染色體、子宮結構、內分泌、甲狀腺、感染、免疫、凝血、代謝與不明原因等 [19,20]。
文獻指出，在反覆流產或自然流產相關研究中，NLR 可能升高，血清與蛻膜組織中也可觀察到 NETs 增加。部分研究也提到，低密度顆粒球 LDGs 在自然流產患者蛻膜組織中比例失衡，且這類細胞更容易活化與釋放 NETs [1,21,22]。
此外，動物研究顯示，sFlt-1 過度表現可能誘發胎盤 NETs 累積與妊娠喪失，而 PAD4 基因敲除可減輕相關不良結果。這提示 NETs 可能是某些妊娠喪失機制的一部分，但文獻也明確指出：目前直接證明 NETs 導致反覆流產的因果證據仍不足，具體分子機制仍待釐清 [1]。
這一點非常重要。
所以在青璞中醫的文章裡，不能寫成「反覆流產就是 NETs 太多」或「中醫可以抑制 NETs 來保胎」。這樣太過度。
比較正確的說法是：現代研究提醒我們，反覆流產不能只用「子宮虛寒」或「氣血不足」來解釋。它可能牽涉到免疫、凝血、胎盤發育、發炎與母胎介面穩定。中醫調理可以從月經、睡眠、腸胃、壓力、氣血、寒熱、痰濕與瘀滯等方向評估身體狀態，但仍需要配合婦產科與生殖醫學檢查。
八、紅斑性狼瘡、抗磷脂症候群：高風險妊娠需要整合照護
八、紅斑性狼瘡、抗磷脂症候群：高風險妊娠需要整合照護
文獻也討論了紅斑性狼瘡 SLE 與抗磷脂症候群 APS 相關的妊娠問題。
SLE 是全身性自體免疫疾病，女性比例高，懷孕時可能增加流產、子癲前症、早產與胎兒生長受限等風險。研究指出，SLE 患者可能存在 NETs 清除不足、低密度顆粒球增加、胎盤 NETs 浸潤，以及與 trophoblast pyroptosis、decidual NK cell 變化相關的胎盤損傷機制 [1,23,24]。
APS 則與抗磷脂抗體、血栓與妊娠不良結果有關。文獻指出，抗磷脂抗體可透過 TLR4 活化嗜中性球，促進 ROS 與 NETs 形成；NETs 進一步可能影響滋養層細胞與血管內皮細胞功能，造成胎盤損傷 [1,25]。
這些內容對青璞中醫的臨床溝通很重要，因為它提醒我們：如果患者有 SLE、APS、反覆流產、血栓病史、免疫用藥或高風險妊娠，絕對不能把問題簡化成一般體質調理。
這類患者需要婦產科、風濕免疫科、生殖醫學科共同追蹤。中醫若要介入，也必須知道患者目前使用的藥物，例如低劑量阿斯匹靈、肝素、hydroxychloroquine、類固醇或其他免疫相關藥物，避免自行加減藥或使用來路不明的中草藥。
九、文獻提到的藥物：重點不是自行吃，而是理解治療機制
九、文獻提到的藥物：重點不是自行吃，而是理解治療機制
這篇文獻也整理了幾種婦產科或免疫相關臨床常見藥物，可能透過調節 NETs 形成或清除，部分解釋其對妊娠結果的幫助，包括 aspirin、metformin、low molecular weight heparin、hydroxychloroquine 與 vitamin D [1]。
例如，aspirin 可能透過抑制血小板活化與 TXA2 生成，間接降低嗜中性球活化與 NETs 形成；metformin 除了降血糖，也可能影響 NADPH oxidase 或促進巨噬細胞清除 NETs；低分子量肝素可能抑制嗜中性球活化與 NETs 形成，也可能透過結合 histones 減少組織傷害；hydroxychloroquine 可能透過 PAD4 或 TLR9 相關路徑影響 NETs；vitamin D 則可能透過全身性發炎細胞激素狀態影響 NETs 生成能力 [1,26-30]。
但這裡一定要強調：這不是鼓勵孕婦自行服用 aspirin、metformin、肝素、hydroxychloroquine 或高劑量 vitamin D。
這些藥物都有明確適應症、風險與監測需求，必須由婦產科、新陳代謝科、風濕免疫科或相關專科醫師判斷。文獻本身也指出，目前許多證據仍來自動物或體外研究，人體懷孕不同孕期的直接證據仍不足，NETs 檢測也尚未形成臨床標準化流程 [1]。
因此，對患者來說，這些研究真正的意義不是「看到什麼就自己補什麼、吃什麼」，而是讓我們更理解：孕期健康是一個免疫、發炎、血管、凝血與代謝共同參與的系統。
十、從中醫角度怎麼轉譯這篇研究？
十、從中醫角度怎麼轉譯這篇研究？
這篇文獻是現代免疫學研究，並不是中醫論文。青璞中醫在轉譯時，不能直接宣稱「中醫可以調控 NETs」或「某個中藥可以治療妊娠併發症」。這樣不夠嚴謹。
但這篇文獻可以幫助我們重新理解「體質調理」這件事。
中醫講氣血、陰陽、寒熱、痰濕、瘀血、肝鬱、脾虛、腎虛，看似是傳統語言；現代研究則用免疫細胞、發炎因子、血管內皮、胎盤滋養層、凝血與代謝來描述身體狀態。兩者不是簡單的一對一對應，但都提醒我們：身體不是單一器官在運作，而是一個動態系統。
所以在備孕與孕期調理中，青璞中醫會特別重視以下幾個面向：
睡眠是否穩定。
長期入睡困難、半夜醒、早醒、睡醒仍累，代表身體修復節律不穩。備孕與懷孕都需要身體有足夠的恢復能力。
腸胃吸收是否良好。
脾胃是氣血來源。如果長期胃脹、腹瀉、便秘、食慾不穩，單純補藥未必吸收得進去，也可能越補越脹。
壓力與肝氣是否鬱結。
壓力大、胸悶、經前乳房脹痛、情緒緊繃、睡眠變差，常常會影響月經與備孕節奏。
痰濕與代謝是否偏重。
身體沉重、水腫、痰多、白帶多、飯後昏沉、體重上升，可能提示痰濕與代謝負擔。
寒熱是否失衡。
有些人怕冷、手腳冰冷、經痛明顯；有些人卻口乾、便秘、長痘、煩躁、睡不好。兩者處理方向不同，不能都用同一套補法。
瘀滯與循環是否順暢。
經痛、血塊、經色暗、下腹悶痛，可能提示循環與瘀滯問題。但若已懷孕，活血藥物使用更要謹慎，必須由醫師判斷。
十一、哪些狀況適合考慮中醫輔助調理？
十一、哪些狀況適合考慮中醫輔助調理？
如果正在備孕，或準備進入人工受孕、試管療程前，中醫可以協助從月經週期、睡眠、腸胃、壓力、氣血與體質狀態進行調理。
如果懷孕期間有孕吐、胃脹、便秘、睡不好、疲倦、水腫、咳嗽、鼻過敏、皮膚癢等不適，也可以在婦產科確認安全後，由中醫師依孕週與體質評估是否適合調理。
如果曾經有反覆流產、胚胎萎縮、著床不穩、妊娠糖尿病、妊娠高血壓、SLE、APS 或血栓相關病史，則更需要先完成婦產科、生殖醫學科或風濕免疫科評估。中醫可以作為輔助角色，但不能取代檢查與專科治療。
十二、哪些狀況不能只看中醫？
十二、哪些狀況不能只看中醫？
懷孕期間若出現以下情況，請優先聯絡婦產科或直接就醫：
陰道出血、明顯腹痛、規則宮縮、破水感、胎動明顯減少、血壓升高、劇烈頭痛、視覺模糊、上腹痛、突然嚴重水腫、發燒、感染症狀、血糖明顯異常，或醫師已告知屬於高風險妊娠。
這些狀況不是「先吃中藥看看」的範圍。
安全永遠比調理更重要。
十三、青璞中醫的備孕與孕期調理方式
十三、青璞中醫的備孕與孕期調理方式
青璞中醫位於桃園青埔，面對備孕與孕期患者時，我們會先了解：
月經週期、經量、經色、經痛與血塊狀況。
是否有排卵紀錄、基礎體溫、AMH、荷爾蒙或婦產科檢查資料。
是否曾有流產、胚胎萎縮、著床失敗或試管療程。
目前是否懷孕、孕週幾週、產檢是否正常。
是否有妊娠糖尿病、妊娠高血壓、甲狀腺疾病、SLE、APS 或血栓病史。
目前是否使用 aspirin、肝素、metformin、hydroxychloroquine、黃體素、類固醇或其他藥物。
睡眠、腸胃、壓力、皮膚、鼻過敏、咳嗽、水腫與疲倦狀態。
我們不會把所有人都歸類成「太虛」，也不會把所有人都用同一套補藥。備孕與孕期調理應該是個別化、安全、保守且能與婦產科照護配合的過程。
十四、結語：懷孕是一個平衡，不是一場盲目進補
十四、結語：懷孕是一個平衡，不是一場盲目進補
這篇關於 NETs 與妊娠併發症的研究，對臨床最大的提醒是：
懷孕不是免疫越強越好，也不是免疫越弱越好。
不是越補越好，也不是越清越好。
真正重要的是平衡。
正常懷孕需要適度免疫防禦，也需要避免過度發炎；需要良好胎盤血流，也需要避免血管內皮與凝血系統過度受刺激；需要足夠營養，也需要穩定代謝。
中醫所說的體質調理，若要放在現代醫學脈絡中理解，不應該只是「補腎、補氣血」幾個字，而是要更細緻地看見每個人的睡眠、腸胃、壓力、寒熱、痰濕、氣血與循環狀態。
如果你正在備孕、懷孕，或曾經歷反覆流產、著床不穩、妊娠糖尿病、妊娠高血壓等問題，建議先完成必要的婦產科檢查，再由合格中醫師依照你的體質與目前醫療狀況，規劃安全的輔助調理方向。
青埔中醫推薦｜青璞中醫
我們重視的不只是症狀，而是症狀背後的身體狀態。備孕與孕期調理，請讓醫師先了解你，再決定該不該補、怎麼調，以及什麼時候應該以婦產科照護優先。
參考文獻
參考文獻
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Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nature Reviews Immunology. 2018;18:134–147. doi:10.1038/nri.2017.105.
Wang H, Kim SJ, Lei Y, et al. Neutrophil extracellular traps in homeostasis and disease. Signal Transduction and Targeted Therapy. 2024;9:235. doi:10.1038/s41392-024-01933-x.
Giaglis S, Stoikou M, Sur Chowdhury C, et al. Multimodal regulation of NET formation in pregnancy: Progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Frontiers in Immunology. 2016;7:565. doi:10.3389/fimmu.2016.00565.
Calo G, Sabbione F, Vota D, et al. Trophoblast cells inhibit neutrophil extracellular trap formation and enhance apoptosis through vasoactive intestinal peptide-mediated pathways. Human Reproduction. 2017;32:55–64. doi:10.1093/humrep/dew292.
Ives CW, Sinkey R, Rajapreyar I, Tita ATN, Oparil S. Preeclampsia-pathophysiology and clinical presentations: JACC state-of-the-art review. Journal of the American College of Cardiology. 2020;76:1690–1702. doi:10.1016/j.jacc.2020.08.014.
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Sweeting A, Wong J, Murphy HR, Ross GP. A clinical update on gestational diabetes mellitus. Endocrine Reviews. 2022;43:763–793. doi:10.1210/endrev/bnac003.
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Shen D, Lu Y, Li G, et al. Mechanism of neutrophil extracellular traps generation and their role in trophoblasts apoptosis in gestational diabetes mellitus. Cell Signalling. 2021;88:110168. doi:10.1016/j.cellsig.2021.110168.
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懷孕不是只要「補」就好：從免疫發炎、胎盤循環到中醫體質調理
懷孕不是只要「補」就好：從免疫發炎、胎盤循環到中醫體質調理
Meta description：
備孕、懷孕與反覆流產，不能只從「身體虛不虛」來看。現代研究指出，孕期免疫發炎平衡、胎盤血管、代謝與凝血狀態，都可能影響妊娠過程。青璞中醫從中醫體質、睡眠、腸胃、壓力、氣血循環與寒熱痰濕出發，協助備孕與孕期女性進行安全、個別化的體質調理。
建議關鍵字：
青埔中醫、青埔中醫推薦、青璞中醫、備孕中醫調理、懷孕中醫調理、反覆流產中醫、妊娠糖尿病中醫、孕期體質調理、桃園中醫
一、為什麼備孕與懷孕調理，不能只問「要不要補」？
一、為什麼備孕與懷孕調理，不能只問「要不要補」？
很多女性在備孕、懷孕初期，或曾經歷著床不穩、胚胎萎縮、反覆流產、妊娠糖尿病、妊娠高血壓時，第一個想到的常常是：
「是不是身體太虛？」
「是不是子宮太寒？」
「是不是要補氣血、補腎、補黃體？」
這些想法並不是完全錯。中醫確實很重視氣血、腎氣、脾胃與子宮環境。但如果把所有備孕與孕期問題都簡化成「身體太虛，所以要補」，反而可能忽略更重要的問題。
懷孕不是單純把營養補進去就好。現代免疫醫學研究顯示，懷孕是一個非常精密的母胎互動過程，牽涉到免疫防禦、胎盤發育、血管內皮、凝血狀態、代謝調節與發炎反應。母體需要有足夠免疫力來防禦感染，但免疫反應又不能過度；胎盤需要良好血流，但血管與凝血系統不能過度緊張；身體需要供應胎兒營養，但血糖與代謝也不能失衡 [1]。
因此，從青璞中醫的角度來看，備孕與懷孕調理的重點不只是「補」，而是要先問：
現在身體是需要補？需要清？需要疏？需要化濕？需要安神？還是需要先讓睡眠、腸胃、壓力與循環穩下來？
二、什麼是 NETs？為什麼和懷孕有關？
二、什麼是 NETs？為什麼和懷孕有關？
近年研究越來越重視一種免疫現象，稱為 neutrophil extracellular traps，簡稱 NETs，中文可稱為「嗜中性球胞外網」。
嗜中性球是人體血液中很重要的一種白血球，也是先天免疫系統的第一線防禦細胞。當身體遇到細菌、病毒、黴菌、寄生蟲，或某些發炎刺激時，嗜中性球可以釋放出由 DNA、組蛋白與顆粒蛋白組成的網狀結構，把病原體困住、限制擴散，協助身體清除感染 [1,2]。
所以 NETs 本來是保護機制。
但問題在於，NETs 是一把雙面刃。適度形成時，它有助於防禦感染；如果形成過多、持續存在，或清除不良，就可能造成發炎放大、血管內皮受損、凝血活化與組織傷害 [1,3]。
在懷孕期間，這件事特別重要。因為母胎介面本來就需要一種很精細的免疫平衡：母體不能完全排斥胎兒，也不能讓感染輕易入侵。文獻指出，正常懷孕時，NETs 在母胎介面可能扮演抗感染防禦角色；但若 NETs 調控失衡，則與多種妊娠併發症有關，包括子癲前症、妊娠糖尿病、早產、反覆流產、紅斑性狼瘡相關妊娠不良結果，以及抗磷脂症候群相關妊娠問題 [1]。
三、正常懷孕：免疫不是變弱，而是重新調節
三、正常懷孕：免疫不是變弱，而是重新調節
很多人以為懷孕就是免疫力下降，但更精確地說，懷孕期間的免疫系統不是單純變弱，而是重新調節。
文獻提到，在正常懷孕過程中，嗜中性球會受到懷孕相關荷爾蒙與細胞激素影響。例如 G-CSF、人類絨毛膜促性腺激素 hCG、雌二醇 E2 等因素，可能促進 NETs 生成；而黃體素 P4 與滋養層細胞分泌的 vasoactive intestinal peptide，則可能抑制過度的嗜中性球活化與 NETs 形成 [1,4,5]。
這個平衡很有意思。
一方面，適度的 NETs 有助於母胎介面抵禦感染。另一方面，黃體素與胎盤相關訊號又會避免 NETs 過度形成，以免傷害血管內皮與胎盤組織 [1]。
用中醫的語言來轉譯，這其實很接近「懷孕不是單純大補，而是要維持陰陽、氣血、寒熱、升降的穩定」。如果身體太虛，確實可能不穩；但如果發炎太旺、熱象太重、痰濕太盛、氣機太鬱、睡眠太差，也一樣會讓身體難以維持穩定。
所以備孕與孕期調理不能只用「補不補」來判斷，而要回到整體體質。
四、子癲前症與妊娠高血壓：血管、胎盤與發炎失衡
四、子癲前症與妊娠高血壓：血管、胎盤與發炎失衡
子癲前症是懷孕 20 週後可能出現的重要妊娠併發症，核心表現包括新發生的高血壓、蛋白尿，或在沒有蛋白尿的情況下出現其他器官受損。這是需要婦產科嚴密監測的狀況，不能用中醫調理取代產檢與必要治療 [6,7]。
文獻指出，子癲前症患者常見嗜中性球增加，而且與疾病嚴重度有關；相較於正常懷孕，子癲前症患者的 NETs 形成增加，母體循環與胎盤組織中也可見嗜中性球過度活化與 NETs 增加 [1,8,9]。
其可能機制包括胎盤來源的 syncytiotrophoblast microparticles、IL-8、sFlt-1 等因素活化嗜中性球，促進 NETs 釋放。過多 NETs 可能造成氧化壓力、滋養層細胞功能受損、血管內皮損傷、補體活化與局部發炎，進一步影響螺旋動脈重塑與胎盤血管發育 [1,10,11]。
從中醫臨床角度來看，這類患者不能被簡化成「孕婦水腫，所以利水」或「懷孕虛，所以補」。如果已經出現血壓升高、蛋白尿、頭痛、視覺模糊、上腹痛、突然水腫、胎動異常，必須優先回婦產科或急診評估。
中醫可以做的是在安全前提下，針對睡眠、壓力、腸胃、體質寒熱與水腫不適做輔助調整，但不能宣稱治療子癲前症，也不能延誤產科處置。
五、妊娠糖尿病：不只是血糖，也是代謝與免疫發炎問題
五、妊娠糖尿病：不只是血糖，也是代謝與免疫發炎問題
妊娠糖尿病是懷孕期間出現或首次發現的葡萄糖耐受異常。它不只是「吃太甜」造成，也不代表孕婦做錯了什麼。懷孕本身會改變胰島素敏感性，胎盤荷爾蒙也會影響血糖調控 [12,13]。
文獻整理指出，妊娠糖尿病患者可能出現嗜中性球活化增加、NETs 形成傾向上升。研究也提到，妊娠糖尿病患者血中 TNF-α 增加、adiponectin 降低、高血糖誘發 PAD4 活化等因素，都可能促進 NETs 過度形成 [1,14,15]。
此外，NETs 不只是出現在血液中，也可在妊娠糖尿病患者的胎盤組織中增加。過多 NETs 可能影響滋養層細胞的增殖、侵入、遷移與血管新生能力，並可能透過 ROS 相關路徑促進滋養層細胞凋亡 [1,15]。
用中醫的語言來說，妊娠糖尿病相關體質往往不只是一個「血糖數字」，而可能牽涉到脾胃運化、痰濕、內熱、陰虛、肝鬱與睡眠壓力。
有些人是飯後昏沉、胃脹、身體沉重、水腫，偏向脾虛痰濕。
有些人是口乾、便秘、容易餓、煩躁，偏向胃熱或陰虛內熱。
有些人是壓力大、睡不好、情緒波動後血糖更不穩，則需要把肝鬱與自律神經壓力納入考量。
但不論是哪一型，妊娠糖尿病都必須以婦產科與營養衛教追蹤為基礎。中醫調理只能作為輔助，協助穩定睡眠、腸胃、壓力與體質狀態，不能取代血糖監測、飲食控制與醫囑用藥。
六、早產風險：感染、發炎與胎膜穩定
六、早產風險：感染、發炎與胎膜穩定
早產是指懷孕未滿 37 週即分娩。文獻指出，子宮內感染是 spontaneous preterm birth 的重要誘發因素之一，而絨毛膜羊膜炎常伴隨大量嗜中性球浸潤與母胎介面發炎反應 [1,16]。
研究顯示，在早產與急性絨毛膜羊膜炎相關情境中，羊水、胎膜與羊膜組織可觀察到 NETs 形成增加。細菌刺激、LPS、B 群鏈球菌、TNF-α 與 MAPK/ROS 相關路徑，都可能促進 NETs 形成 [1,17,18]。
NETs 可能進一步促進 ROS 生成，誘導羊膜上皮細胞凋亡，影響胎膜完整性。由於 NETs 含有 neutrophil elastase 等水解酶，文獻也推測其可能影響膠原纖維與胎膜機械強度，但這部分仍需要更多研究確認 [1]。
這對臨床的提醒是：懷孕期間如果有規則宮縮、出血、破水感、異常分泌物、發燒、下腹痛或胎動改變，不能先想著「吃中藥安胎」，而是要立即回婦產科評估是否有感染、早產徵象或其他急性問題。
中醫在孕期可以協助處理某些體質性不適，例如睡眠差、胃脹、便秘、疲倦、咳嗽、鼻過敏等，但凡涉及早產風險，都必須以婦產科處置優先。
七、反覆流產：免疫、凝血與母胎介面不能被忽略
七、反覆流產：免疫、凝血與母胎介面不能被忽略
反覆流產通常指連續兩次或以上的妊娠喪失。原因可能非常複雜，包括胚胎染色體、子宮結構、內分泌、甲狀腺、感染、免疫、凝血、代謝與不明原因等 [19,20]。
文獻指出，在反覆流產或自然流產相關研究中，NLR 可能升高，血清與蛻膜組織中也可觀察到 NETs 增加。部分研究也提到，低密度顆粒球 LDGs 在自然流產患者蛻膜組織中比例失衡，且這類細胞更容易活化與釋放 NETs [1,21,22]。
此外，動物研究顯示，sFlt-1 過度表現可能誘發胎盤 NETs 累積與妊娠喪失，而 PAD4 基因敲除可減輕相關不良結果。這提示 NETs 可能是某些妊娠喪失機制的一部分，但文獻也明確指出：目前直接證明 NETs 導致反覆流產的因果證據仍不足，具體分子機制仍待釐清 [1]。
這一點非常重要。
所以在青璞中醫的文章裡，不能寫成「反覆流產就是 NETs 太多」或「中醫可以抑制 NETs 來保胎」。這樣太過度。
比較正確的說法是：現代研究提醒我們，反覆流產不能只用「子宮虛寒」或「氣血不足」來解釋。它可能牽涉到免疫、凝血、胎盤發育、發炎與母胎介面穩定。中醫調理可以從月經、睡眠、腸胃、壓力、氣血、寒熱、痰濕與瘀滯等方向評估身體狀態，但仍需要配合婦產科與生殖醫學檢查。
八、紅斑性狼瘡、抗磷脂症候群：高風險妊娠需要整合照護
八、紅斑性狼瘡、抗磷脂症候群：高風險妊娠需要整合照護
文獻也討論了紅斑性狼瘡 SLE 與抗磷脂症候群 APS 相關的妊娠問題。
SLE 是全身性自體免疫疾病，女性比例高，懷孕時可能增加流產、子癲前症、早產與胎兒生長受限等風險。研究指出，SLE 患者可能存在 NETs 清除不足、低密度顆粒球增加、胎盤 NETs 浸潤，以及與 trophoblast pyroptosis、decidual NK cell 變化相關的胎盤損傷機制 [1,23,24]。
APS 則與抗磷脂抗體、血栓與妊娠不良結果有關。文獻指出，抗磷脂抗體可透過 TLR4 活化嗜中性球，促進 ROS 與 NETs 形成；NETs 進一步可能影響滋養層細胞與血管內皮細胞功能，造成胎盤損傷 [1,25]。
這些內容對青璞中醫的臨床溝通很重要，因為它提醒我們：如果患者有 SLE、APS、反覆流產、血栓病史、免疫用藥或高風險妊娠，絕對不能把問題簡化成一般體質調理。
這類患者需要婦產科、風濕免疫科、生殖醫學科共同追蹤。中醫若要介入，也必須知道患者目前使用的藥物，例如低劑量阿斯匹靈、肝素、hydroxychloroquine、類固醇或其他免疫相關藥物，避免自行加減藥或使用來路不明的中草藥。
九、文獻提到的藥物：重點不是自行吃，而是理解治療機制
九、文獻提到的藥物：重點不是自行吃，而是理解治療機制
這篇文獻也整理了幾種婦產科或免疫相關臨床常見藥物，可能透過調節 NETs 形成或清除，部分解釋其對妊娠結果的幫助，包括 aspirin、metformin、low molecular weight heparin、hydroxychloroquine 與 vitamin D [1]。
例如，aspirin 可能透過抑制血小板活化與 TXA2 生成，間接降低嗜中性球活化與 NETs 形成；metformin 除了降血糖，也可能影響 NADPH oxidase 或促進巨噬細胞清除 NETs；低分子量肝素可能抑制嗜中性球活化與 NETs 形成，也可能透過結合 histones 減少組織傷害；hydroxychloroquine 可能透過 PAD4 或 TLR9 相關路徑影響 NETs；vitamin D 則可能透過全身性發炎細胞激素狀態影響 NETs 生成能力 [1,26-30]。
但這裡一定要強調：這不是鼓勵孕婦自行服用 aspirin、metformin、肝素、hydroxychloroquine 或高劑量 vitamin D。
這些藥物都有明確適應症、風險與監測需求，必須由婦產科、新陳代謝科、風濕免疫科或相關專科醫師判斷。文獻本身也指出，目前許多證據仍來自動物或體外研究，人體懷孕不同孕期的直接證據仍不足，NETs 檢測也尚未形成臨床標準化流程 [1]。
因此，對患者來說，這些研究真正的意義不是「看到什麼就自己補什麼、吃什麼」，而是讓我們更理解：孕期健康是一個免疫、發炎、血管、凝血與代謝共同參與的系統。
十、從中醫角度怎麼轉譯這篇研究？
十、從中醫角度怎麼轉譯這篇研究？
這篇文獻是現代免疫學研究，並不是中醫論文。青璞中醫在轉譯時，不能直接宣稱「中醫可以調控 NETs」或「某個中藥可以治療妊娠併發症」。這樣不夠嚴謹。
但這篇文獻可以幫助我們重新理解「體質調理」這件事。
中醫講氣血、陰陽、寒熱、痰濕、瘀血、肝鬱、脾虛、腎虛，看似是傳統語言；現代研究則用免疫細胞、發炎因子、血管內皮、胎盤滋養層、凝血與代謝來描述身體狀態。兩者不是簡單的一對一對應，但都提醒我們：身體不是單一器官在運作，而是一個動態系統。
所以在備孕與孕期調理中，青璞中醫會特別重視以下幾個面向：
睡眠是否穩定。
長期入睡困難、半夜醒、早醒、睡醒仍累，代表身體修復節律不穩。備孕與懷孕都需要身體有足夠的恢復能力。
腸胃吸收是否良好。
脾胃是氣血來源。如果長期胃脹、腹瀉、便秘、食慾不穩，單純補藥未必吸收得進去，也可能越補越脹。
壓力與肝氣是否鬱結。
壓力大、胸悶、經前乳房脹痛、情緒緊繃、睡眠變差，常常會影響月經與備孕節奏。
痰濕與代謝是否偏重。
身體沉重、水腫、痰多、白帶多、飯後昏沉、體重上升，可能提示痰濕與代謝負擔。
寒熱是否失衡。
有些人怕冷、手腳冰冷、經痛明顯；有些人卻口乾、便秘、長痘、煩躁、睡不好。兩者處理方向不同，不能都用同一套補法。
瘀滯與循環是否順暢。
經痛、血塊、經色暗、下腹悶痛，可能提示循環與瘀滯問題。但若已懷孕，活血藥物使用更要謹慎，必須由醫師判斷。
十一、哪些狀況適合考慮中醫輔助調理？
十一、哪些狀況適合考慮中醫輔助調理？
如果正在備孕，或準備進入人工受孕、試管療程前，中醫可以協助從月經週期、睡眠、腸胃、壓力、氣血與體質狀態進行調理。
如果懷孕期間有孕吐、胃脹、便秘、睡不好、疲倦、水腫、咳嗽、鼻過敏、皮膚癢等不適，也可以在婦產科確認安全後，由中醫師依孕週與體質評估是否適合調理。
如果曾經有反覆流產、胚胎萎縮、著床不穩、妊娠糖尿病、妊娠高血壓、SLE、APS 或血栓相關病史，則更需要先完成婦產科、生殖醫學科或風濕免疫科評估。中醫可以作為輔助角色，但不能取代檢查與專科治療。
十二、哪些狀況不能只看中醫？
十二、哪些狀況不能只看中醫？
懷孕期間若出現以下情況，請優先聯絡婦產科或直接就醫：
陰道出血、明顯腹痛、規則宮縮、破水感、胎動明顯減少、血壓升高、劇烈頭痛、視覺模糊、上腹痛、突然嚴重水腫、發燒、感染症狀、血糖明顯異常，或醫師已告知屬於高風險妊娠。
這些狀況不是「先吃中藥看看」的範圍。
安全永遠比調理更重要。
十三、青璞中醫的備孕與孕期調理方式
十三、青璞中醫的備孕與孕期調理方式
青璞中醫位於桃園青埔，面對備孕與孕期患者時，我們會先了解：
月經週期、經量、經色、經痛與血塊狀況。
是否有排卵紀錄、基礎體溫、AMH、荷爾蒙或婦產科檢查資料。
是否曾有流產、胚胎萎縮、著床失敗或試管療程。
目前是否懷孕、孕週幾週、產檢是否正常。
是否有妊娠糖尿病、妊娠高血壓、甲狀腺疾病、SLE、APS 或血栓病史。
目前是否使用 aspirin、肝素、metformin、hydroxychloroquine、黃體素、類固醇或其他藥物。
睡眠、腸胃、壓力、皮膚、鼻過敏、咳嗽、水腫與疲倦狀態。
我們不會把所有人都歸類成「太虛」，也不會把所有人都用同一套補藥。備孕與孕期調理應該是個別化、安全、保守且能與婦產科照護配合的過程。
十四、結語：懷孕是一個平衡，不是一場盲目進補
十四、結語：懷孕是一個平衡，不是一場盲目進補
這篇關於 NETs 與妊娠併發症的研究，對臨床最大的提醒是：
懷孕不是免疫越強越好，也不是免疫越弱越好。
不是越補越好，也不是越清越好。
真正重要的是平衡。
正常懷孕需要適度免疫防禦，也需要避免過度發炎；需要良好胎盤血流，也需要避免血管內皮與凝血系統過度受刺激；需要足夠營養，也需要穩定代謝。
中醫所說的體質調理，若要放在現代醫學脈絡中理解，不應該只是「補腎、補氣血」幾個字，而是要更細緻地看見每個人的睡眠、腸胃、壓力、寒熱、痰濕、氣血與循環狀態。
如果你正在備孕、懷孕，或曾經歷反覆流產、著床不穩、妊娠糖尿病、妊娠高血壓等問題，建議先完成必要的婦產科檢查，再由合格中醫師依照你的體質與目前醫療狀況，規劃安全的輔助調理方向。
青埔中醫推薦｜青璞中醫
我們重視的不只是症狀，而是症狀背後的身體狀態。備孕與孕期調理，請讓醫師先了解你，再決定該不該補、怎麼調，以及什麼時候應該以婦產科照護優先。
參考文獻
參考文獻
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Front Immunol. 2026 Apr 10;17:1798749. doi: 10.3389/fimmu.2026.1798749
Neutrophil extracellular traps in pregnancy complications
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PMCID: PMC13106339 PMID: 42039209
Abstract
Neutrophil extracellular traps (NETs) are fibrous, web-like structures released by activated neutrophils that consist of decondensed chromatin DNA coated with antimicrobial granular proteins. These structures play a dual role in host defense and pathology by effectively entrapping and eliminating pathogens. Under normal physiological conditions during pregnancy, appropriately regulated NET formation at the maternal–fetal interface functions as a crucial antimicrobial defense mechanism. However, emerging evidence indicates that excessive NET formation or defective clearance is strongly linked to the pathogenesis of several pregnancy complications such as preeclampsia, gestational diabetes mellitus, preterm birth, recurrent pregnancy loss, systemic lupus erythematosus, and obstetric antiphospholipid syndrome. This review systematically examines the regulatory mechanisms and pathophysiological contributions of NETs to these pregnancy complications. This review further explores the potential therapeutic mechanisms of common obstetric medications—including aspirin, metformin, low molecular weight heparin, hydroxychloroquine, and vitamin D-which may exert beneficial effects by suppressing NET formation or enhancing NET clearance.
Keywords: neutrophil, neutrophil extracellular traps, obstetric drugs, preeclampsia, pregnancy complications
1. Introduction
Neutrophils are key effector cells in host defense against pathogens. In addition to their antimicrobial mechanisms, recent research has highlighted a distinctive fibrous mesh-like chromatin structure called neutrophil extracellular traps (NETs) (1). NETs enable neutrophils to immobilize and capture pathogens and subsequently eliminate bacteria, viruses, fungi, and other microbes via associated antimicrobial components, thus constituting a significant addition to the innate immune defense system (2). Beyond their primary role in microbial clearance, NETs also participate in diverse physiological processes, including immunomodulation, thrombosis, inflammation resolution, and tissue repair. However, NETs act as a double-edged sword, whereby excessive or persistent accumulation in vivo may exacerbate inflammatory responses and even induce tissue damage (3).
Pregnancy is a unique physiological state characterized by complex maternal-fetal interactions. The maintenance of immune homeostasis at the maternal-fetal interface is essential for the normal progression of pregnancy. As vital innate immune cells, neutrophils are strongly involved in placental development and the regulation of homeostasis at the maternal-fetal interface (4–6). A growing body of research suggests that during normal pregnancy, finely tuned NET formation under the precise regulation of the maternal-fetal interface microenvironment serves as an essential line of defense against pathogenic infections (6). Circulating factors such as granulocyte colony-stimulating factor (G-CSF), human chorionic gonadotropin (hCG), and estradiol (E2) promote NET generation, whereas progesterone (P4) and vasoactive intestinal peptide (VIP) secreted by trophoblasts inhibit neutrophil activation, thereby preventing excessive NET formation and tissue injury, together forming a dynamically balanced regulatory network (7, 8).
In recent years, increasing evidence has demonstrated that dysregulation of NET homeostasis is closely associated with the pathogenesis and progression of various pregnancy complications. Aberrant upregulation of NET formation or compromised clearance has been reported in common obstetric disorders, including preeclampsia (PE) (9), gestational diabetes mellitus (GDM) (10), preterm birth (PTB) (11), and recurrent pregnancy loss (RPL) (12) as well as in pregnancies complicated by autoimmune diseases such as systemic lupus erythematosus (SLE) (13) and antiphospholipid syndrome (APS) (14). Excessive NETs disrupt maternal-fetal interface homeostasis through multiple mechanisms, including the induction of inflammatory responses, impairment of vascular endothelium and placental tissues, interference with spiral artery remodeling, and promotion of thrombogenesis, ultimately leading to adverse pregnancy outcomes (APOs) (14–16). Given the involvement of NETs in the pathophysiology of obstetric disorders, targeting NET generation may represent a potential therapeutic strategy. Commonly used clinical agents in obstetrics, such as aspirin, metformin, low molecular weight heparin (LMWH), hydroxychloroquine (HCQ) and vitamin D, have been shown to exert potential therapeutic effects by inhibiting NET formation or promoting NET clearance (17–21); however, their specific regulatory mechanisms in pregnancy complications require further investigation.
This review synthesizes the existing research to elucidate the causes, regulatory mechanisms, and pathophysiological roles of NETs in various pregnancy complications. Additionally, it examines potential novel mechanisms by which commonly used obstetric medications modulate NET homeostasis, offering new theoretical insights and research avenues for diagnosing and managing these conditions.
2. Introduction to neutrophil extracellular traps
2.1. Neutrophil
Neutrophils are the most abundant leukocytes in human blood. As a core component of the innate immune system, they form the first line of defense against pathogens (22). Neutrophils are derived from the bone marrow and then enter the circulatory system. Upon pathogen invasion, they are recruited to sites of infection or inflammation, where they transmigrate across the vascular endothelium through a multistep process involving rolling, adhesion, and crawling to eliminate microbes (23). Upon encountering invading pathogens, neutrophils exert their cytotoxic effects through two main mechanisms: phagocytosis, which involves the internalization and degradation of pathogens within phagolysosomes via proteolytic enzymes, antimicrobial proteins, and reactive oxygen species (ROS); and degranulation, whereby antimicrobial factors are released directly into the extracellular space to neutralize pathogens (24). However, in 2007, Brinkmann et al. reported a novel antimicrobial mechanism in neutrophils termed NETosis, which involves the release of NETs to capture and kill pathogens. Classically, neutrophils primarily die through apoptosis, necrosis, or the highly regulated necroptosis, whereas NETosis is a cell death program that is mechanistically distinct from apoptosis and necrosis (25).
Not all neutrophils exhibit identical functional profiles; however, compared with conventional neutrophils, low-density granulocytes (LDGs) are a heterogeneous neutrophil subset isolated in the low-density fraction of peripheral blood mononuclear cells that possess unique proinflammatory and functional characteristics, with markedly stronger proinflammatory potential, including enhanced secretion of proinflammatory cytokines and ROS. Notably, LDGs exhibit increased NET-forming activity and more easily activated to release NETs (26).
2.2. Neutrophil extracellular traps
NETs are fibrous, web-like structures consisting of decondensed chromatin fibers decorated with granular proteins, such as myeloperoxidase (MPO), neutrophil elastase (NE), and cathepsin G (27). Studies have demonstrated that various infectious and sterile stimuli can trigger NET formation, including bacteria (28), viruses (28), fungi (29), parasites (30), interleukins (31), tumor necrosis factor α (TNF-α) (32), placental micro-debris (33), activated platelets (34), cholesterol crystals (35), monosodium uric acid (36), autoantibodies (37), and complements (38). Histone citrullination catalyzed by peptidylarginine deiminase 4 (PAD4) contributes to NET formation (39). However, the dependency of NET formation on histone citrullination remains highly controversial, particularly in response to phorbol myristate acetate (PMA) stimulation. For instance, Li et al. (40) and Holmes et al. (41) reported detectable levels of histone citrullination in PMA-activated murine and human neutrophils, respectively (40, 41). In contrast, Neeli and Radic (43) and König and Andrade (42) failed to detect citrullinated histone H3 in PMA-stimulated human neutrophils at the 2-hour time point by Western blotting (42, 43). Collectively, these conflicting results indicate that PAD4-mediated citrullination is not absolutely necessary for PMA-induced NET formation. In addition, NET formation involves ROS production and the activation of MPO and NE (44), which promote histone degradation, chromatin decondensation, and the release of DNA and antimicrobial molecules (45).
2.3. NETosis pathways
NET formation occurs through two primary pathways (Figure 1). The first, known as suicidal NETosis (or lytic NETosis), relies on NADPH oxidase activity. Upon neutrophil stimulation, calcium is released from the endoplasmic reticulum, leading to the activation of protein kinase C (PKC). The activated NADPH oxidase complex then promotes increased levels of ROS, which in turn triggers the degradation of cytoplasmic granules containing MPO and NE (46). NE and MPO subsequently cooperate with PAD4 to induce citrullination of histone H3 (40). This modification facilitates nuclear chromatin decondensation, followed by the rupture of both the nuclear envelope and the plasma membrane, ultimately resulting in the release of NETs into the extracellular space (47). This pathway can be induced by antibodies, microbes, cholesterol crystals, TNFα or IL-6/8 (48, 49). Unlike the suicidal pathway, vital NETosis (also known as non-lytic NETosis) is independent of the activity of NADPH oxidase and can be induced by activated platelets, specific microbes, or the calcium ionophore A23187 (48). Additionally, vital NETosis is a non-lytic process that does not induce cell death. Upon neutrophil activation, calcium influx into cells occurs via small conductance potassium channel member 3, and elevated intracellular Ca
2+
levels activate PAD4, thereby promoting the citrullination of histone H3 (50). Neutrophils then extrude chromatin and granular components into the extracellular space, where they assemble into NETs, leaving behind an active nuclear cytoplast that retains its capacity for phagocytosis and chemotaxis (51, 52). An alternative mechanism involves mitochondrial DNA-driven NETosis, a pathway characterized by the induction of NETs through the release of mitochondrial DNA, rather than nuclear DNA, in response to specific stimuli such as complement component 5a and lipopolysaccharide (53). This process occurs independently of cell death but depends on ATP generated through glycolysis to power structural reorganizations of the microtubule network and filamentous actin. These cytoskeletal rearrangements are indispensable for both mitochondrial DNA release and degranulation (54).
Figure 1.
NET formation pathways. Suicidal NETosis involves a stepwise cellular process: nuclear lobulation, nuclear membrane breakdown, loss of cell polarity, chromatin decondensation, and ultimately, plasma membrane rupture. In contrast, vital NETosis is a non-lethal pathway that mediates chromatin extrusion and granular protein release without causing cell death. Following the extracellular assembly of NET components, the resulting anucleate phagocytes remain metabolically active and retain functional capabilities for microbial phagocytosis and chemotaxis. An alternative pathway is mtDNA-driven NETosis: this noncell death-dependent process induces NETs via mitochondrial (not nuclear) DNA, which relies on glycolysis-derived ATP for the cytoskeletal rearrangements essential for mtDNA release and degranulation. Figure created with BioRender.com.
2.4. Clearance of NETs
Efficient clearance of NETs is critical for maintaining immune homeostasis. This process is a complex biological event involving multiple steps and various cell types. To date, NET clearance is known to occur primarily through two mechanisms: nuclease-mediated backbone degradation and phagocyte-mediated fragment removal (55). In the extracellular compartment, the core event is the specific hydrolysis of the DNA backbone of NETs by nucleases, which largely depends on the coordinated action of deoxyribonuclease (DNase) and three prime repair exonuclease (TREX) families (56). The DNase family comprises two subfamilies: DNase I (including DNase I, DNase1L1, DNase1L2, and DNase1L3) and DNase II (including DNase II α, DNase II β, and L-DNase II). Although these DNase subfamilies differ in their biochemical properties, their functions partially overlap. Both subfamilies function by hydrolyzing the phosphodiester bonds of DNA molecules and serve as key enzymes in maintaining low levels of circulating cell-free DNA (56, 57). Among them, the degradation of DNA by DNase I and DNase1L3 represents the rate-limiting step in NET accumulation. These two enzymes can efficiently eliminate intravascular NETs under pathological conditions such as sepsis or sterile neutrophilia (56). In contrast, DNase II is predominantly localized in the lysosomes of various cells, including macrophages, and its core function is to degrade exogenous DNA internalized by macrophages, particularly DNA fragments derived from apoptotic cells (58). In addition to the DNase family, TREX1 and TREX2 act as important supplementary enzymes in NET clearance. A key advantage of these nucleases is their ability to degrade oxidized DNA that is resistant to DNase I and DNase II (56). Following pretreatment of NETs with extracellular nucleases, macrophages take up NET fragments via macropinocytosis and endocytosis. After phagocytosis, NETs are ultimately degraded within lysosomes (59).
2.5. Physiological role of NETs
The core physiological function of NETs is to restrict pathogen dissemination and directly eliminate microorganisms including bacteria, fungi, viruses, and parasites, thereby aiding the host in combating infections (60). Beyond their well-established function in innate immunity, NETs are critically involved in a variety of physiological processes (Figure 2). For instance, they increase neutrophil-mediated defense (61), induce macrophage polarization (62), facilitate the differentiation of dendritic cells (DCs) (63, 64), and contribute to the activation of CD4
+
T cells and B cells (65, 66), underscoring their broad immunomodulatory functions. Moreover, NETs participate in immunothrombosis by activating coagulation factor XII (67), binding von Willebrand factor (VWF) (68), and promoting platelet activation via histones H3 and H4 (69, 70). Moreover, aggregated NETs can inhibit extracellular matrix proteolysis by degrading proinflammatory cytokines and sequestering NE, thereby facilitating inflammation resolution and tissue repair (71–73).
Figure 2.
Role of NETs in health. NETs are critical for maintaining homeostasis and functions as follows: (1) host defense via pathogen entrapment and immobilization; (2) immune regulation by boosting neutrophil defense, promoting macrophage polarization, facilitating DC differentiation, and supporting CD4
+
T/B-cell activation; (3) immunothrombosis through FXII activation, VWF binding, and histone H3/H4-mediated platelet activation; (4) wound healing via AggNET-driven proinflammatory cytokine degradation and NE sequestration to protect the extracellular matrix from proteolysis, thus resolving inflammation and accelerating repair. Figure created with BioRender.com.
2.6. Controversial role of NETs
While NETs have essential protective effects in physiological processes, emerging evidence has revealed their controversial role in the pathogenesis of various diseases. Excessive NET formation or impaired clearance can disrupt immune homeostasis and trigger exacerbated inflammation and tissue damage, thereby contributing to the development and progression of multiple pathological conditions, including infectious diseases, metabolic disorders, autoimmune diseases, and cancer (74). In infectious diseases, NETs initially act to trap and eliminate invading pathogens (2, 75), but sustained inflammatory stimulation leads to excessive NET release, which aggravates tissue injury and systemic inflammation (76, 77). Neutrophils from diabetic patients exhibit increased susceptibility to NETosis (78), and elevated NET markers are correlated with disease severity and complications (79). In metabolic dysfunction-associated steatotic liver disease, free fatty acids and cholesterol crystals induce excessive NET formation, promoting chronic hepatic inflammation and progression to hepatocellular carcinoma (80, 81). In rheumatoid arthritis (RA), NETs release citrullinated histones that induce ACPA production, exacerbating synovial inflammation (82–84). In SLE, impaired NET clearance leads to the accumulation of NET remnants, triggering complement activation and autoantibody production (85, 86). In cancer, NETs primarily exert protumorigenic effects by promoting tumor cell proliferation, metastasis, and immunosuppression (87, 88). Notably, the pathogenic role of NETs is context dependent, with specific mechanisms varying across diseases. Targeting NET formation or clearance has emerged as a potential therapeutic strategy, highlighting the importance of further exploring their regulatory networks in disease progression.
3. NETs in normal pregnancy
Pregnancy refers to the entire process starting from oocyte fertilization, followed by blastocyst implantation in the uterine cavity, development into an embryo and subsequent fetus, and culminating in the delivery of a mature fetus from the maternal body (89). As a unique physiological state involving maternal-fetal interaction, maintaining the balance of local and systemic immunity is crucial for the progression of normal pregnancy (90). As a key component of the innate immune system, neutrophils are dynamically regulated during normal pregnancy and participate in maternal adaptive regulation of pregnancy through multiple mechanisms, including the formation of NETs (91). Abnormal neutrophil function and dysregulated NET formation have been linked to various pregnancy complications, such as PE, GDM, and RPL (92). In comparison with those nonpregnant women, neutrophils during normal pregnancy are modulated by multiple factors to increase NETosis and NET release, a response that progressively increases as gestation advances. The modulation of NET formation during normal pregnancy (first trimester: 1–12 weeks, second trimester: 13–27 weeks, and third trimester: 28 weeks to term) is tightly regulated by pregnancy-related hormones and cytokines with stage-specific effects. Circulating G-CSF levels increase during pregnancy, and G-CSF acts as a core pro-NETotic factor that drives NET formation. hCG exerts a pro-NETotic effect primarily during the first trimester, whereas E2 functions as a pro-NETotic hormone during late pregnancy. In contrast, P4, which peaks during the third trimester, antagonizes the pro-NETotic effects of E2 and G-CSF by blocking NE translocation from the cytoplasm to the nucleus, thus confining neutrophils to a primed pro-NETotic state without full NETosis. This hormonal regulation exerts key physiological effects: moderate pro-NETotic effects of G-CSF, hCG and E2 enhance antimicrobial defense at the maternal-fetal interface via NETs to fend off intrauterine infections. The inhibitory effect of P4 prevents excessive NET release-induced endothelial and placental damage, safeguarding maternal-fetal immune homeostasis, and the primed state maintained by P4 enables rapid NET formation in response to pathogenic stimuli when needed (7). Furthermore, trophoblast-derived VIP suppresses ROS production in neutrophils, thereby inhibiting NET formation. This VIP-mediated dual regulation of neutrophils maintains maternal-fetal immune homeostasis at the placental interface, thus safeguarding the normal progression of early pregnancy (8). As key neutrophil effector products, NETs contribute to maternal-fetal interface defense during normal pregnancy. However, their precise roles in placental development and maternal adaptation remain unclear. A well-balanced NET formation is essential for normal pregnancy, but NET dysregulation leads to adverse outcomes.
4. NETs in pregnancy complications
This section sequentially discusses the specific molecular mechanisms, clinical manifestations, and existing evidence of NET involvement in various obstetric complications (Figure 3).
Figure 3.
NETs in pregnancy complications. NETs play pivotal roles in the pathogenesis of various pregnancy complications: (a) in PE, STBM, IL-8 and sFlt-1 drive elevated NETosis, triggering inflammation, endothelial injury, spiral artery remodeling disorder and placental infarction; (b) in GDM, increased TNFα levels, reduced adiponectin levels and hyperglycemia-induced PAD4 activation promote NET overproduction, which impairs trophoblast proliferation, invasion and glucose metabolism; (c) in PTB, intrauterine infection and TNFα induce NET formation via MAPK/ROS pathways, leading to amniotic epithelial cell apoptosis and premature rupture of membranes; (d) in RPL, a dysregulated percentage of LDGs and sFlt-1-mediated NET accumulation cause recurrent embryo loss; (e) in SLE with APOs, impaired DNase-mediated NET clearance and elevated LDGs cause NET accumulation, which induces trophoblast pyroptosis and alters dNK subsets to worsen placental injury. (f) in OAPS, aPLs induce NET formation via TLR4, impairing trophoblast and endothelial function through multiple pathways to cause placental injury and APOs. Figure created with BioRender.com.
4.1. Preeclampsia
PE is a pregnancy-specific condition categorized among the hypertensive disorders of pregnancy, which typically manifests after 20 weeks of gestation. Its core characteristics include de novo hypertension and proteinuria or the development of other organ damage in the absence of proteinuria (93). This condition poses a severe threat to maternal and fetal health and constitutes one of the leading causes of maternal and perinatal morbidity and mortality. To date, termination of pregnancy remains the only effective curative intervention (94).
In patients with PE, neutrophil counts increase significantly as early as the second trimester, and they are correlated with disease severity (95). Notably, compared with those with normal pregnancies, those with PE exhibit a marked increase in NET formation via the non-lytic pathway (9). Moreover, neutrophils in the maternal circulation and placental tissues of PE patients exhibit excessive activation, accompanied by increased NET formation (13, 96).
The underlying mechanisms contributing to this phenomenon are multifaceted. Reports have indicated that BCL2-related protein A1 (BCL2A1, an anti-apoptotic BCL-2 family protein) and G0/G1 switch gene 2 (G0S2, a lipid metabolism-and apoptosis-related protein) are overexpressed in neutrophils within the placental tissues of PE patients and that overexpression of these two molecules promotes NET release from neutrophils (97). Additional studies have suggested that placenta-derived syncytiotrophoblast microparticles (STBMs) and interleukin-8 (IL-8) in PE patients can activate neutrophils and subsequently induce NETosis in a dose-dependent manner (33, 98). Furthermore, these findings revealed that phospholipase A/acyltransferase 3 (PLAAT3, a phospholipid-metabolizing enzyme) expression is upregulated in the syncytiotrophoblasts (STB) of PE placentas, and this upregulated PLAAT3 activates neutrophils via the LPA-LPAR5 axis (lysophosphatidic acid and its receptor 5 signaling pathway), thereby leading to NET release (99). In addition, the level of soluble fms-like tyrosine kinase 1 (sFlt-1), an anti-angiogenic protein, is elevated in the serum of PE patients (100), and sFlt-1 has been shown to induce neutrophils to release NETs (101). However, it has been reported that in some special clinical scenarios, such as pregnant women with PE complicated by human immunodeficiency virus (HIV) infection, placental NET infiltration is conversely reduced. This phenomenon may be explained by the HIV-triggered release of the anti-inflammatory cytokine interleukin-10 from DCs in affected individuals, which subsequently inhibits the formation of NETs (102–104).
NETs contribute to the pathogenesis and progression of PE through multiple pathophysiological pathways. NETs induce oxidative stress, apoptosis, and dysfunction in human umbilical vein endothelial cells (HUVECs) and trophoblasts (105). Sera from PE patients can promote NET formation, which activates complement activity and further aggravates placental endothelial injury (16). In addition, NETs suppress trophoblast function via their component high mobility group B1 (HMGB1) and promote the release of ROS and proinflammatory cytokines (e.g., IL-1β, IL-6, IL-8, and TNF-α), thereby exacerbating placental inflammation and tissue injury (15). The combined effects of endothelial damage, trophoblast dysfunction, and the procoagulant activity of NETs ultimately impair spiral artery remodeling, disrupt placental vascular development, and contribute to placental injury, infarction, and APOs (1, 106, 107).
4.2. Gestational diabetes mellitus
GDM is traditionally defined as the onset or first identification of impaired glucose tolerance during pregnancy. This condition has long been associated with various obstetric and neonatal complications, particularly fetal macrosomia, and it is increasingly recognized as a significant risk factor for future cardiometabolic diseases in both mothers and their offspring (108). The pathogenesis of GDM has not yet been fully elucidated, but dysregulated immune modulation is considered one of its key mechanisms (109).
Increasing evidence supports a central role for NETs in GDM pathophysiology. The neutrophil-to-lymphocyte ratio (NLR) is significantly increased in the serum of patients with GDM (110). Peripheral blood neutrophils from GDM patients exhibit enhanced activation and a greater propensity to form NETs in vitro, which may be driven by elevated circulating TNF-α levels (111). Compared with healthy pregnant women, pregnant women with GDM are characterized by greater spontaneous NET formation and lower serum adiponectin levels. Since adiponectin normally attenuates NET release by inhibiting ROS production, its reduction may contribute to the increased NETs observed in GDM (112). Furthermore, hyperglycemia, a common feature of GDM, has been reported to promote NET formation by modulating PAD4 activity (113, 114).
Notably, elevated NETs are detected in both the peripheral circulation and placental tissues of women with GDM, and these excessive NETs directly impair the proliferation, invasion, migration, and angiogenic capacity of placental trophoblasts, indicating that NETs contribute to the pathogenesis of GDM by disrupting trophoblast function. Importantly, the choline metabolite trimethylamine N-oxide (TMAO) can alleviate these deleterious effects by suppressing NET formation. Consistent with these findings, dietary TMAO supplementation in GDM mouse models reduces systemic NET generation and improves placental and fetal development, further supporting the involvement of NETs in GDM (10). In addition to direct structural and functional damage, neutrophil-derived NE impairs trophoblast physiology and glucose metabolism by downregulating the expression of the glucose transporter GLUT4 (115). Moreover, NETs amplify placental injury in GDM by inducing trophoblast apoptosis through activation of the ROS-dependent mitochondrial pathway and inhibiting of the pro-survival ERK1/2 signaling pathway (112).
Taken together, these findings demonstrate that multiple pathological triggers of GDM, including inflammation, low adiponectin levels, and hyperglycemia, converge to promote excessive NET formation, which in turn leads to impaired trophoblast function, disrupted glucose metabolism, and enhanced placental damage, thereby contributing to the development and progression of GDM.
4.3. Preterm birth
PTB is defined as delivery occurring before 37 weeks of gestation (116). The majority of preterm births are spontaneous, arising from two primary pathways: (1) spontaneous labor with intact membranes and (2) preterm premature rupture of membranes (117). The precise pathogenesis of PTB remains incompletely understood, and intrauterine infection is a well-recognized key trigger, accounting for approximately 40% of spontaneous PTB cases (116, 118). Chorioamnionitis, the typical pathological manifestation of intrauterine infection, is characterized by massive neutrophil infiltration and a robust inflammatory response at the maternal-fetal interface (119, 120), and accumulating evidence has confirmed the close association between NETs and the occurrence of PTB.
Clinically, the peripheral blood neutrophil count and NLR are significantly increased in women with PTB and can serve as potential predictive biomarkers for PTB (121). In contrast to neutrophils from the peripheral blood of normal pregnancies, the amniotic fluid neutrophils of patients with PTB are capable of spontaneous NET formation (122). Notably, elevated neutrophil levels and substantial NET formation have been detected in the placental membranes, amniotic fluid and amnion of preterm patients with acute chorioamnionitis (123–125). Lipopolysaccharide, from gram-negative bacteria is a common microbial stimulant in intrauterine infection, and group B Streptococcus is a pathogenic bacterium that can cause intrauterine infection complicated by preterm birth; both induce NET formation at the maternal-fetal interface (11, 126, 127). Fetal membrane tissues secrete a variety of proinflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) in response to microbial stimulation (128), among which IL-8 specifically recruits peripheral neutrophils to the maternal-fetal interface (129), and TNF-α further activates neutrophils and promotes NET formation through the mitogen-activated protein kinase (MAPK) signaling pathway to induce ROS production (11).
NETs can activate the ERK1/2 signaling pathway to promote ROS generation, which in turn induces the apoptosis of human amniotic epithelial cells and further aggravates fetal membrane damage and PTB progression (125). In addition, activated neutrophils have been shown to reduce chorioamniotic membrane integrity and tensile strength (130). As NETs contain hydrolytic enzymes such as NE capable of degrading collagen fibers, the mechanism by which NETs may contribute to PTB may be attributable to a reduction in fetal membrane elasticity and mechanical strength. Further research is needed to verify this mechanism.
4.4. Recurrent pregnancy loss
RPL is clinically defined as the occurrence of two or more consecutive pregnancy losses prior to 20–24 weeks of gestation, encompassing both embryonic loss and fetal death (131). While the exact etiology of RPL has not been fully elucidated, current studies suggest that dysregulated immune modulation at the maternal-fetal interface, particularly aberrant neutrophil activation and NET formation, may be closely associated with the pathogenesis of some RPL cases (132).
Compared with healthy pregnant women, women with RPL have a significantly elevated NLR in serum, suggesting that NLR may serve as a potential early auxiliary diagnostic marker for RPL (133). There is direct evidence indicating the increased formation of NETs in the serum and decidual tissues of patients with RPL (134), which points to a close association between excessive NET generation and pathogenesis of RPL. Notably, RPL represents repeated episodes of spontaneous abortion (SA) (135), and the pathological mechanisms underlying SA constitute the fundamental basis for recurrent miscarriage. Therefore, relevant evidence from SA is highly informative for understanding RPL. A dysregulated percentage of LDGs was found in the decidual tissues of patients with SA (12). LDGs isolated from the decidual tissues of SA patients show increased cellular activation, as evidenced by the elevated expression of CD11b, a well-established marker of neutrophil activation. Moreover, extensive NET infiltration is also detected in the decidual tissues of SA patients. These findings imply that LDGs and the NETs they form may contribute to the pathogenesis of SA (12), which may further contribute to the recurrent pregnancy loss. Overexpression of sFlt-1 induces significant pregnancy loss and massive NET accumulation in mouse placentas. Notably, gene knockout of PAD4 in mice markedly ameliorated the APOs such as miscarriage induced by sFlt-1 (101). These results further suggest that excessive NET formation may be a common pathological driver of pregnancy loss, which is highly relevant to RPL given its recurrent nature.
Studies directly investigating the role of NETs in RPL are relatively scarce. Nevertheless, the above evidence suggests that NETs contribute to pregnancy loss in single miscarriages and that repetitive activation of this mechanism may underlie the recurrent phenotype of RPL.
Although evidence has confirmed an association between NETs and RPL such as the abnormal accumulation of NETs in serum and decidual tissues direct causal evidence linking NETs to the pathogenesis of RPL is still lacking, and the specific molecular mechanisms by which NETs induce pregnancy loss remain unclear.
4.5. Autoimmune diseases
4.5.1. Systemic lupus erythematosus
SLE is a chronic autoimmune disease characterized by systemic inflammation and immune-mediated damage affecting multiple organ systems, frequently involving the mucocutaneous, musculoskeletal, hematological, and renal systems (136). SLE affects women in approximately 90% of cases, and these patients face a significantly elevated risk of APOs, including miscarriage, PE, PTB, and fetal growth restriction (137). Placental injury resulting from dysregulated immune adaptation at the maternal-fetal interface is a key mechanism underlying APOs in patients with SLE (138). Recent studies have demonstrated that patients with SLE complicated by APOs exhibit an elevated serum NLR, suggesting that the NLR may serve as a potential biomarker for predicting the risk of APOs in patients with SLE (139, 140). Additionally, the proportion of LDGs is greater in the peripheral blood of pregnant women with SLE than in those with healthy pregnancies (141, 142). Moreover, studies in patients with SLE have demonstrated reduced secretion and decreased activity of DNase1 and DNase1L3, leading to impaired NET clearance (143, 202). Although these findings were primarily obtained in non-pregnant individuals, they provide a mechanistic basis for understanding excessive NET accumulation in patients with SLE with APOs.
High levels of NET infiltration have been observed in the intervillous spaces of placental villi from SLE patients with APOs, indicating a potential role for NETs in the pathogenesis of APOs in this patient population (13). Further mechanistic studies revealed that NETs can promote glycolysis in trophoblasts and increase lactylation (a novel post-translational modification driven by lactate) of the NLRP3 inflammasome, thereby activating the NLRP3 inflammasome and inducing trophoblast pyroptosis, ultimately leading to placental damage. Consistently, in SLE mouse models, blocking NETs either by NET degradation with DNase1 or by inhibiting NET formation via PAD4 knockout has been shown to attenuate these pathological processes and reduce APOs (144). Decidual natural killer cells (dNKs) contribute to the maintenance of maternal-fetal interface immune tolerance, the promotion of trophoblast invasion, and the remodeling of spiral arteries through the secretion of cytokines and chemokines (145). Alterations in the number and functional activity of dNK cells during pregnancy are closely associated with the development of APOs (146). In SLE patients with APOs, dNKs are significantly increased in the placental intervillous space, with a notable increase in the level of cytotoxic CD56
+
CD16
+
NK cell subset. Moreover, the extent of NET infiltration is positively correlated with the number and subtype distribution of dNKs. The inhibition of NET formation attenuates the aberrant infiltration of dNKs, suggesting that NETs may contribute to placental dysfunction in patients with SLE by modulating the subset composition and quantity of dNKs (147).
4.5.2. Antiphospholipid syndrome
APS is an autoimmune disorder mediated by antiphospholipid antibodies (aPLs) and is characterized by thrombosis and APOs (148). Based on its primary clinical manifestations, APS can be categorized into two distinct subtypes: thrombotic APS (TAPS), which is dominated by thrombotic complications, and obstetric APS (OAPS), which is defined by pregnancy complications. Typical features of OAPS include RPL, unexplained fetal death beyond 10 weeks of gestation, early-onset PE, and PTB due to placental dysfunction (149). aPLs mediate pregnancy complications by initiating the complement cascade, and elevated levels of local complement activation fragments have severe detrimental effects on fetal development (150). Furthermore, circulating NET levels are found to be elevated in patients with APS. In in vitro assays, aPLs have been demonstrated to activate neutrophils via Toll-like receptor 4 (TLR4), thereby promoting ROS production and inducing NET formation (37).
The underlying mechanisms of placental injury in OAPS have not been fully elucidated. In recent years, studies from our research group have demonstrated that NETs play a pivotal role in the pathogenesis and progression of OAPS. First, our findings revealed that pregnant women with APS exhibit elevated serum NET levels, and neutrophils isolated from their peripheral blood show an enhanced spontaneous ability to release NETs in vitro. Further experimental evidence has confirmed that purified aPLs from the peripheral blood of pregnant women with APS can directly induce NETosis, and that these NETs inhibit the functional activity of both trophoblasts and HUVECs (14). Second, increased NET infiltration has been observed in placental tissues from both OAPS patients and corresponding mouse models. Mechanistically, NETs promote the generation of ROS in trophoblasts, which activates BNIP3 (a key mitophagy regulator)-mediated mitophagy and subsequently induces trophoblast apoptosis, thereby exacerbating placental damage (151). In addition, NETs can also trigger trophoblast pyroptosis via the MAPK and NF-κB signaling pathways, leading to further impairment of placental function. Notably, HCQ administration effectively alleviated NET-induced trophoblast injury (152). Taken together, these findings highlight the critical role of NETs in aPL-mediated placental pathology and associated APOs.
5. Pharmacological modulation of NETs in obstetrics
Given the critical role of NETs in the pathophysiology of a wide range of pregnancy-related complications, targeted regulation of NET formation has become a highly promising therapeutic approach. Notably, several drugs already employed in the clinical management of these complications have recently been shown to modulate NET formation to varying extents, revealing a previously unrecognized dimension of their pharmacological activity (Table 1).
Table 1.
Obstetric drugs targeting NETs formation.
Drugs
Indication
Mechanism of action
Human evidence
(in vitro/ vivo)
Aniaml model evidence
Reference
Aspirin
Preeclampsia OAPS
Inhibits platelet activation and TXA
2
production, which in turn inhibits neutrophil activation and subsequent NET formation.
1. Inhibits NET formation in human neutrophils stimulated by COVID-19 patient serum
2. Blocks platelet-human neutrophil interaction and subsequent NET formation
1. Reduces NET formation and venous thrombosis in mouse thrombosis models
2. Alleviates lung injury by inhibiting NET formation in mouse transfusion/PGD models
Metformin
GDM
Modulates NET formation either by inhibiting NADPH oxidase activation or by enhancing the phagocytic capacity of macrophages.
1. Reduces NET accumulation in human CRC tissues of T2DM patients
2. Enhances macrophage-mediated NET clearance in ARDS patients
2. Inhibits high glucose/PMA/HMGB1-induced NETosis in human neutrophils
Inhibits adipocyte-induced NET formation in obese mouse pancreatic tissue
LMWH
RPL OAPS
1. Directly inhibits neutrophil activation and NET formation.
2. Alleviates tissue damage by binding to histones and mitigating their cytotoxicity.
1. Reduces NET release from human neutrophils stimulated by COVID-19 patient serum
2. Inhibits pro-thrombotic stimulus-induced NETosis in human neutrophils
1. Reduces NET accumulation and lung injury in COVID-19 mouse models
2. Improves survival in mouse models of histone-induced organ dysfunction
3. Attenuates rat histone-mediated endothelial cells injury by histone binding
HCQ
SLE with APOs OAPS
1. Inhibits NET formation through suppressing PAD4 enzymatic activity and blocking TLR9 signaling pathway
2. Inhibits PRL2 degradation, regulating Rac GTPase/ROS-mediated NETosis
Reduces spontaneous NET formation in peripheral blood neutrophils of healthy donors
1. Alleviates liver ischemia/reperfusion injury by inhibiting NET formation in mice
2. Ameliorates NET-induced tissue damage in malaria and acute lung injury model mouse models
3. Inhibits mouse neutrophil NETosis via TLR9 pathway
Vitamin D
VitaminD deficiency
1. Inhibits NET-forming capacity of neutrophil activation and NET formation
2. Synergizes with ω3 PUFAs to inhibit NETosis
1. Reduces PMA-induced NET formation in SLE patient neutrophils
3. Combined with ω3 PUFAs exerts inhibit the ability of neutrophils to generate NETs in T2DM patient
1. Suppresses NET formation and ameliorates alveolarization disorders in hyperoxia-induced BPD rat models
2. Mitigates NET-induced ovarian fibrosis in premature ovarian insufficiency mouse models
5.1. Aspirin
Aspirin is clinically used for the prevention of PE and the management of OAPS (153–155). As a nonsteroidal anti-inflammatory drug, aspirin exerts its antithrombotic effect primarily by inhibiting cyclooxygenase activity, thereby reducing the synthesis of thromboxane A
2
(TXA
2
) (156). TXA
2
is a potent vasoconstrictor that activates and promotes platelet aggregation (157). In addition, activated platelets in the circulation not only contribute to thrombogenesis but also stimulate NET formation through the release of HMGB1, which engages receptors for advanced glycation end products and TLR4 on neutrophils (158, 159). Given the regulatory role of platelets in neutrophil activation and NET formation, antiplatelet agents such as aspirin may reduce NET formation by targeting platelet function.
Multiple experimental studies have provided evidence in support of this mechanism. For instance, serum from COVID-19 patients can induce robust NETosis and NET formation in neutrophils, and these effects can be significantly suppressed by aspirin (17). In vitro assays have further revealed that platelets activated by intrahepatic cholangiocarcinoma cells via P-selectin can promote neutrophil NET release and cancer cell migration, both of which are inhibited by aspirin treatment (160). Similarly, a study by Lapponi et al. demonstrated that aspirin, but not the steroid immunomodulatory drug dexamethasone, effectively suppresses NET formation (161). In a mouse model of venous thrombosis, aspirin exerts its antithrombotic effects by inhibiting platelet-derived TXA
2
production, which in turn suppresses neutrophil activation and subsequent NET formation (162). Moreover, in murine models of lung injury and primary graft dysfunction, aspirin attenuates lung tissue damage by inhibiting platelet activation and subsequent NET generation (163, 164).
5.2. Metformin
Metformin is a hypoglycemic agent clinically indicated for the management of GDM (165). Its primary pharmacological action is mediated by the inhibition of mitochondrial complex I activity, which subsequently activates AMP-activated protein kinase (AMPK) and suppresses hepatic gluconeogenesis, ultimately exerting a glucose-lowering effect (166). In recent years, emerging evidence has revealed that metformin plays a regulatory role in the formation of NETs. In patients with type 2 diabetes mellitus, metformin administration has been shown to reduce the enrichment of tumor-associated neutrophils and NETs in colorectal cancer tissues (18). In obese mouse models, metformin decreases neutrophil infiltration in pancreatic tissue and inhibits adipocyte-induced NET formation (167). Further in vitro cellular assays have demonstrated that metformin is capable of suppressing NET formation induced by various stimuli, including high glucose, PMA, and HMGB1 (85, 168–170).
These findings collectively indicate that metformin participates in the regulation of NET formation, although the underlying mechanisms remain incompletely elucidated. It has been reported that metformin can inhibit the activation of NADPH oxidase by preventing the translocation of PKC from the cytoplasm to the cell membrane, thereby interfering with NETosis (171). In addition, metformin can activate AMPK signaling pathway in macrophages, increasing their ability to phagocytose NETs and consequently reducing NET accumulation in acute respiratory distress syndrome (ARDS) patients (172).
5.3. Low molecular weight heparin
LMWH is a commonly used agent for improving APOs, such as RPL, in patients with OAPS (173). As a depolymerized fragment derived from unfractionated heparin via chemical or enzymatic approaches, LMWH is widely employed in clinical anticoagulant therapy (174). LMWH can inhibit neutrophil activation, autophagy, and the capacity to form NETs (19). LMWH reduces NETs levels in neutrophils stimulated with COVID-19 patient serum (17). Furthermore, LMWH reduces NET accumulation and alleviates lung injury in COVID-19 animal models (175, 176). In addition to its direct inhibitory effects on NET generation, LMWH can also antagonize the pathological effects of histones, which are key structural components of NETs. Histones can activate the NF-κB signaling pathway to promote cytokine release, thereby amplifying inflammatory responses and inducing organ damage (177–179). Both in vitro and in vivo experiments have verified that heparin can bind to histones, attenuate their cytotoxicity, mitigate subsequent tissue injury, and protect mice from histone-mediated organ dysfunction and even mortality (180).
5.4. Hydroxychloroquine
HCQ is a commonly used agent in the management of SLE with obstetric complications and OAPS (181). Initially introduced into clinical practice as an antimalarial drug, HCQ was subsequently found to possess potent immunomodulatory and anti-inflammatory properties during long-term clinical application, which has led to its progressive repurposing for the treatment of a broad spectrum of autoimmune disorders, including SLE, APS, RA, and primary Sjögren’s syndrome (182). Findings from recent investigations have demonstrated that HCQ inhibits NET formation through multiple mechanisms. In vitro experiments have confirmed the inhibitory effect of HCQ on NET formation (183–185), a mechanism potentially attributed to its ability to regulate PAD4 either by inhibiting its enzymatic activity or by suppressing its expression by blocking the Toll-like receptor 9 (TLR9) signaling pathway (20, 186). In a murine model of hepatic ischemia/reperfusion injury, HCQ can alleviate liver tissue damage by inhibiting NET formation (20). Additionally, in mouse malaria and acute lung injury models, HCQ also participates in the regulation of NET formation by inhibiting the degradation of phosphatase of regenerating liver 2, which negatively regulates NETosis by modulating Rac GTPase activity and ROS production (187).
5.5. Vitamin D
Vitamin D, a fat-soluble secosteroid hormone, plays a critical role in maintaining homeostasis across multiple organ systems (188). Vitamin D deficiency is commonly observed in individuals with inadequate sun exposure, those with darker skin pigmentation, and pregnant women (189). Vitamin D deficiency is closely associated with various APOs, such as hypertensive disorders of pregnancy, GDM, PTB, and being small for gestational age (190–193). Therefore, timely vitamin D supplementation in deficient pregnant women is recommended to mitigate some of these risks (194).
Vitamin D supplementation has been shown to reduce the incidence of PE and GDM (195), promote the release of proinflammatory cytokines (IL-1β and IL-8) from neutrophils isolated from the peripheral blood of healthy people (196), and simultaneously inhibit the formation of NETs-an effect that is more pronounced when combined with ω-3 polyunsaturated fatty acids (PUFAs) (197). However, two clinical in vivo studies in healthy Saudi populations (198, 199) confirmed that a single high-dose (80,000 IU) vitamin D
3
bolus significantly reduced serum IL-6, IL-8, and TNF-α levels without disrupting calcium-phosphorus homeostasis. This discrepancy between in vitro and in vivo findings may be because vitamin D modulates the entire immune system to exert systemic anti-inflammatory effects in vivo, which is distinct from its effect on isolated cells. Vitamin D supplementation significantly alleviates NET-induced early apoptosis of HUVECs by reducing NET release from the neutrophils of vitamin D-deficient SLE patients (200). In the field of reproductive health, vitamin D can mitigate NET-induced oxidative stress and fibrosis in ovarian tissues by inhibiting NET formation, thereby delaying the onset of premature ovarian insufficiency (201). In addition, vitamin D supplementation increases the survival rate of rats with hyperoxia-induced bronchopulmonary dysplasia and ameliorates alveolarization disorders by suppressing NET formation (21). Notably, vitamin D supplementation may regulate the NET-forming capacity of neutrophils by altering the systemic proinflammatory cytokine profile. Changes in cytokine status serve as an important intermediate links connecting vitamin D levels and NET formation and are key confounding factors. Currently, the direct molecular mechanisms by which vitamin D regulates NET formation (e.g., whether it directly targets key molecules involved in NET formation, such as PAD4 or NADPH oxidase) remain to be verified by more in-depth mechanistic experiments.
Although aspirin, metformin, LMWH, HCQ and vitamin D have been shown to regulate NET formation or counteract its pathological effects through distinct pharmacological approaches, direct experimental or clinical evidence verifying the specific regulatory effects of these drugs on NETs in obstetric complications remains insufficient to varying degrees. Collectively, the aforementioned findings indicate that targeting the homeostasis of NETs is a promising potential therapeutic strategy for pregnancy complications, and further in-depth clinical and basic research is needed to clarify the specific regulatory mechanisms of these clinical obstetric drugs on NETs during pregnancy to provide a more solid theoretical basis for their clinical application in preventing and treating pregnancy complications mediated by the imbalance of NETs.
6. Conclusion and outlook
While NETs play a beneficial role in host defense by trapping and eliminating pathogens, the concomitant release of proteolytic enzymes and cytotoxic proteins can cause tissue damage, thereby implicating NETs in the pathogenesis of various diseases. As a result, the regulation of NET formation is increasingly being explored as a therapeutic target for multiple disorders. This review systematically examines the dual functions of NETs in normal pregnancy and in obstetric complications such as PE, GDM, PTB, and RPL, along with their pathological roles in pregnancies complicated by autoimmune diseases, including APS and SLE. Growing evidence suggests that as key elements of innate immunity, NETs play a protective physiological role at the maternal-fetal interface, helping to maintain the immune microenvironment and defend against infections. However, excessive NET formation or inadequate clearance may contribute to placental dysfunction and pregnancy-related pathology through various mechanisms, such as impaired trophoblast function, induction of a prothrombotic state, and amplification of inflammatory responses.
This review also synthesizes emerging evidence on how common obstetric medications, such as aspirin, metformin, LMWH, HCQ, and vitamin D, may exert therapeutic benefits. These findings suggest that the positive effects of these compounds on pregnancy outcomes could be partly mediated through the modulation of NET formation and clearance. These findings expand the understanding of the pharmacological mechanisms of existing drugs and offer new insights for optimizing clinical treatment strategies.
Despite the significant progress of current research, substantial limitations remain. Most studies have focused on animal models and in vitro experiments, while research on human pregnancy, particularly across different gestational stages, remains insufficient. Notably, the regulatory effects of pregnancy-related hormones on NET formation and homeostasis in pregnancy complications remain to be fully elucidated because of the lack of definitive experimental evidence, which is a critical research gap in the field of NET and pregnancy-related disorder research. Furthermore, the absence of standardized methods for the detection and quantification of NETs in vivo hinders their development as clinical diagnostic markers. Additionally, the long-term safety and efficacy of NET-targeted therapies in pregnancy have not been fully validated.
Based on the existing research foundation, future research directions can focus on the following aspects. First, a standardized NET detection system that integrates imaging and molecular biology techniques to enable precise monitoring of NET levels throughout pregnancy should be established, with the aim of identifying specific biomarkers for early warning of pregnancy complications. Second, large-sample, multi-center longitudinal clinical studies should be conducted to elucidate the regulatory dynamics of NETs across gestational ages, clarify the correlation between disrupted NET homeostasis and the severity of pregnancy complications, and provide a basis for stratified disease management. Third, the development of NET-targeted therapies, such as optimizing the administration regimen of DNase1 preparations and developing specific PAD4 inhibitors, while exploring combination strategies to enhance efficacy and reduce potential risks to the mother and fetus. Fourth, integrate multi-omics technologies should be integrated to explore the interactions between NETs and immune cells and cytokine networks at the maternal-fetal interface, thereby revealing the molecular pathways through which NETs regulate pregnancy outcomes from a systemic perspective. Fifth, there should be a focus on special populations, such as pregnant individuals with HIV infection, obesity, or other high-risk factors, to analyze their NET metabolic profiles and develop individualized intervention strategies.
In summary, this review systematically elucidates the central role of NET homeostasis imbalance in pregnancy complications and emphasizes the significance of targeted NET regulation for improving maternal and fetal outcomes. With further research, NETs are expected to become key targets for the precise diagnosis and treatment of pregnancy complications, offering novel breakthroughs in the prevention and management of obstetric disorders.
Funding Statement
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by funding from Youth Science and Technology Innovation Project of Shandong Provincial Maternal and Child Health SFYZXJJ-2024004).
Footnotes
Edited by: Davide Randazzo, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH), United States
Reviewed by: Shuichiro Nakabo, Kyoto University Hospital, Japan
Jorge Romo-Tena, National Institutes of Health (NIH), United States
Author contributions
MZ: Writing – review & editing. CW: Writing – original draft.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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