Birth Defects Registry, New York State Department of Health, Albany, New York, USA.
Department of Epidemiology and Biostatistics, School of Public Health, University at Albany, Rensselaer, New York, USA.
Birth Defects Res. 2023 Jan 15;115(2):133-144. doi: 10.1002/bdr2.2074. Epub 2022 Aug 14.
Heparin and low-molecular-weight heparin are the preferred anticoagulants during pregnancy as they do not cross the placenta. Although research on the safety of heparin products has been reassuring, previous studies have considered birth defects as a single outcome or by larger organ system and have not examined associations with specific birth defects.
We analyzed data from the National Birth Defects Prevention Study, a multisite, population-based case-control study from 1997 to 2011. We used unconditional logistic regression with Firth's penalized likelihood to calculate adjusted odds ratios (ORs) and profile likelihood 95% confidence intervals (CIs) for defects with at least five exposed cases. For defects with 3-4 exposed cases, we estimated crude ORs and exact 95% CIs.
Of the 42,743 women in our analysis, 117 (0.4%) case and 44 (0.4%) control mothers reported using a heparin product in early pregnancy. The adjusted ORs ranged from 0.9 to 3.9 and were elevated for anorectal atresia (OR = 2.0, 95% CI = 0.8-4.3), longitudinal limb deficiency (3.5, 1.3-7.8), transverse limb deficiency (1.8, 0.6-4.3), atrioventricular septal defect (3.9, 1.4-9.0), and secundum atrial septal defect (2.2, 1.2-3.8).
We observed elevated associations for some birth defects, although heparin is a rare exposure, which limited our ability to evaluate many associations. Future studies that can explore specific birth defects and adequately control for confounding by indication are needed. Given that women with an indication for heparin products during pregnancy often need to take medication, one must remain mindful of the underlying risk of a birth defect that exists regardless of medication use.
肝素和低分子量肝素是妊娠期间首选的抗凝剂，因为它们不会穿过胎盘。尽管肝素产品的安全性研究令人安心，但以前的研究仅将出生缺陷视为单一结果，或通过更大的器官系统来考虑，并未检查与特定出生缺陷的关联。
我们分析了 1997 年至 2011 年进行的多地点、基于人群的病例对照研究——国家出生缺陷预防研究的数据。我们使用无条件逻辑回归和 Firth 罚似然法计算了至少有 5 例暴露病例的畸形的调整比值比（OR）和轮廓似然 95％置信区间（CI）。对于有 3-4 例暴露病例的畸形，我们估计了粗 OR 和确切的 95％CI。
在我们的分析中，42743 名女性中有 117 名（0.4％）病例和 44 名（0.4％）对照母亲在孕早期使用肝素产品。调整后的 OR 范围为 0.9 至 3.9，并且肛门直肠闭锁（OR=2.0，95％CI=0.8-4.3）、肢体纵向缺陷（3.5，1.3-7.8）、肢体横向缺陷（1.8，0.6-4.3）、房室间隔缺损（3.9，1.4-9.0）和继发孔房间隔缺损（2.2，1.2-3.8）的 OR 值升高。
尽管肝素是一种罕见的暴露，但我们观察到某些出生缺陷的关联有所上升，这限制了我们评估许多关联的能力。需要未来的研究能够探索特定的出生缺陷，并充分控制指示性混杂因素。鉴于妊娠期间有肝素产品适应症的妇女通常需要服药，人们必须时刻牢记无论是否使用药物，都存在出生缺陷的潜在风险。
