Kate Johnson

October 27, 2014

HONOLULU — In some babies conceived by in vitro fertilization (IVF), cardiac dysfunction might be linked to excessive maternal hormone levels at conception and during pregnancy, new research suggests.

Ovarian hyperstimulation syndrome, a rare and life-threatening over-response to regular IVF ovarian stimulation, can result in supraphysiologic estrogen levels in utero, Gu-feng Xu, MD, from Zhejiang University in Hangzhou, China, told Medscape Medical News.

"What we can do is avoid ovarian hyperstimulation during IVF," he said. In fact, an approach to eliminate maternal complications, including ovarian torsion or rupture, thrombophlebitis, and renal insufficiency, is already widely used.

Dr. Xu and his team compared cardiac function, using Doppler echocardiography, in 42 IVF children born to mothers who had ovarian hyperstimulation, 34 IVF children whose mothers did not have hyperstimulation, and 48 spontaneously conceived children.

He presented the results here at the American Society for Reproductive Medicine 2014 Annual Meeting; they were published online September 30 in the Journal of Clinical Endocrinology and Metabolism.

"Ovarian hyperstimulation was diagnosed and classified according to the criteria of Golan and Weissman," said Dr. Xu (Reprod Biomed Online. 2009;19:28-32). "The hyperstimulation we mention in the study is characterized by elevated serum estradiol levels, massive cystic ovarian enlargement, and fluid shift from the intravascular compartment into the peritoneal, pleural, or pericardial cavities."

All children were 3 to 7 years of age at the time of the assessment, and children whose mothers had a history of cardiac disease were excluded from the analysis.

On pulsed wave Doppler echocardiography, after birthweight and gestational age at delivery were controlled for, children who had been exposed to ovarian hyperstimulation in utero had a significantly lower mitral E/A ratio (1.63) than IVF children not exposed (1.75; P = .054) and than spontaneously conceived children (1.79; P < .01).

Exposed children had smaller systolic diameters of common carotid arteries than unexposed IVF children (P = .02) and spontaneously conceived children (P < .01), and smaller diastolic diameters than unexposed IVF children (P = .12) and spontaneously conceived children (P < .01).

Exposed children also had more impairment in flow-mediated dilation (5.13%) than unexposed IVF (7.63%; P = .01) and spontaneously conceived children (9.82%; P < .01).

Effect on Protein Expression

In a separate study, umbilical cords were collected from seven women with ovarian hyperstimulation and seven with spontaneously conceived pregnancies. A proteomics analysis showed that many proteins were differentially expressed in the two groups.

"We observed that the ovarian hyperstimulation group showed a distinct gene-expression pattern, compared with the spontaneous conception group, suggesting a significant impact of ovarian hyperstimulation on protein expression," Dr. Xu noted.

He emphasized that the alterations in that study were still mostly within the normal range and were subclinical. "Although these differences are recognized as potential cardiovascular risk factors, their long-term persistence and association with adult cardiovascular diseases remain unclear," he noted. "Therefore, it is necessary to carry out the longer follow-up of these children to determine whether ovarian hyperstimulation pregnancy remains a risk factor in later life."

This "is a very interesting paper, and understandably very concerning," said Roger Hart, MD, from the University of Western Australia and medical director of Fertility Specialists of Western Australia, both in Perth, who was involved in a review of the long-term outcomes of IVF children (Hum Reprod Update. 2013;19:232-243).

"There is obviously the concern that the children had some bias toward cardiovascular dysfunction at the time of recruitment, as very little is stated about the selection process," he told Medscape Medical News. "There are possibly genetic differences in the women who are at risk of ovarian hyperstimulation, which may lead to an increased propensity to cardiovascular dysfunction in their children."

The good news is that "most IVF units are now very good at keeping the rates of hyperstimulation low, as there are many treatments available to prevent this from occurring," Dr. Hart said.

The study was supported by the National Basic Research Program of China, the National Natural Science Foundation of China, the Talent Project of Zhejiang Province, and the Public Welfare Technology Project of Zhejiang Province. Dr. Xu has disclosed no relevant financial relationships. Dr. Hart reports being part owner and shareholder of an IVF company; receiving travel grants and honoraria from pharmaceutical manufacturers of gonadotrophins; and being on the medical advisory board of pharmaceutical companies that manufacture gonadotrophins.

American Society for Reproductive Medicine (ASRM) 2014 Annual Meeting: Abstract O-67. Presented October 20, 2014.

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