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PubMed2000

Calmodulin regulation of basal and agonist-stimulated G protein coupling by the mu-opioid receptor (OP(3)) in morphine-pretreated cell.

Calmodulin (CaM) has been shown to suppress basal G protein coupling and attenuate agonist-stimulated G protein coupling of the mu-opioid receptor (OP(3)) through direct interaction with the third intracellular (i3) loop of the receptor. Here we have investigated the role of CaM in regulating changes in OP(3)-G protein coupling during morphine treatment, shown to result in CaM release from plasma membranes. Basal and agonist-stimulated G protein coupling by OP(3) was measured before and after morphine pretreatment by incorporation of guanosine 5'-O-(3-[(35)S]thiotriphosphate) into membranes, obtained from HEK 293 cells transfected with human OP(3) cDNA. The opioid antagonist beta-chlornaltrexamine fully suppressed basal G protein coupling of OP(3), providing a direct measure of basal signaling. Pretreatment of the cells with morphine enhanced basal G protein coupling (sensitization). In contrast, agonist-stimulated coupling was diminished (desensitization), resulting in a substantially flattened morphine dose-response curve. To test whether CaM is involved in these changes, we constructed OP(3)-i3 loop mutants with reduced affinity for CaM (K273A, R275A, and K273A/R275A). Basal signaling of these mutant OP(3) receptors was higher than that of the wild-type receptor and, moreover, unaffected by morphine pretreatment, whereas desensitization to agonist stimulation was only slightly attenuated. Therefore, CaM-OP(3) interactions appear to play only a minor role in the desensitization of OP(3). In contrast, release of CaM from the plasma membrane appears to enhance the inherent basal G protein coupling of OP(3), thereby resolving the paradox that OP(3) displays both desensitization and sensitization during morphine treatment.

Amino Acid Substitution↗

PubMed1983

Treatment-independent pregnancy among infertile couples.

We analyzed a two- to seven-year follow-up of 1145 infertile couples to determine the frequency of pregnancy occurring independently of treatment. Pregnancy occurred in 246 of 597 treated couples (41 per cent) and in 191 of 548 untreated couples (35 per cent). Thirty-one per cent of the pregnancies in treated couples occurred more than 3 months after the last medical treatment or more than 12 months after adnexal surgery. These pregnancies plus the 191 pregnancies in untreated couples constituted the category of "treatment-independent pregnancies" and accounted for 61 per cent of all pregnancies; for 44 per cent of those among couples with ovulation deficiency; for 61 per cent of those in couples with endometriosis, tubal defects, or seminal deficiencies; and for 96 per cent of those in couples with cervical factors or idiopathic infertility. We conclude that the potential for a spontaneous cure of infertility is high, that treatment for many classes of infertility should be evaluated by randomized clinical trials, and that in such trials random assignment of subjects to untreated control groups would be ethically acceptable.

Counseling↗

PubMed2006

Triplet-triplet energy-transfer coupling: theory and calculation.

Triplet-triplet (TT) energy transfer requires two molecular fragments to exchange electrons that carry different spin and energy. In this paper, we analyze and report values of the electronic coupling strengths for TT energy transfer. Two different methods were proposed and tested: (1) Directly calculating the off-diagonal Hamiltonian matrix element. This direct coupling scheme was generalized from the one used for electron transfer coupling, where two spin-localized unrestricted Hartree-Fock wave functions are used as the zero-order reactant and product states, and the off-diagonal Hamiltonian matrix elements are calculated directly. (2) From energy gaps derived from configuration-interaction-singles (CIS) scheme. Both methods yielded very similar results for the systems tested. For TT coupling between a pair of face-to-face ethylene molecules, the exponential attenuation factor is 2.59 A(-1)(CIS6-311+G(**)), which is about twice as large as typical values for electron transfer. With a series of fully stacked polyene pairs, we found that the TT coupling magnitudes and attenuation rates are very similar irrespective of their molecular size. If the polyenes were partially stacked, TT couplings were much reduced, and they decay more rapidly with distance than those of full-stacked systems. Our results showed that the TT coupling arises mainly from the region of close contact between the donor and acceptor frontier orbitals, and the exponential decay of the coupling with separation depends on the details of the molecular contacts. With our calculated results, nanosecond or picosecond time scales for TT energy-transfer rates are possible.

Algorithms↗

PubMed1981

A critique of the chemosmotic model of energy coupling.

The chemosmotic model provides a framework for visualizing energy-coupled reactions (vectorial reaction sequences, membrane-dependent gradient formation, and charge separation of reacting species) and a mechanism for energy coupling (indirect coupling between the driving and driven reaction sequences mediated by a membrane potential or a protonmotive force). The mechanistic parameters of this model have been examined from four standpoints: compatibility with the experimental realities, supporting evidence that is unambiguous, compatibility with the enzymic nature of energy coupling, and the capability for generating verifiable predictions. Recent developments that have clarified the mechanism of ion transport, the nature of the protonic changes that accompany energy coupling, and the enzymic nature of energy coupling systems have made such an examination both timely and necessary. After weighing the available evidence, it has been concluded that the chemosmotic principle of indirect coupling has no basis in fact and that it is physically unsound in respect to the mechanism of energy coupling and enzymic catalysis.

Adenosine Triphosphatases↗

PubMed1989

Role of coupling entropy in establishing the nature and magnitude of allosteric response.

The coupling free energy between an allosteric ligand and a substrate, delta Gax, is an explicit measure of the nature as well as the magnitude of impact that an allosteric ligand has on the binding of the substrate ligand to the enzyme, with positive values indicating inhibition and negative values indicating activation. By measuring the variation with temperature of the coupling free energy between the allosteric ligand and the substrate, it is possible to determine the enthalpic and entropic components that give rise to the coupling free energy. We have performed this analysis on two different K-type allosteric systems: the allosteric inhibition of rat liver phosphofructokinase by MgATP, and the allosteric activation of beef heart NAD+-dependent isocitrate dehydrogenase by ADP. In both cases the coupling free energy arises as the net result of opposing enthalpic and entropic components, with the coupling enthalpy (delta Hax) favoring activation and the coupling entropy (delta Sax) favoring inhibition. For phosphofructokinase at 25 degrees C, the absolute value of T delta Sax is greater than the absolute value of delta Hax, and net inhibition of rat liver phosphofructokinase by MgATP is realized. For isocitrate dehydrogenase, delta Hax dominates; however, the net activation is substantially mitigated by the magnitude of T delta Sax. Hence, the coupling entropy plays an important role in establishing both the nature and magnitude of the allosteric response. We hypothesize that the negative coupling entropy arises from the particular constraint placed upon the internal dynamical properties of the enzyme by the simultaneous binding of both allosteric and substrate ligands.

Allosteric Regulation↗

PubMed2000

Effect of G protein heterotrimer composition on coupling of neurotransmitter receptors to N-type Ca(2+) channel modulation in sympathetic neurons.

Voltage-dependent (VD) inhibition of N-type Ca(2+) channels is mediated primarily by neurotransmitter receptors that couple to pertussis toxin (PTX)-sensitive G proteins (such as G(o) and G(i)). To date, however, the composition of heterotrimeric complexes, i.e., specific Galphabetagamma combinations, capable of coupling receptors to N-type Ca(2+) channels has not been defined. We addressed this question by heterologously expressing identified Galphabetagamma combinations in PTX-treated rat sympathetic neurons and testing for reconstitution of agonist-mediated VD inhibition. The heterologously expressed Galpha subunits were rendered PTX-insensitive by mutating the codon specifying the ADP ribosylation site. The following results were obtained from this approach. (i) Expression of Galpha(oA), Galpha(oB), and Galpha(i2) (along with Gbeta(1)gamma(2)) reconstituted VD inhibition mediated by alpha(2)-adrenergic, adenosine, somatostatin, and prostaglandin E(2) receptors. Conversely, expression of Galpha(i1) and Galpha(i3) was ineffective at restoring coupling. (ii) Coupling efficiency, as determined from the magnitude of reconstituted Ca(2+) current inhibition, depended on both the receptor and Galpha subtype. The following rank order of coupling efficiency was observed: Galpha(oA) = Galpha(oB) > Galpha(i2) for alpha(2)-adrenergic receptor; Galpha(i2) > Galpha(oA) = Galpha(oB) for adenosine and prostaglandin E(2) receptors; and Galpha(oB) = Galpha(i2) > Galpha(oA) for the somatostatin receptor. (iii) In general, varying the Gbetagamma composition of Galpha(oA)-containing heterotrimers had little effect on the coupling of alpha(2)-adrenergic receptors to the VD pathway. Taken together, these results suggest that multiple, diverse Galphabetagamma combinations are capable of coupling neurotransmitter receptors to VD inhibition of N-type Ca(2+) channels. Thus, if exquisite Galphabetagamma-coupling specificity exists in situ, it cannot arise solely from the inherent inability of other Galphabetagamma combinations to form functional signaling complexes.

Animals↗

PubMed1995

Selective coupling of prostaglandin E receptor EP3D to Gi and Gs through interaction of alpha-carboxylic acid of agonist and arginine residue of seventh transmembrane domain.

Prostaglandin (PG) E receptor EP3D is coupled to both Gi and Gs. To examine the roles of the interaction of alpha-carboxylic acid of PGE2 and its putative binding site, the arginine residue in the seventh transmembrane domain of EP3D, in receptor-G protein coupling, we have mutated the arginine residue to the noncharged glutamine. PGE2 with a negatively charged alpha-carboxylic acid and sulprostone, an EP3 agonist with a noncharged modified alpha-carboxylic acid, inhibited the forskolin-stimulated adenylate cyclase activity via Gi activation in the EP3D receptor in the same concentration-dependent manner. In contrast, the adenylate cyclase stimulation via Gs activation by sulprostone was much lower than that by PGE2. On the other hand, both PGE2 and sulprostone showed potent Gi activity but failed to show Gs activity in the mutant receptor. EP3D receptor showed a high affinity binding for PGE2 in the form coupled to either Gi or Gs. Although the mutant receptor showed high affinity binding when coupled to Gi, it lost high affinity binding in the condition of Gs coupling. Furthermore, sulprostone bound to the Gi-coupled EP3D receptor with higher affinity than the Gs-coupled receptor. Among various EP3 agonists, alpha-carboxylic acid-unmodified agonists showed both Gi and Gs activities, but the modified agonists showed only Gi activity. These findings suggest that the interaction between the alpha-carboxylic acid of PGE2 and the arginine residue of the receptor regulates the selectivity of the G protein coupling.

Abortifacient Agents, Nonsteroidal↗

PubMed1997

Gbetagamma subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation.

In many cells, stimulation of mitogen-activated protein kinases by both receptor tyrosine kinases and receptors that couple to pertussis toxin-sensitive heterotrimeric G proteins proceed via convergent signaling pathways. Both signals are sensitive to inhibitors of tyrosine protein kinases and require Ras activation via phosphotyrosine-dependent recruitment of Ras guanine nucleotide exchange factors. Receptor tyrosine kinase stimulation mediates ligand-induced receptor autophosphorylation, which creates the initial binding sites for SH2 domain-containing docking proteins. However, the mechanism whereby G protein-coupled receptors mediate the phosphotyrosine-dependent assembly of a mitogenic signaling complex is poorly understood. We have studied the role of Src family nonreceptor tyrosine kinases in G protein-coupled receptor-mediated tyrosine phosphorylation in a transiently transfected COS-7 cell system. Stimulation of Gi-coupled lysophosphatidic acid and alpha2A adrenergic receptors or overexpression of Gbeta1gamma2 subunits leads to tyrosine phosphorylation of the Shc adapter protein, which then associates with tyrosine phosphoproteins of approximately 130 and 180 kDa, as well as Grb2. The 180-kDa Shc-associated tyrosine phosphoprotein band contains both epidermal growth factor (EGF) receptor and p185(neu). 3-5-fold increases in EGF receptor but not p185(neu) tyrosine phosphorylation occur following Gi-coupled receptor stimulation. Inhibition of endogenous Src family kinase activity by cellular expression of a dominant negative kinase-inactive mutant of c-Src inhibits Gbeta1gamma2 subunit-mediated and Gi-coupled receptor-mediated phosphorylation of both EGF receptor and Shc. Expression of Csk, which inactivates Src family kinases by phosphorylating the regulatory carboxyl-terminal tyrosine residue, has the same effect. The Gi-coupled receptor-mediated increase in EGF receptor phosphorylation does not reflect increased EGF receptor autophosphorylation, assayed using an autophosphorylation-specific EGF receptor monoclonal antibody. Lysophosphatidic acid stimulates binding of EGF receptor to a GST fusion protein containing the c-Src SH2 domain, and this too is blocked by Csk expression. These data suggest that Gbetagamma subunit-mediated activation of Src family nonreceptor tyrosine kinases can account for the Gi-coupled receptor-mediated tyrosine phosphorylation events that direct recruitment of the Shc and Grb2 adapter proteins to the membrane.

Animals↗

PubMed1998

Localization in the II-III loop of the dihydropyridine receptor of a sequence critical for excitation-contraction coupling.

Skeletal and cardiac muscles express distinct isoforms of the dihydropyridine receptor (DHPR), a type of voltage-gated Ca2+ channel that is important for excitation-contraction (EC) coupling. However, entry of Ca2+ through the channel is not required for skeletal muscle-type EC coupling. Previous work (Tanabe, T., Beam, K. G., Adams, B. A., Niidome, T., and Numa, S. (1990) Nature 346, 567-569) revealed that the loop between repeats II and III (II-III loop) is an important determinant of skeletal-type EC coupling. In the present study we have further dissected the regions of the II-III loop critical for skeletal-type EC coupling by expression of cDNA constructs in dysgenic myotubes. Because Ser687 of the skeletal II-III loop has been reported to be rapidly phosphorylated in vitro, we substituted this serine with alanine, the corresponding cardiac residue. This alanine-substituted skeletal DHPR retained the ability to mediate skeletal-type EC coupling. Weak skeletal-type EC coupling was produced by a chimeric DHPR, which was entirely cardiac except for a small amount of skeletal sequence (residues 725-742) in the II-III loop. Skeletal-type coupling was stronger when both residues 725-742 and adjacent residues were skeletal (e.g. a chimera containing skeletal residues 711-765). However, residues 725-742 appeared to be critical because skeletal-type coupling was not produced either by a chimera with skeletal residues 711-732 or by one with skeletal residues 734-765.

Amino Acid Sequence↗

PubMed1998

Extreme C terminus of G protein alpha-subunits contains a site that discriminates between Gi-coupled metabotropic glutamate receptors.

Metabotropic glutamate receptors (mGlu receptors), the Ca2+-sensing receptor, gamma-aminobutyric acid type B receptors, and one group of pheromone receptors constitute a unique family (also called family 3) of heptahelical receptors. This original family shares no sequence similarity with any other G protein-coupled receptors. The identification and comparison of the molecular determinants of receptor/G protein coupling within the different receptor families may help identify general rules involved in this protein/protein interaction. In order to detect possible contact sites important for coupling selectivity between family 3 receptors and the G protein alpha-subunits, we examined the coupling of the cyclase-inhibiting mGlu2 and mGlu4 receptors to chimeric alphaq-subunits bearing the 5 extreme C-terminal amino acid residues of either Galphai, Galphao, or Galphaz. Whereas mGlu4 receptor activated all three chimeric G proteins, mGlu2 receptor activated Galphaqi and Galphaqo but not Galphaqz. The mutation of isoleucine -4 of Galphaqz into cysteine was sufficient to recover coupling of the mutant G protein to mGlu2 receptor. Moreover, the mutation of cysteine -4 of Galphaqo into isoleucine was sufficient to suppress the coupling to mGlu2 receptor. Mutations at positions -5 and -1 had an effect on coupling efficiency, but not selectivity. Our results emphasize the importance of the residue -4 of the alpha-subunits in their specific interaction to heptahelical receptors by extending this finding on the third family of G protein-coupled receptors.

Cell Line↗

PubMed1995

Intimacy and sexual risk behaviour in serodiscordant male couples.

Several studies have demonstrated individual-level determinants of HIV sexual risk behaviour. Very little research has been conducted to identify couple-level factors associated with unsafe sexual behaviour. As part of a three-year study of more than 100 serodiscordant male couples, we conducted an in-depth qualitative study of 15 Latino and non-Latino male couples via focus groups and a follow-up telephone survey. We identified the sexual risk behaviour that occurs in these male couples, their perceptions of susceptibility for HIV transmission, and numerous couple-level and intrapsychic factors associated with their risk behaviour. We also describe the challenges confronted by these couples and barriers to emotional intimacy and couple satisfaction. Finally, we provide suggestions for ways of intervening to facilitate improved couple functioning, pleasure, satisfaction, and communication, and ways of reducing sexual risk behaviour without loss of emotional intimacy.

Adaptation, Psychological↗

PubMed2004

Couples becoming parents: something special after IVF?

The majority of catamnestic studies on successful IVF treatment deal with the development of the children and the parent-child-relationship. Far fewer studies pay attention to the changes within the relationship of couples that become parents. This particular study focused on the transition from partnership to parenthood with assessments at different measuring points (T1: the last trimester of pregnancy; T2: 3 months after birth; and T3: 12 months after birth) and compared 47 IVF couples with 45 couples that conceived naturally. The couples were observed with psychodynamic couple interviews and standardized as well as non-standardized questionnaires. The most striking result of our study was the inconspicuousness of IVF couples and their parent-child-relationship. Partnerships featured a high degree of satisfaction among the couples; the progress of pregnancy was described as very satisfying and free of complaints. Surprisingly these descriptions were given despite more frequent and longer hospital stays by the IVF women during their pregnancy. However, IVF couples acted less openly in the interviews and expressed their own feelings less often, especially the more negative ones. In the partnerships we found that IVF women displayed more avoiding tendencies in their relationships 1 year after the birth of their child/children.

Child↗

PubMed1978

Electrical coupling and uncoupling of exocrine acinar cells.

The electrical communication network in the mouse pancreatic acinar tissue has been investigated using simultaneous intracellular recording with two separate microelectrodes and direct microscopical control of the localizations of the microelectrode tips. All cells within one acinus were electrically coupled, and the coupling coefficient (the electrotonic potential change in a cell neighboring to the cell into which current is injected [V2] divided by the electrotonic potential change in the cell of current injection [V1]) between two cells near each other (less than 50 micron) was always close to 1. Cells farther apart (50-100 micron) were, in some cases, coupled; in other cases, there was no coupling at all. Coupling coefficients varied between 0 and 1. There was rarely electrical coupling over distances of more than 110 micron. Using microiontophoretic acetylcholine (ACh) application, it was possible to evoke almost complete electrical uncoupling of two previously coupled pancreatic or lacrimal acinar cells from different acini or within one acinus. The effects were fully and quickly reversible. While the ACh-evoked uncoupling in the pancreas was associated with membrane depolarization, ACh caused hyperpolarization in the lacrimal acinar cells. The uncoupling was associated with a very marked reduction in electrical time constant, indicating a reduction in input capacitance (effective surface cell membrane area). The concentrations of stimulants needed to evoke reduction in pancreatic cell-to-cell coupling were 1 micron for ACh, 0.14 nM for caerulein, and 3 nM for bombesin. These concentrations are smaller than those required to evoke maximal enzyme secretion.

Acetylcholine↗

PubMed2003

A naive Bayes model to predict coupling between seven transmembrane domain receptors and G-proteins.

MOTIVATION: An understanding of the coupling between a G-protein coupled receptor (GPCR) and a specific class of heterotrimeric GTP-binding proteins (G-proteins) is vital for further comprehending the function of the receptor within a cell. However, predicting G-protein coupling based on the amino acid sequence of a receptor has been a daunting task. While experimental data for G-protein coupling exist, published models that rely on sequence based prediction are few. In this study, we have developed a Naive Bayes model to successfully predict G-protein coupling specificity by training over 80 GPCRs with known coupling. Each intracellular domain of GPCRs was treated as a discrete random variable, conditionally independent of one another. In order to determine the conditional probability distributions of these variables, ClustalW-generated phylogenetic trees were used as an approximation for the clustering of the intracellular domain sequences. The sampling of an intracellular domain sequence was achieved by identifying the cluster containing the homologue with the highest sequence similarity. RESULTS: Out of 55 GPCRs validated, the model yielded a correct classification rate of 72%. Our model also predicted multiple G-protein coupling for most of the GPCRs in the validation set. The Bayesian approach in this work offers an alternative to the experimental approach in order to answer the biological problem of GPCR/G-protein coupling selectivity. AVAILABILITY: Academic users should send their request for the perl program for calculating likelihood probabilities at jack.cao@astrazeneca.com. SUPPLEMENTARY INFORMATION: The materials can be viewed at http://www.astrazeneca-montreal.com/AZRDM_info/supporting_info.pdf.

Algorithms↗

PubMed2001

Inspiratory timing during anaesthesia: a model of cardioventilatory coupling.

We describe a simple model of cardioventilatory coupling in which a hypothetical inspiratory pacemaker is stimulated by a signal related to cardiac action. At suitable values for the control variables (cardiac signal magnitude, heart rate, inspiratory pacemaker rate and inspiratory rate variability), the model was found to: (1) replicate all clinically described patterns of coupling; (2) predict variations in these described patterns and new patterns which were subsequently found in clinical time series; (3) simulate variations in clinically observed breathing frequency variations associated with each coupling pattern; (4) simulate the clinically observed distribution of coupling patterns between heart rate and breathing frequency; (5) explain the invariability of coupling below a critical heart rate/breathing frequency ratio; and (6) simulate the changes in breathing frequency and transitions between coupling patterns from the heart rate time series of human subjects. Although cardioventilatory coupling causes complex breathing rate irregularities during anaesthesia, these are readily explained by three variables, heart rate, intrinsic breathing frequency, and the strength of their interaction. This simple model, along with clinical observations of cardioventilatory coupling may provide a useful non-invasive method to study the respiratory central pattern generator.

Anesthesia, General↗

PubMed1996

Mismatch repair mutants in yeast are not defective in transcription-coupled DNA repair of UV-induced DNA damage.

Transcription-coupled repair, the targeted repair of the transcribed strands of active genes, is defective in bacteria, yeast, and human cells carrying mutations in mfd, RAD26 and ERCC6, respectively. Other factors probably are also uniquely involved in transcription-repair coupling. Recently, a defect was described in transcription-coupled repair for Escherichia coli mismatch repair mutants and human tumor cell lines with mutations in mismatch repair genes. We examined removal of UV-induced DNA damage in yeast strains mutated in mismatch repair genes in an effort to confirm a defect in transcription-coupled repair in this system. In addition, we determined the contribution of the mismatch repair gene MSH2 to transcription-coupled repair in the absence of global genomic repair using rad7 delta mutants. We also determined whether the Rad26-independent transcription-coupled repair observed in rad26 delta and rad7 delta rad26 delta mutants depends on MSH2 by examining repair deficiencies of rad26 delta msh2 delta and rad7 delta rad26 delta msh2 delta mutants. We found no defects in transcription-coupled repair caused by mutations in the mismatch repair genes MSH2, MLH1, PMS1, and MSH3. Yeast appears to differ from bacteria and human cells in the capacity for transcription-coupled repair in a mismatch repair mutant background.

Cell Cycle Proteins↗

PubMed1998

Attitudes about genetic risk of couples undergoing in-vitro fertilization.

Many couples undergoing in-vitro fertilization (IVF) are at a higher risk of having a child with a genetic abnormality. In a sample of 55 consecutive couples starting IVF, only 33% had no genetic risk factor. The most common genetic risks were advanced maternal age and possible abnormalities associated with severe male infertility. Despite education on these risks, 71% of couples had no interest in receiving formal genetic counselling. Only 14% of couples at risk would consider using a gamete donor to avoid transmitting a genetic disorder to a child. The triple test to screen for fetal abnormalities was acceptable to 82% of couples, but only 47% planned to have amniocentesis or chorionic villi sampling. Couples were significantly more likely to opt for prenatal testing if they would consider terminating a pregnancy should the fetus have a severe genetic abnormality (P < 0.01). Roman Catholic couples tended to have more conservative attitudes about pregnancy termination. Socio-economic status and whether the infertility factor was male or female were not predictors of a couple's attitudes.

Abortion, Eugenic↗

PubMed2006

Epilepsy and febrile seizures in children of treated and untreated subfertile couples.

BACKGROUND: Only few studies have addressed the long-term neurological outcomes of children born by subfertile couples. We studied the risk of epilepsy and febrile seizures in children of treated and untreated subfertile couples. METHODS: The study included 83 194 live singletons born by mothers who took part in the Danish National Birth Cohort (DNBC). Information on time to pregnancy (TTP) and infertility treatment was reported by the mothers in computer-assisted telephone interviews. Data on epilepsy and febrile seizures were extracted from the Danish National Hospital Register. RESULTS: Overall, children of subfertile couples (TTP > 12 months) had a 51% higher risk of epilepsy [incidence rate ratio (IRR): 1.51; 95% confidence interval (95% CI): 1.17-1.94] compared with children of couples with a TTP of 0-5 months. The corresponding estimates were 1.71 (95% CI: 1.21-2.42) if the couples had received infertility treatment and 1.38 (95% CI: 1.00-1.89) if they conceived spontaneously. Children of subfertile couples did not have a higher risk of febrile seizures except for those who received hormonal treatment (HT) with or without intrauterine insemination (IRR = 1.37; 95% CI: 1.14-1.66). CONCLUSIONS: Children of subfertile couples had a slightly increased risk of epilepsy, and the risk tended to be higher for children of couples who received infertility treatment. Whether this reflects side effects of treatment or severity of subfecundity is not known.

Child↗